Zilkha Neurogenetic Institute ANNUAL REPORT 2016 - 2017 The period covered in this report is July 2016 through June 2017. All photos are by Chris Shinn unless otherwise noted. Special thanks to Emily Chu for her work preparing this report. 2 CONTENTS 4 Director’s Letter 5 History and Mission 7 ZNI Faculty 10 Faculty News 14 Faculty Research Programs 22 Scientific Advancements 33 Academic and Community Activities 37 Collaborations 48 FY 15 Faculty Publications 66 Teaching 69 ZNI Postdoctoral Trainees 72 ZNI Graduate Students 76 Zach Hall Travel Award Winners 77 NRSA Grant Training 78 Grants and Contracts ZNI Events 90 ZNI Seminar Series Special Lectures 93 7th Annual Zach Hall Lecture 94 Mary Hayley and Selim Zilkha Chair in Alzheimer’s Disease Research 95 4th Annual Zilkha Symposium on Alzheimer’s Disease & Related Disorders ZNI Collaborative Events 96 Joint ADRD ZNI Pilot Program 97 Los Angeles/Irvine Brain Bee 98 Music to Remember 99 ZNI Administration 100 ZNI Development

3 Director’s Letter

As I complete my 5th year as Director of the Zilkha Neurogenetic Institute (ZNI), I find myself reflecting on the many significant advances this outstanding group of researchers has made, while I also consider all the exciting developments the new era may hold. Most similar institutes have been around decades longer than ZNI, which is just over 12 years old, yet our accomplishments–detailed in this report–rival or best some of the leading research neuroscience institutes in the world.

For example, we continue to secure grants from a wide breadth of sponsors and in FY17 we increased our external funding to $24.3M in total costs. ZNI Investigators further promote advancements in science by publishing in high-impact journals. The newly formed department of Physiology & Neuroscience–where the majority of ZNI faculty hold primary appointments–has been rising in the rankings, from 51 in 2012 to 20 in 2016; and as more awards are received, we expect in short order to be ranked among the top five in the nation. And ZNI has welcomed scores of leaders in their respective fields to share their findings via our international symposia and regular seminar series.

During the last five years, working together, we have transformed the Institute into a well-integrated USC powerhouse of discovery and translational neuroscience research by forming new centers and cores, and strengthening and expanding other programs.

Discoveries from ZNI have contributed to the development of clinical trials in Alzheimer’s patients (Phase 2 and 3 studies) based on clearance of Alzheimer’s toxin amyloid-beta from the brain and/or blockade of its re-entry into the brain, with a goal to arrest and/or reverse cognitive decline, and for stroke based on activated protein C treatment (currently in phase 2 studies in stroke patients) to protect the brain from damage caused by a loss of blood flow to the brain during stroke attack. We have also identified genes associated with the risk for schizophrenia, and discovered molecular pathways in cerebral blood vessels linked to some key genes influencing the pathophysiology of Alzheimer’s disease pointing to new therapeutic targets. These are just a few of the advancements being made at ZNI.

When I accepted the position of director in 2012, I stated that my clear goal is to make ZNI one of the top neurosciences institutions in the country and the world. We have been working persistently to achieve this goal with the critical help of all ZNI faculty and ZNI administrative support, and close collaboration and support from the Keck School of Medicine and USC administration and the community at large. To help drive the ZNI closer to the top endowed neuroscience institutes in the US, over the next few years we will be looking to increase our development activities by securing more funds for endowed chairs and the ZNI endowment.

As we look to the future, I invite you to join us on our journey through this world of discovery.

All the best,

Berislav V. Zlokovic, MD, PhD 4 Director's Letter History and Mission

The Zilkha Neurogenetic Institute built in 2003.

Dementias and Alzheimer’s disease are the fifth leading cause of death, with more than 5 million Americans living with Alzheimer’s Disease in 2017; by 2050, this number could rise to 16 million. The direct costs to American society of caring for those with Alzheimer’s and other dementias will total an estimated $259 billion; by 2050, these costs could rise to $1.1 trillion.

The Zilkha Neurogenetic Institute (ZNI) has a broad focus and mission on examining pathogenesis and treatment of neurological and psychiatric disorders.

For example, Investigators study Alzheimer and Related Diseases in multiple labs at ZNI. The Protein Structure group investigates the structure of proteins involved in Alzheimer’s, Parkinson’s and Huntington’s disease. Other investigators are studying brain circuits involved in vision and hearing, the role of the immune system in dementia, the role of cerebral blood vessels and blood-brain barrier in brain degeneration, genes that influence the risk for schizophrenia, depression and autism, and the biology of genes carrying the risk for Alzheimer’s and Down syndrome. These studies aim to help investigators understand the molecular and cellular basis of neurological and psychiatric disorders, looking toward devising new treatments for the cure and prevention.

ZNI Investigators are also developing new molecular biomarkers and new imaging techniques in the living human brain for early diagnosis of Alzheimer’s and other neurological disorders associated with cognitive impairment.

History and Mission 5 Established in 2003 by a generous gift from Selim Zilkha and Mary Hayley and further support from the WM Keck Foundation, the Zilkha Neurogenetic Institute serves as the nexus for a larger USC Neuroscience Initiative, encompassing scientists throughout the University. An organized research unit of the Keck School of Medicine at the University of Southern California, the ZNI is housed in a five-story, 125,000 sq ft building on the Health Sciences Campus, a state-of-the-art facility that allows basic scientists and physician-researchers to concentrate and collaborate.

Faculty, postdocs, staff and students from a large and diverse array of USC departments, institutes, divisions and centers participate in collaborative interactions between researchers working at ZNI, including the Alzheimer’s Disease Research Center, the Broad Center for Regenerative Medicine and Stem Cell Research, Stevens Institute for Neuroimaging and Informatics, Departments of Neurology, Neurosurgery, Psychiatry & the Behavior Sciences, Integrated Anatomical Sciences, Biochemistry & Molecular Medicine, Otolaryngology, Molecular Microbiology & Immunology and the division of Bioinformatics (department of Preventive Medicine), as well as the Dornsife College, Andrus School of Gerontology and Viterbi School of Engineering.

The hallmark of our vision is to create a highly participatory and creative scientific culture where investigators from a myriad of disciplines abandon their research silos and unite to conduct science research that matters to those affected by these diseases. Clinicians, physician-scientists along with researchers and trainees at all levels are dedicated to understanding the complexities of brain diseases and disorders, developing innovative therapies and ultimately discovering and translating cures from bench to bedside. At ZNI, we try to break through the typical barriers that separate the public from the scientific process, inviting the community to become catalysts in the discovery process by helping fund promising new research initiatives.

6 History and Mission ZNI Faculty

Frank Attenello, MD, MS Alexandre Bonnin, PhD Daniel Campbell, PhD Assistant Professor Assistant Professor Assistant Professor Neurological Surgery Cell & Neurobiology Psychiatry & the Behavioral Sciences

Karen Chang, PhD Jeannie Chen, PhD Robert H. Chow, MD, PhD Assistant Professor Professor Professor Cell & Neurobiology Cell & Neurobiology Physiology & Biophysics

Marcelo Coba, PhD David V. Conti, MD, PhD Hong-Wei Dong, MD, PhD Assistant Professor Professor Associate Professor Psychiatry & the Preventitive Medicine Neurology Behavioral Sciences

ZNI Faculty 7 Oleg Evgrafov, PhD Rick A. Friedman, MD, PhD Russell E. Jacobs, PhD Associate Professor of Research Professor Professor of Research Psychiatry & the Otolaryngology Physiology & Biophysics Behavioral Sciences

Radha Kalluri, PhD James A. Knowles, MD, PhD Ralf Langen, PhD Assistant Professor of Research Professor Professor Otolaryngology Psychiatry & the Biochemistry & Behavioral Sciences Molecular Biology

Brian Lee, MD, PhD William Mack, MD Axel Montagne, PhD Assistant Professor Assistant Professor Assistant Professor of Research Neurological Surgery Neurological Surgery Physiology & Biophysics

Takahiro Ohyama, PhD Mariangela Nikolakopoulou, PhD Janos Peti-Peterdi, MD, PhD Assistant Professor of Research Assistant Professor of Research Professor Otolaryngology Physiology & Biophysics Physiology & Biophysics

8 ZNI Faculty Ahbay Sagare, PhD Derek Sieburth, PhD Ansgar Siemer, PhD Assistant Professor of Associate Professor Assistant Professor Research Cell & Neurobiology Biochemistry & Physiology & Biophysics Molecular Biology

Huizhong W. Tao, PhD Terrence Town, PhD Tobias S. Ulmer, PhD Associate Professor Professor Associate Professor Cell & Neurobiology Physiology & Biophysics Biochemistry & Molecular Biology

Jobin Varkey, PhD Kai Wang, PhD Gabriel Zada, MD Assistant Professor of Research Assistant Professor Assistante Professor Physiology & Biophysics Psychiatry & the Neurological Surgery Behavioral Sciences Behavioral Sciences

Zhen Zhao, PhD Li Zhang, PhD Berislav V. Zlokovic, MD, PhD Assistant Professor Professor Director, Zilkha Neurogenetic Institute Physiology & Biophysics Physiology & Biophysics Professor & Chair Physiology & Biophysics

ZNI Faculty 9 Faculty News

ZNI principal investigators continued their success in securing external funding, receiving in FY17 24 new awards out of 77 submitted, for a 31% success rate, bringing in $24.3M total costs.

The ZNI does not correspond to a unit that is nationally ranked by US News and World Report, or the Blue Ridge Institute for Medical Research. However, in Spring of 2017, the department of Physiology & Neuroscience was formed, and most faculty of the ZNI, along with all members of the former department of Physiology & Biophysics, adjusted their primary appointments to the new department. Having risen in the rankings from 51 (in 2012) to 39 in 2015, and then to 20 in 2016, we expect next year the new department will be ranked among the top five in the nation.

As mentioned in our prior report, ZNI established examines the function of the blood-brain barrier a Neuroscience MRI/PET core for small animals, and drug delivery to the brain and the role of recruiting Russell Jacobs PhD from Caltech and neurovascular unit in the pathogenesis and acquiring from MR Solutions, a high-powered 7T, treatment of neurodegenerative disorders such as cryogen-free, preclinical PET-MRI multi-modality Alzheimer’s disease using stem cell technology to imaging system, now installed. The simultaneous generate human models of neurological diseases. acquisition of PET and MR images marries the exquisite sensitivity of PET with the high spatial Karen Chang PhD was promoted to Associate resolution and soft tissue contrast of MRI. This Professor with tenure, Physiology & Neuroscience. pre-clinical imaging center is now available to Dr Chang uses highly creative applications of the researchers and clinicians throughout the Keck Drosophila model system to answer key questions School of Medicine of USC, a service that will about regulation of synaptic functions that have a significantly facilitate the translation of laboratory broad impact in the field of neurosciences in general, findings to clinical practice. particularly to our understanding of the molecular mechanisms of synaptic dysfunction behind Down Zhen Zhao PhD was appointed Assistant Professor syndrome, Alzheimer disease, autism spectrum and of Physiology and Neuroscience. Dr Zhao’s work learning and memory.

10 Faculty News ZNI hosted Drs Eric R. Kandel and Denise Kandel In April 2017, Berislav Zlokovic MD PhD organized as keynote speakers for the 7th Annual Zach Hall the 4th Annual Zilkha International Symposium on Lecture in November 2017. Dr Eric Kandel is Professor Alzheimer Disease and Related Disorders, “From at Columbia University, Kavli Professor and Director Investigation to Integration: New Basic, Translational at the Kavli Institute for Brain Science, Co-Director & Clinical Efforts in Alzheimer’s Disease & Related at the Mortimer B. Zuckerman Mind Brain Behavior Disorders,” at the Zilkha Neurogenetic Institute. A Institute and a Senior Investigator at the Howard dozen speakers presented unpublished work, including Hughes Medical Institute. He has been recognized Virginia Lee PhD and John Trojanowski MD PhD (U with many notable awards, including the Nobel Prize Penn), Ronald Petersen MD PhD and Len Petrucelli for Physiology or Medicine (2000). Dr Denise Kandel is PhD (Mayo Clinic), with discussions led by seven Professor of Sociomedical Sciences in Psychiatry at the moderators and chairs, including Roger Nitsch MD Department of Psychiatry at the College of Physicians (Univ Zurich), Robert Vassar PhD (Northwestern) and and Surgeons, Professor at the Mailman School of Maria Carrillo PhD (Alzheimer’s Association). Public Health at Columbia University, and Head of the Department of the Epidemiology of Substance Abuse at the New York State Psychiatric Institute. Their joint talk, entitled “The Gateway Hypothesis of Substance Abuse: Developmental, Biological and Societal Perspectives,” described how tobacco or alcohol use precedes marijuana and other illicit drug use and the Roughly 1 in 15,000 people event was standing room only. worldwide have the disease with symptoms generally appearing between the ages of Huntington’s disease is an inherited 30 and 50. disorder involving the progressive loss of nerve cells in the brain, causing dementia.

Marcelo Coba PhD created the first map that Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang highlights the brain’s network of protein associations as Y, Ahuja A, Lazic D, Tsai PS, Zhao Z, Zhou Y, Boas DA, published in Nature Neuroscience. The goal is for the Sakadžić S, Zlokovic BV (2017) Pericyte degeneration protein map software to help researchers create new leads to neurovascular uncoupling and limits oxygen therapies that hone in on problem pathways. supply to brain. Nature Neuroscience 20, 406-416.

In a paper in Nature Neuroscience, Berislav Zlokovic Ralf Langen PhD received a two-year $1.5M award MD PhD reviews abnormalities with pericytes–special from the CHDI, a private research foundation devoted cells that wrap around blood vessels in the brain– to funding research to develop drugs that will slow leads to neuron deterioration, possibly affecting the the progression of Huntington’s disease and provide development of Alzheimer’s disease. The goal is to meaningful clinical benefit to patients as quickly identify whether pericytes could be an important new as possible. Recipients of CHDI awards frequently therapeutic target for treating neuron deterioration. develop a relationship with the foundation that leads to “whole lab” funding, similar to the HHMI model.

Faculty News 11 Berislav Zlokovic MD PhD is at the center of four this gene. Results of this work could lead to a new prestigious research awards made to USC: key new therapeutic target to treat dementia in • The National Institute of Neurological APOE4 carriers. Disorders & Stroke (NINDS) granted $3.6M over five years to Berislav Zlokovic MD PhD • The Fondation Leducq based in Paris provides to study the role of pericytes in white matter funding for international collaborative research disease. As up to 45% of all dementias in cardiovascular and neurovascular disease. worldwide are estimated to be wholly or partly Berislav Zlokovic MD PhD was named the due to age-related small vessel disease, this North American coordinator of a multi- study will contribute towards under¬standing institutional transatlantic program that totals the mechanistic basis of white matter $6M over five years. This is the first time disease in vascular cognitive impairment and USC has received a grant from this renowned dementia. foundation. Dr Zlokovic will host at ZNI on 12- 13 October 2017, the 2nd Leducq Transatlantic • The National Institute on Aging (NIA) Network Meeting, “The Perivascular Space in awarded $12.3M to Berislav Zlokovic MD PhD Small Vessel Disease.” and Art Toga PhD (Director of the Stevens Neuroimaging and Informatics Institute, INI) to By altering serotonin signaling, SSRI oversee a multi-disciplinary program project antidepressants could affect brain areas involved with multiple projects, cores, institutions and in social cognition and lead to life-long problems. investigators across eight different institutions. Alexandre Bonnin PhD received a NARSAD The aim of the project is to establish whether (formerly Brain & Behavior Research Foundation) the neuro¬vas¬culature plays a major role Independent Investigator Award to measure the in cognitive decline, specifically to help molecular effects of exposure to citalopram before determine if cerebrovascular dysfunction and after birth using pharmacological methods and disruption in the neurovascular as well as 3D imaging techniques. Previously Dr. integrity underlies and contributes to the Bonnin received a NARSAD Young Investigator onset and progression of cognitive decline. Award in 2007 and again in 2011. Understanding the vascular contributions to dementia will help with developing new therapeutic targets to treat dementia and Alzheimer Disease.

• The Alzheimer’s Association awarded $3M In 2017, Alzheimer’s and to Berislav Zlokovic MD PhD and Art Toga other dementias cost the PhD to conduct research that complements nation nearly $260 billion. the NIA project. The goal of this work is to By 2050, these costs could advance current knowledge on the vascular rise as high as $1.1 trillion. contributions to dementia in individuals with the major genetic risk factor for late-onset Alzheimer Disease, i.e., apolipoprotein E (APOE4) gene who develop early vascular dysfunction and significant cerebro¬vascular pathology compared to those who do not carry

12 Faculty News Photo credit: Russell Jacobs Russell credit: Photo

In 2017, the Zilkha Neurogenetic Institute installed a 7 Tesla (7T) small animal MRI scanner and integral PET Scanner from MR Solutions, Inc. The scanner is the first on the west coast and will be made available to investigators through the ZNI Functional Biological Imaging (FBI) core.

Berislav Zlokovic MD PhD was included in Dr Attenello is dedicated to advancing the Thomson Reuters list of ‘The World’s Most understanding of gliomas, a type of tumor Influential Scientific Minds’ 2016 – as one the that arises from glial cells, in the brain or most cited authors in the field of Neurosciences spine. Through his research, he is working to and Behavior (December 2016). characterize tumor-pericyte interactions with glioblastoma grafts in transgenic mouse models. Berislav Zlokovic MD PhD gave the plenary He is further leveraging his experience with lecture on Alzheimer’s disease and Parkinson’s CRISPR technologies to alter tumor expression disease International meeting in Vienna, 2017, levels in studies. and delivered the prestigious Del Monte Lecture in Neuroscience at the University of Rochester NY, Dr Lee is investigating how a brain-machine 2017. interface (BMI)–which is a unit implanted into the brain of a paralyzed or injured patient to control Berislav Zlokovic MD PhD was installed formally an external assistive device, such as a cursor on in May 2017 as initial holder of Selim K. Zilkha a computer screen, a motorized wheelchair, or and Mary Hayley endowed Chair for Alzheimer’s a robotic limb–might be expanded to generate disease research. the percept of sensation. Current BMI are guided by visual feedback but Dr Lee’s group would ZNI expanded the clinician-scientist incubator like to engineer artificial sensation via subdural program in Neurosurgery to welcome in 2016, ECoG electrodes, which would be interpreted by Frank Attenello MD and Brian Lee MD, both subjects as “touch.” Clinical Assistant Professors Neurosurgery.

Faculty News 13 Faculty Research Programs

Alzheimer Disease & Related Disorders A number of diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, type 2 diabetes) are thought to be caused by the misfolding of proteins into abnormal and toxic structures. How this misfolding occurs on a molecular level, how it can be prevented therapeutically and how risk factors can promote misfolding is only poorly understood. The Ralf Langen lab is working on these aspects in order to develop better therapeutics and biomarkers.

The Ansgar Siemer lab investigates the detailed atomistic structure and dynamics of protein fibrils that are found in (neurodegenerative) diseases and fibrils that are found in non-disease contexts. Investigating the differences and similarities of these two types of fibrils will not only help us understand how fibrils can be functional, but also help find cures for neurodegenerative diseases. In particular, the Siemer lab is working on two fibril forming proteins: Huntingtin is a protein that causes Huntington’s Diseases (HD) in its mutated form. The lab investigates its structure and dynamics as well as interactions with other cellular components. Orb2, the second protein, is an important factor for the development of long-term memories in fruit flies. Similar to huntingtin, the Siemer lab investigates the structure and dynamics of Orb2 fibrils and how they interact with other components of the cell. This work will give us a deeper understanding of the molecular mechanisms of long-term memory and, possibly, how they relate to neurodegenerative diseases.

Next to the above described integrin cell adhesion receptors, the Tobias Ulmer lab is studying enzymes of the carnitine palmitoyltransferase 1 (CPT1) family. Biological organisms maintain their living state by extracting energy from the breakdown of nutrient molecules in a series of interconnected and highly regulated chemical reactions. Mitochondrial oxidative phosphorylation is the primary source of ATP formation in eukaryotes. In most mammalian tissues, this process utilizes either pyruvate or long-chain fatty acids (LCFA) as substrates. The rate of mitochondrial ß-oxidation of LCFA is controlled by the enzyme CPT1, assigning it a central role in fuel selection and utilization in health and disease. Moreover, in the brain, an isoform of CPT1 is found that they recently implicated in spastic paraplegia.

14 Faculty Research Programs Dr. Terrence Town and his team are working at the interface between the brain and the immune system to develop a treatment for Alzheimer’s disease by targeting a peripheral immune cell known as the macrophage. Most therapies targeting the disease are thwarted by the blood-brain barrier, a natural mechanism that protects brain cells from entry of peripheral substances, and by the fact that immune responses in the brain are typically muted. However, in laboratory mice programmed to develop Alzheimer’s-like disease, Dr Town’s group has shown that peripheral macrophages can be instructed to enter the brain from the circulation, where they attack the damaging sticky plaque buildup that is a defining feature of Alzheimer’s disease. Earlier this year, Dr Town’s lab revolutionized the field of Alzheimer’s disease research by applying advanced mathematical frameworks to non-invasive neuro- imaging studies on the first rat model of the disease that manifests all of the clinico-pathological hallmarks of the human syndrome. These transgenic rats over-express two mutant human transgenes that are each independently causative of familial early-onset Alzheimer’s disease. With these state-of- the-art “hybrid diffusion imaging (HYDI)” neuroimaging results (see Fick et al., 2017), this makes this exciting rat model an invaluable tool for understanding Alzheimer’s disease etiology and for testing cutting-edge therapeutics pre-clinically.

Dr. Berislav Zlokovic’s laboratory has a long standing interest in understanding the role of cerebral blood vessels and blood-brain barrier (BBB) in pathogenesis of Alzheimer’s disease (AD), related neurodegenerative disorders and stroke, as foundations for development of new therapies for these diseases. Using laboratory models of neurological disorders and studying human brain, his laboratory has shown that dysfunction in the BBB and brain microcirculation can accumulate before neuronal dysfunction and contribute to the onset and progression of neurodegeneration, cognitive impairment and dementia. His research team has identified the cellular and molecular mechanisms in blood vessels (RAGE, LRP1, PICALM) regulating clearance of Alzheimer’s Abeta toxin from brain, and discovered molecular pathways by which APOE4 gene (carrying a major risk for AD) disrupts BBB causing neurodegeneration and brain accumulation of Abeta. His group showed that capillary pericytes control BBB integrity and oxygen brain delivery necessary for proper neuronal functioning. His group also developed new imaging technique in the living human brain and novel vascular molecular biomarkers in biofluids that are currently being studied in individuals at genetic risk for AD (e.g., APOE4 carriers and non-carriers; PSEN1 mutations carriers and non-carriers), and those with vascular risk factors (e.g., hypertension). Discoveries of his research team have contributed to the development of clinical trials for AD based on clearance of amyloid-beta or inhibition of its re-entry into the brain that are currently being tested in Phase 2 and Phase 3 (800 patients) studies in AD patients, respectively. They also developed a new therapy for stroke, based on activated protein C treatment as a neuroprotective agent in stroke patients that has completed Phase 2 enrollment (110 patients).

Dr. Hong Wei Dong’s research focuses primarily on the Mouse Connectome Project. He uses well- established state-of-the-art tract-tracing technologies to systematically reveal and map neuronal networks of the whole mouse brain, and has developed a high-throughput pipeline for data production, collection, and informatics. To date, his lab has collected over 100 TB of high-resolution, high-quality data from 700 mice (an aggregation of >1200 neuronal pathways). About one third of these raw imaging data have been made freely accessible to the neuroscience community and general public. To facilitate their use, the lab has also developed a powerful visualization tool that enables users to visualize and annotate this data (www.MouseConnectome.org). This type of open resource will guide hypothesis- driven neuroscience research on brain function and behavior. In addition, Dr. Dong’s group will begin to apply their connectomics approach to systematically characterize connectopathies in mouse models of several neurological and neuropsychiatrical diseases, such as Huntington’s and Alzheimer’s diseases.

Faculty Research Programs 15 1 in 3 seniors dies with Alzheimer’s or another dementia.

Alzheimer Disease and Synaptic Functions

The overall goals of Karen Chang’s research are to understand how neurons communicate with high fidelity and to elucidate molecular and cellular mechanisms leading to neuronal dysfunctions seen in various neurological disorders. There two main areas of research: 1) mechanisms regulating synaptic development and plasticity, and 2) genotype-phenotype relationships in Down syndrome. She believes that Drosophila, with its powerful genetics and well conserved genes and signaling pathways, is an ideal model system for identifying the network of genes responsible for learning disability and dementia seen in Down syndrome, and for elucidating fundamental mechanisms regulating synaptic functions.

Psychiatric Genetics The Center for Genomic Psychiatry investigates the role of genetic risk factors in disorders of the mind. Human genetic studies have uncovered several genes associated with complex psychiatric and developmental disorders. Human synapses and synaptic proteins have been in many of these disorders. Dr. Marcelo Coba uses a systems biology approach to understand how the disruption in the communication between neurons at the synapse might play a role in psychiatric disease. He uses a combination of state-of-the-art proteomic assays, together with mouse genetics, CRISPR technology, hiPSC derived neurons, computational biology, and synaptic physiology. These methods are used to investigate how mutations associated to psychiatric disease impairs synaptic function by modifications in protein signaling networks. This aim is to define protein-network maps that will allow us to stratify patients by their correspondent mutations signatures.

Dr. Dan Campbell focuses on defining functional genetic variants that contribute to the etiology and treatment effectiveness of autism and schizophrenia. The long-term goals of these studies are to better understand the causes of the disorders and to improve the ability to treat them on an individualized basis. His continuing work seeks to determine how genetic variants influence expression of noncoding RNAs in the brain and what environmental factors contribute to altered noncoding RNA expression.

16 Faculty Research Programs Dr. Alex Bonnin aims at understanding how maternal-fetal interactions affect fetal brain development; this is key to understanding the developmental origins of mental disorders. The current focus is on deciphering how serotonin signaling affects the mechanisms by which maternal and environmental factors shape fetal brain development and trigger mental disorders later in life. These studies will ultimately provide new clues into the developmental origins of mental health-related disorders in humans, such as autism and schizophrenia. Dr Bonnin’s research focuses on the serotonergic modulation of axon guidance mechanisms, which is important for the refinement of neuronal circuits formation in utero, and therefore is critical for normal fetal brain wiring. Dr Bonnin’s group is pursuing a translational approach, working with OB/GYN and Maternal-fetal Medicine Division at LAC+USC, aiming at understanding and potentially reducing the effects of maternal infections during pregnancy as well as examining how therapeutic drugs, in particular antidepressants, impact fetal brain development.

The overall interest of Dr. James Knowles’s laboratory is the genetic basis of behavior, cognition and affect. Most of the lab’s studies search for the genetic factors that have an etiological role in psychiatric illness. Finding genes for the psychiatric disorders is by necessity a collaborative effort. These are large-scale studies that require multiple sites to collect the sample sizes necessary to have adequate power. These studies also require teams of clinicians, geneticists and statisticians, working together, to make progress. Dr. Knowles is the geneticist/molecular biologist on several such teams. In the past, his work with these investigators has focused on anxiety disorders, depression and addictive disorders. Currently, most of the lab’s effort is focused on schizophrenia and OCD, along with several smaller projects.

Genomics A main goal of the Kai Wang lab is to develop data mining algorithms to extract more information from genomic data, such as genome sequencing data and transcriptome sequencing data. In addition, Dr. Wang is working on creating an automated pipeline for RNA-Seq analysis of single neuronal cells.

Dr. David Conti is working to elucidate the genetic contribution of complex diseases from population- based samples, using both applied genetic epidemiologic studies and the development of statistical methods. Presently, Dr Conti’s applied work focuses on examining the causal variant in over 100 prostate cancer risk regions and their contribution to prostate cancer risk differences across populations. His research in statistical methodology concentrates on the integration of prior information and the incorporation of other ‘omic’ data sets in the evaluation of genetic associations.

Dr. Berislav Zlokovic currently studies how genes that influence AD risk (e.g., APOE4, PSEN1, PICALM, CLU) affect the cerebrovascular system using transgenic models, human inducible pluripotent stem cell-derived neuronal and BBB models of human neurological disorders. He remains interested in developing advanced approaches with activated protein C therapy for stroke and neurological disorders.

Genomics and Brain Tumors Dr. Gabriel Zada utilizes next-generation genomic and epigenomic profiling (i.e. DNA Methylation analysis) to study the behavior of various brain tumors. In particular, he is interested in studying the process of local tumor invasion and developing molecular classification systems for various skull base tumors, including pituitary tumors and meningiomas. He is also working to develop novel treatment strategies for skull base tumors using intranasal therapy systems.

Faculty Research Programs 17 Brain Tumors Dr. Frank Attenello and his laboratory are interested in the factors contributing to growth, invasion, and angiogenesis of human glioblastoma. Their focus is on pericyte contributions to glioblastoma growth and angiogenesis utilizing transgenic rodent models to evaluate tumor growth, immune cell response and vasculature in models. While early attempts to target angiogenesis have found modest success, it is their hypothesis that a focus on pericyte-tumor interactions will yield insight into tumor development and therapeutics.

In addition, the Attenello lab aims to characterize the role of the neural stem cell niche, the subventricular zone, in response to cortical injury during exposure to environmental toxins such as pollution. Finally, they are developing functional high-throughput CRISPR screens for the characterization of long noncoding RNAs in tumor behavior.

See also Imagine: Russell Jacobs.

Vascular Dr. William Mack is focused on translational efforts to treat stroke and cerebrovascular disease. He and his group are interested in inflammation and resultant microvascular failure in a range of experimental and clinical models. Dr. Mack has refined an experimental model of bilateral carotid artery stenosis to examine the role of inflammation in the setting of chronic cerebral hypoperfusion. This system has enabled his team to assess the impact of vascular disease on cognition and neurodegeneration. The group has identified the C5 complement protein as a critical effecter of injury through histological and behavioral outcome measures. These findings lend insight into the role of complement in progressive cognitive injury and neurodegenerative conditions such as vascular dementia and Alzheimer’s disease. Dr. Mack’s laboratory also studies biomarkers of cerebral vasospasm following subarachnoid hemorrhage and employs novel endovascular delivery platforms in the setting of acute stroke. He utilizes advanced MR permeability imaging sequences and serum analysis to quantify blood brain barrier breakdown in subarachnoid hemorrhage patients.

See also Brain Tumors: Frank Attenello and Alzheimer’s Disease: Bersialv Zlokovic

Vascular Imaging The broad interest of the Janos Peti-Peterdi lab is renal (patho)physiology, specifically the intrarenal mechanisms involved in the control and maintenance of systemic blood circulation and vessels to important organs (heart, brain, pancreas, kidneys, etc), blood pressure, body fluid balance under normal and disease conditions (chronic kidney disease, hypertension, diabetes). A new research direction focuses on mechanisms of endogenous nephron repair and their augmentation in the development of new therapeutic approaches. They also study a new mechanism of kidney-to-brain crosstalk via a newly identified kidney-derived angiogenic hormone, and its role in the development of cognitive impairment in aging and Alzheimer’s disease.

18 Faculty Research Programs Circuits The Robert Chow laboratory studies the function of electrically excitable cells, such as neurons and endocrine cells. The major projects involve (a) characterizing the function of synaptic proteins in nerve- nerve signaling; (2) correlating the physiology and transcriptomes of neurons in adult and fetal brain; (3) testing the role in cancer invasion/metastasis of novel non-coding RNAs derived from regulators of neural development; (4) evaluating the role of amyloid proteins in cell death in diabetes and neurodegenerative diseases.

Dr. Li Zhang’s ultimate research goal is to decipher brain circuits, and to understand how perception and behaviors are generated and controlled, how the brain’s cortex adapts in response to changes in the dynamic external environment, and how specific changes in cortical functions result in neurological and psychiatric disorders. To address these highly challenging questions, Dr Zhang’s approach is to resolve the neural circuitry (how neurons are wired in the brain), i.e. the structural basis underlying the brain functions. In the past years, Dr Zhang and his collaborators have committed substantial efforts toward developing molecular/genetic and electrophysiological/imaging techniques for elucidating the neural circuits for both local neuronal computation and for controlling animal behavior. To this end, he and his group pioneered in applying in vivo whole-cell voltage-clamp recording, to reveal at the synaptic connection level, how the excitatory and inhibitory synaptic interplay determines the sensory response/ processing properties.

Dr. Huizhong Tao’s work mainly concentrates on the organization of neural circuits underlying visually evoked behavior and perception and how the circuits are established during development (please see Vision/Eye below). In recent years, her lab has developed various optogenetic tools to achieve selective activation and inactivation of specific types or groups of neurons in visual structures, utilizing different Cre-driver mouse lines. Her lab has also developed quantitative methods to measure behavioral outputs. Besides long-range neural pathways, they study local synaptic circuits with not only in vitro but also in vivo electrophysiological methods, assisted by newly developed retrograde and anterograde labeling techniques.

Derek Sieburth is interested in understanding how neuronal signal transduction pathways regulate neurotransmitter secretion and how this impacts the function of underlying neuronal circuits that control behavioral output. The Sieburth lab uses C. elegans as a model organism for studying neuronal function, because of its simple neuronal circuitry, the ability to visualize synapses by fluorescent imaging in live animals, and its powerful genetics. The lab combines state-of-the-art behavioral, genetic, cell biological, and in vivo neuronal imaging techniques to study the cellular molecular mechanisms underlying secretion of synaptic vesicles and dense core vesicles. The lab is interested in three major areas: 1) How does localized sphingolipid signaling at presynaptic terminals regulate synaptic transmission at neuromuscular junctions; 2) The mechanisms by which oxidative stress regulates synaptic transmission and behavior; and 3) How does a neuropeptide signaling pathway deliver timing information from a pacemaker to activate a rhythmic behavioral circuit. Many of the genes Dr. Sieburth studies are conserved in humans, so these experiments provide novel insight into the mechanisms by which neurotransmitter secretion may be regulated in humans.

Faculty Research Programs 19 Neurophysiology Dr. Brian Lee’s clinical and research focus is on developing neurorestorative technologies and cognitive- based brain-computer interface (BCI) devices for patients with neurological disorders such as epilepsy, Parkinson’s disease, essential tremor, and dystonia. In particular, he is interested in utilizing clinical neurophysiological recording and stimulation platforms (deep brain stimulator (DBS), intracranial subdural electrocorticography (ECoG), and stereotactic EEG (SEEG)) to understand the circuitry of the brain and develop novel, yet safe, next-generation closed-loop BCI systems. Vision/Eye Photoreceptor cells are light sensitive neurons in the retina that initiate the first steps of vision. One of the main objectives of Dr. Jeannie Chen’s laboratory is to understand the molecular cascade that underlie the ability of retinal photoreceptor cells to perceive light, and how defects in this cascade leads to human blindness. The photoreceptors are wired to the sophisticated circuitry in the neural retina. This circuitry comprises of up to 20 different channels of information that encodes our visual scene. These channels include contrast, motion and color. Death of photoreceptor cells leads to re-wiring of this circuitry. Another objective of Dr. Chen’s laboratory is to understand how this pathological change of the retinal circuitry may affect recovery of functional vision after the photoreceptor cells have been rescued by gene therapy or replaced by stem cell therapy.

Dr. Huizhong Tao is interested in the architecture of visual cortical circuits. To dissect the circuits that consist of excitatory and inhibitory neurons, Dr. Tao’s lab applies in vivo electrophysiology, in particular two-photon imaging guided recording, to target different types of neurons in rodent visual cortex. From the response properties of individual neurons and the pattern of excitatory and inhibitory synaptic inputs to these neurons, they attempt to deduce the connectivity rules governing the construction of cortical circuits. This work will shed light onto the mechanisms for how diverse visual processing functions are realized in cortical circuits. Dr. Tao is also interested in how functional visual circuits are established during development. The development of visual system not only depends on molecular and genetic programs, but also can be profoundly influenced by sensory experience and neural activity along the visual pathways. The Tao lab examines how neural activity of various patterns leads to modulations of synaptic connections and shapes the formation of visual circuits. The aim is to provide insights into how abnormal visual experience in early life, such as in the condition of strabismus and visual deprivation, can lead to abnormal wiring in the brain, and how they can correct it. Image credit: Jeannie Chen credit: Image Signaling molecules in the photoreceptor cell and how defective signaling may lead to cell death.

20 Faculty Research Programs Hearing/Ear The most common sensory abnormality in the world is age-related hearing loss. The second most common form of hearing loss is noise-induced. Dr. Rick Friedman’s laboratory has demonstrated that both of these traits can be treated as common diseases and can be approached through association mapping. The primary objective of Dr. Friedman’s laboratory is to study these common forms of hearing loss using a genome-wide association approach in mice. Dr. Friedman’s laboratory has begun to define the genetic architecture of age-related hearing loss in mice and has identified several loci leading to susceptibility to noise-induced hearing loss. This work will provide important insights into the mechanisms underlying these common forms of hearing loss and studies in the mouse provide the power to begin to understand gene X environment interactions.

The Radha Kalluri lab is interested in understanding the biophysical mechanisms by which the auditory and vestibular sensory peripheries encode information about sound and head movements. They are specifically interested in how these functions develop and degrade with age and insult.

Hearing loss is one of the most common birth defects. Approximately one in five hundred newborns suffer from significant hearing impairment. In addition, once mechanosensory hair cells in the inner ear are damaged and lost by any of a variety of reasons such as aging and loud noises, they never regenerate. Thus, majority of sensorineural hearing loss, such as age-related hearing loss and noise- induced hearing loss is permanent and significantly affect the quality of one’s life. Recently, stem cell research has shed light on the possibility of regeneration of hair cells in humans. The research goal of the Takahiro Ohyama lab is to understand the molecular mechanisms of inner ear development and to explore the possibility of regenerating sensory cells to treat hearing and balance disorders.

Imaging Research in the Russell Jacobs lab focuses on development and application of multimodal four- dimensional (3 spatial plus time) in vivo imaging of rodent models of brain dysfunction and cancer. Emphasis is always on potential translation of these technologies to the clinic. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are their principal modalities due to their versatility, complementarity and ready clinical translation. The non-invasive nature of MRI and PET allows longitudinal imaging of the same animal. Thus, Dr. Jacobs’s group is examining brain alterations over time in rodent models of Alzheimer’s Disease to map out the etiology of this disease. One hallmark of cancers is that tumors are able to evade the body’s immune system. Dr. Jacobs’s group is investigating the ability of low dose focused ultrasound (ldFUS) to modulate the tumor immune environment in conjunction with immunotherapies which, in combination, make the tumor susceptible to attack by the immune system. Applying ldFUS during MRI/PET provides immediate assessment of ldFUS effects. They seek to understand disease mechanisms through assaying spatiotemporal changes in structure and function with MRI and PET.

Faculty Research Programs 21 Scientific Advancements In the following pages are some notable accomplishments by ZNI faculty over the past year. Frank Attenello Research in the Attenello lab has focused on understanding the growth and angiogenesis of glioblastoma in mouse models. His laboratory has invested efforts in the first year in both obtaining grants and setting up laboratory models. Dr. Attenello has therefore secured pilot grants to evaluate 1) the effect of pericyte-deficient transgenic mouse model hosts on implanted glioma cell line growth;, 2) the effect of noncoding RNA (lncRNA) knockdown via the CRISPR- interference platform on tumor migration; and 3) the behavior of subventricular zone neural stem cells (and possible tumor stem cells) during exposure to environmental toxins and cortical injury. Work during the last year has developed baseline glioblastoma and neurosphere cell lines and CRISPRi models for studies moving forward.

Alexandre Bonnin Research in the Bonnin lab focused on understanding how adverse prenatal events increase the risk of developing mental disorders in adulthood. Efforts were centered around two common types of prenatal insults: 1) maternal infections during pregnancy, and 2) maternal stress/depression as well as exposure to antidepressant drugs. The Bonnin lab demonstrated that maternal infection directly affects important molecular pathways in the placenta which then alter the development of serotonin neurons in the fetal brain. This is expected to have long term consequences on offspring brain function, such as increased anxiety or depression. The Bonnin lab also characterized how maternal depression and the use of SSRI antidepressants during pregnancy directly affect fetal brain development. In addition, they started to characterize the role of a novel adaptor protein in fetal brain development. The results were published in The Journal of Neuroscience, ACS Chemical Neuroscience and Neuroscience.

22 Scientific Advancements Daniel Campbell The rates of autism continue to rise, creating challenges for an increasing number of children and families. The Campbell lab contributed three important publications toward understanding and treating autism this year. First, they published a genetic review of the potential for personalized medicine relevant to autism. The review allowed the lab to propose practical measures to describe how their work can be translated to helping individuals with autism. Second, they published two papers showing the global changes in gene expression and neuronal architecture when the expression of an autism-associated noncoding RNAs was manipulated in human neural progenitor cells. Noncoding RNAs are genes that do not code for a protein but instead regulate the expression of other genes during brain development. Using state-of-the-art RNA sequencing in human neural progenitor cells, they found that the differentially expressed genes change how DNA is available for gene expression and how ribosomes translated RNAs into protein. Remarkably, these are the same biological processes that are impacted by rare mutations in individuals with autism, suggesting that there are convergent biological processes identified by different genetic approaches. These results indicate that noncoding RNAs are likely to hold key regulatory roles in gene networks underlying neuronal differentiation and neurodevelopmental disorders.

Karen Chang The Chang laboratory discovered: 1) a novel activator of integrin released in response to neuronal excitation is important for strengthening and stabilization of the synapse; 2) a protein mutated in Autism and upregulated in Down syndrome differentially regulates the recycling of synaptic vesicles. These studies shed light on mechanisms regulating communication between neurons, and how dysregulations of these mechanisms could contribute to neurological disorders.

Jeannie Chen Photoreceptor cell death is the major cause of blindness. Genetic mutations that affect the ability of photoreceptor to detect light is a frequent cause of human blindness. Some of these mutations lead to increased concentration of a small signaling molecule, cGMP. It is known that toxic cGMP buildup kills photoreceptor cells, but the mechanisms of cell death are not fully understood. The Chen lab found that cGMP has two cellular targets: first, it opens up too many membrane channels, allowing the influx of calcium; second, it stimulates protein kinase G. Both of these targets are known agents of cell death. Identifying these targets is an important step towards the formulation of drugs to prolong vision.

Robert Chow In the process of correlating physiology and transcriptomes of individual brain neurons, Dr. Chow and his group have identified a neuron in fetal brain that has never been described previously. Work is ongoing to further characterize the neuron, and they hope to publish a detailed description in spring 2018.

With Dr. I-Chueh Huang, the Chow lab has performed the first study of Zika virus tropism in human fetal brain slices. This work was recently published in Scientific Reports.

With Jim Weiland and Mark Humayun’s laboratory, the Chow group has continued to study electrical stimulation protocols that improve the visual acuity of patients with the Argus II epiretinal implants. Since publishing a paper in Science Translation in 2015, they have identified another protocol, which is the subject of a new paper (in review).

Scientific Advancements 23 Robert Chow (cont.) With Ralf Langen’s laboratory, Dr. Chow published a paper showing that three molecules found elevated in blood of patients with type 2 diabetes each accelerate amyloid peptide misfolding. In collaboration with Ralf Langen and Terrence Town, the lab is currently studying whether one class of these molecules – the monophthalates – may play a role in Alzheimers. With Cheng-Ming Chuong’s laboratory, Chow’s group has identified the role of specific ion channels in controlling feather bud orientation during chick development (manuscript in review). With neurosurgeons John Russin and William Mack and stem cell biologist Michael Bonaguidi, Dr. Chow has developed a pipeline to study human brain tissue, resected for the treatment of medical refractory mesial temporal sclerosis epilepsy (MTSE), with the aim to study the etiology of MTSE and to study therapeutic drug candidates.

Marcelo Coba

Over the last decade, human genetics studies have identified a number of disease-associated genes (risk factors) from post-synaptic proteins linked to psychiatric and other complex brain disorders such as schizophrenia, autism, intellectual disability and developmental delay, suggesting that synaptic dysfunction is central to the etiology of these diseases. However, it is not known how these large-collection of risk factors are functionally connected at the synapse. Using large-scale analysis of protein interactions, mouse genetics and bioinformatics, the Coba lab recently described the organization of the core signaling machinery of the postsynaptic site, their assembly in protein-interaction networks and show how mutations associated with complex brain disorders are distributed along spatio-temporal protein complexes. They Park Steven credit: Figure determined how mutations in highly-connected nodes alter protein-protein interactions and regulates macromolecular complexes enriched in disease risk candidates. These results were integrated into a software platform: Synaptic Protein/Pathways Resource (SyPPRes, http://neurocomplex.usc.edu), enabling the prioritization of disease risk factors and their placement within synaptic protein interaction networks, thus providing the first roadmap of protein interactions associated with complex brain disorders at the synapse.

Figure shows a cartoon representation of the synapse, and the protein-protein interaction networks involved in complex brain disorders. Each disease-subnetwork is highlighted in a different color code

24 Scientific Advancements David Conti The Conti group has continued to focus on methodological advances in three main areas of research in genetic association studies: (1) fine-mapping, (2) integrated analysis, and (3) gene-environment interaction. Motivated by recent applied work in which they examined over 100 prostate cancer risk regions in populations of European, African, Japanese and Latino ancestry, they have developed a novel approach for multi-ethnic fine mapping that uses marginal associations to better identify a small set of variants for further functional follow-up via laboratory experiments. To leverage the availability of various omics data, they have recently proposed an integrated analysis approach that models the causal relationships of the various data types, such as germline, omic and disease data, to estimate relevant clusters of individuals to better characterize the underlying disease mechanism. Finally, they have expanded their approach to better identify gene-environment interactions by using Bayes model averaging to: (1) balance the robustness of a case-control approach with the power of the case-only approach; (2) leverage marginal SNP effects; (3) allow for the incorporation of prior information; and (4) allow the data to determine the most appropriate model.

Hong Wei Dong The major direction of Hong Wei Dong’s research focuses primarily on the Mouse Connectome Project (MCP), which aims to create a three-dimensional, Google Earth-like, digital Connectome atlas of the C57BL/6J mouse brain. His lab has constructed the first comprehensive and precise connectome of the entire cerebral hemisphere and thalamus. The first major milestone, Neural Networks of the Mouse Neocortex, was published in 2014 (Zingg et al., 2014, Cell, 156, 1096-1111). As another major achievement of the MCP project, recently they constructed a mouse cortico-striatal projectome: a comprehensive projection map from the entire cortex to the dorsal striatum in the mouse brain (Hintiryan et al., Nature Neuroscience, 2016). In this study, the Dong group developed an innovative computational neuroanatomic method to systematically and quantitatively map and analyze large scale connectivity data, which allowed them for the first time to identify 29 distinct functional domains in any mammalian brain. Additionally, this connectomics approach was applied to characterize circuit-specific cortico-striatal connectopathies in mouse models of disconnection syndromes such as autism spectrum disorder and Huntington disease. This work was reported by many news media (see http://www.mouseconnectome.org/press/).

Russell Jacobs During the past year, the Jacobs lab has made a major transition from Caltech to USC. Installation of a scanner with capability to do high resolution MRI simultaneously with high resolution PET has been a major effort. The group has employed MRI and PET with labeled natural killer (NK) cells (part of the innate immune system) to show that low dose focused ultrasound (ldFUS) can promote NK accumulation into tumors in a rodent model – a prerequisite for tumor eradication. They are currently examining how ldFUS modulates the immune system and can be used in combination with immunotherapies to destroy tumors and suppress metastasis. In collaboration with other labs at the Keck School of Medicine, Dr. Jacobs and his team are developing sophisticated MR techniques and analyses that will elucidate how connections across the brain change during the development of Alzheimer’s Disease, thus shedding light on how physiological changes become manifest as behavioral changes. In ongoing work using MRI’s unique ability to highlight changes in anatomy, the Jacobs’s lab has employed high-resolution scanning to examine human inner ear structure and early heart development.

Scientific Advancements 25 Radha Kalluri The Kalluri lab studies the biophysical processes underlying sensory signaling at the first synapse between the sensory cells of the inner ear and their partner neurons. They use a combination of patch-clamp electrophysiology, modeling, and anatomical methods to study the connectivity patterns of sensory cells in developing auditory and vestibular sensory epithelia during a critical period of development when synapses are forming and stabilizing. The group has made major advances in the following four directions: 1. Sensory-neural hearing loss is a waste-basket term for a wide range of hearing impairments. Using non-invasive measures of auditory function, they have proposed a method for refining the classification of hearing loss. Ongoing experiments are testing this new approach for understanding the etiology of hearing impairments. 2. They have recently found that the synaptic features that typically serve as markers for functional specificity in the auditory periphery may be driven by developmental signals that are independent of true sensory experience. 3. They have identified candidate ion channels in the vestibular system whose differential expression within sub-groups of vestibular afferent neurons may serve as the substrate upon which vestibular sensory information is parsed into parallel channels. 4. In collaboration with the Segil, Ohyama, and Ichida laboratories, they are characterizing the biophysical properties of reprogrammed inner ear hair cells and neurons using patch-clamp techniques.

James Knowles The overall theme of the Knowles lab is the identification of genetic risk variants for neuropsychiatric disorders, determining how these variants alter transcription, then how these transcriptional changes alter brain structure and function and finally, how these changes in the brain alter risk. During the past year, significant progress has been made towards the discovery of risk genes for obsessive-compulsive disorder (OCD). The Knowles lab, as part of the Psychiatric Genomics Consortium (PGC) has completed a meta- analysis of the available OCD GWAS data, which was recently published. The results are close to having a genome-wide significant finding and the Knowles group has a substantial amount of new data to add in the upcoming academic year, making it very likely they will have significant findings. The lab is continuing to study a mouse model of OCD (it lacks the gene encoding the transcription factor BTBD3) which has multiple compulsive behaviors. They have identified three regions of the thalamus that have decreased connectivity and have now completed brain imaging of 40 subjects in a pilot experiment to see if the same regions are altered in OCD patients (in collaboration with Drs. Art Toga and Yonggang Shi).

Dr. Knowles completed a Transcriptome Wide Association study (TWAS) of schizophrenia (led by Dr. Oleg Evgrafov) using neuronal cell lines they derived from individuals with schizophrenia, that is implicating about 53 transcripts in the neurodevelopmental aspect of the disorder. Three of these have been previously implicated in the large GWAS study of the disorder (PGC2 SCZ GWAS). This work has been submitted for publication. Additional analysis of these cell lines is in process with microRNAs (miRNA) and epigenetic marks (as part of the PsychEncode Consortium).

The Knowles lab has also completed a study of Cajal-Retzius neurons, the first neurons in the developing human brain, in collaboration with the Chow laboratory. They have the first electrophysiological recording of human Cajal-Retzius neurons, and have used single-cell RNA sequencing to determine the transcriptome that defines Cajal-Retzius neurons, and have compared it to the transcriptomes of cortical plate and subplate neurons from the same stage period of brain development.

26 Scientific Advancements Ralf Langen The Langen lab has on ongoing interest in the structural changes that occur in protein misfolding diseases such as Alzheimer, Parkinson, Huntington disease as well as type 2 diabetes. The overall focus has been on understanding the structural changes of proteins known to promote the aforementioned diseases with the goal of developing potential therapeutic molecules that can reverse or prevent these structural changes. With excessively high numbers of glutamine building blocks (>36 consecutive glutamines), huntingtin proteins are known to cause Huntington disease. How these large numbers of glutamine residues alter the protein structure and cause disease is not known. Such knowledge would be an essential first step for devising potential therapeutic treatments aimed at guiding the protein structures away from the toxic to the non-toxic forms. The Langen lab has now made significant advances by delineating the shapes of different toxic forms of the huntingtin protein. In addition, they identified the early molecular steps that lead to the formation of toxic species. The inhibition of these steps can now be targeted in order to arrive at therapies.

Similar studies have also been performed on proteins involved in Parkinson’s and Alzheimer’s disease. In addition, the Langen lab has also been generating molecules that are designed to serve as better diagnostic markers for neurodegenerative diseases.

Brian Lee As a new laboratory to the ZNI, the Lee computational neuroscience laboratory has focused on developing the infrastructure needed to perform human neurophysiological recordings, analysis, and modeling of neurological diseases, particularly epilepsy, Parkinson’s disease, essential tremor, and dystonia. This includes development of high-performance computing, analysis, and storage systems. Capabilities include multichannel human neurophysiology recordings in short-term intraoperative studies during clinical electrode implantation surgery, and longer week-long recording sessions in the intensive care unit (ICU) in patients undergoing intracranial seizure monitoring. The Lee lab currently has projects related to identifying biomarkers in Parkinson’s disease, modeling seizure activity in epilepsy, and engineering artificial sensation through direct subdural electrocorticography (ECoG) electrode stimulation for use in a closed-loop brain-computer interface (BCI) system.

William Mack The Mack laboratory completed the third year of a grant studying the effects of air pollution from vehicular exhaust in the setting of acute stroke. The R01- NIH/NIEHS ONES (Outstanding New Environmental Scientist) research program seeks to determine the impact of particulate matter (PM) exposure on white matter injury and neurocognitive decline. These associations are further examined in the setting of underlying cerebrovascular disease (chronic cerebral hypoperfusion). The team has demonstrated white matter and neurocognitive changes in the setting of nanoparticulate matter exposure that are exacerbated by chronic cerebral hypoperfusion. Recently and in addition to this work, Dr. Mack was awarded a five year NIH/ NINDS R25 grant to train USC Neurosurgery Residents in translational neuroscience research

Scientific Advancements 27 Takahiro Ohyama The Ohyama Lab is investigating how the cochlea, the auditory organ, develops during embryonic development. They discovered that the BMP signaling pathway is important for cell fate decision between sensory and non-sensory structure of mammalian cochlea. The Ohyama lab is also analyzing the mechanisms how migrating neural crest cells are incorporated into the non-sensory structure of developing cochlea, which is crucial for proper hearing functions. These projects aim to understand disease mechanisms of hearing impairment, as the group develops further translational research studies such as regeneration of auditory cells.

Janos Peti-Peterdi The Peti-Peterdi lab investigated the cellular and molecular mechanisms of glomerular kidney diseases, crosstalk between the kidneys and distant organs such the brain and heart, and renal tissue repair. They identified several new potential therapeutic targets for further development. The main focus of their studies last year was the role of a special chief cell type in the kidney called macula densa, and their role in endogenous nephron repair and/or the maintenance of systemic vascular beds. The laboratory deployed serial multiphoton microscopy to track the fate and function of individual cells in the same region of the living intact kidney over several days, during physiological adaptive responses, and in disease development. This approach has led to significant advances in understanding the highly dynamic kidney tissue and glomerular environment, and the mechanisms of glomerular injury and regeneration. Ongoing work in the laboratory is studying the fate and function of renal stem cells, and their role in endogenous kidney repair. Based on targeting specific molecular mechanisms within macula densa cells that control a newly discovered tissue repair process, the Peti-Peterdi lab is currently developing a new regenerative therapeutic approach for the treatment of chronic kidney disease. Another focus was the role of a pericyte-like cell type within the glomerulus called podocyte, in the development of glomerulosclerosis and chronic kidney disease. They identified purinergic calcium signaling mediated by the P2Y2 receptor, and the cell membrane calcium channel TRPC6 as the most significant mechanisms of podocyte cell-to- cell communication and propagation of podocyte injury. The lab is currently testing the effects of various pharmacological approaches that target these podocyte mechanisms, to investigate if they provide benefit in chronic kidney disease.

Derek Sieburth This year Dr. Sieburth identified a previously undescribed neuronal circuit that controls an ultradian rhythm in C. elegans. This circuit uses neuropeptides released from a single neuron to activate muscle contraction. This circuit has provided the lab with a platform to study the molecular mechanisms underlying the regulation of neuropeptide release in vivo. To date, the lab found that a protein implicated in Parkinson Disease functions to regulate the position of neuropeptide-containing dene core vesicles within axons. They also have developed an in vivo system for examining how the coupling of neurons by gap junctions impacts synaptic function and neurotransmitter release. Finally, the lab also discovered a neuroendocrine signaling pathway that protects organisms from the toxicity of oxidative stress through the stress-induced release of specific neuropeptides from neurons that activate the oxidative stress response in distal tissues.

28 Scientific Advancements Ansgar Siemer The Siemer lab investigated structural details of the protein Orb2, which is a key regulator of long-term memory in fruit flies. Previously, the lab had shown that the N-terminus of the Orb2 isoform A (Orb2A) is able to interact with lipid membranes. In the past year, they showed that this interaction seems to prevent the formation of Orb2A amyloid fibrils, indicating that this interaction might be important for the regulation of memory. They further completed a study investigating the metal binding ability of Orb2 and showed that if Orb2 interacts with nickel, no amyloid fibrils are formed.

Almost all Huntington’s Disease (HD) patients have a good (wild-type) and a mutant huntingtin (HTT) protein. In collaboration with Dr. Ralf Langen, the Siemer lab investigated how these two proteins interact. They showed that wild-type HTT, which usually does not form toxic fibrils, forms these fibrils in the presence of mutant HTT fibril. So formed wild-type HTT fibrils speed up the formation of mutant HTT fibrils. Both fibril types have a very similar structure, but the core of the wild-type fibril is more compact.

In a new collaboration with Dr. Janine Kirstein at the FMP in Berlin, the Siemer lab investigates the interaction of HTT with chaperones that can specifically detect and disaggregate HTT fibrils. This work will deepen their understanding of how toxic fibrils can be removed by the cell.

Huizhong Tao During FY17, Dr. Tao’s lab made two major discoveries. First, in layer (L)4 neurons of mouse visual cortex, they found a strong correlation between direction selectivity (DS) and spatial asymmetry in the distribution of excitatory input strengths and the preferred direction of excitatory input was always from the stronger to weaker side of its spatial receptive field. They also found that a simple linear summation of asymmetrically distributed excitatory responses to stationary flash stimuli however failed to predict the correct directionality. Using sequential 2 flash-bar stimulation the Tao lab has revealed a short-term suppression of excitatory input evoked by the late bar. More importantly, the level of the suppression positively correlated with the relative amplitude of the early-bar response. Implementing this amplitude-dependent suppressive interaction, they have successfully predicted DS of excitatory input. The results suggest that via nonlinear temporal interactions, the spatial asymmetry can be transformed into differential temporal integration of inputs under opposite directional movements, resulting in DS. Second, using a newly developed method of AAV-based anterograde transsynaptic tagging, Dr. Tao and her team has been able to express light-sensitive channels in separate neuronal groups in the superior colliculus (SC), receiving inputs from auditory cortex and visual cortex respectively. By activating these different SC neuron subsets, they revealed different functions performed by SC neuron subsets, with auditory cortex receiving SC neurons mediating flight responses while visual cortex receiving neurons mediating freezing responses. A neural pathway downstream of visual cortex receiving SC neurons has also been identified.

Scientific Advancements 29 Terrence Town The lab’s focus continues on developing a treatment for Alzheimer’s disease by targeting inflammation and the immune system. For the first time, in two papers (Guillot-Sestier et al., 2016 and Mori et al., 2017) Dr. Town and his group have shown that ‘re-balancing’ the immune system in pre-clinical Alzheimer’s rodent models leads to clearance of amyloid plaques by a type of cell called a macrophage. Further, they published four papers on their work related to the role of the immune system in human disease (see Breunig et al., 2016, Acharya et al., 2016, Paul et al., 2016, and Matundan et al., 2016). By generating the first rat model of the disease that manifests all of the clinico-pathological hallmarks of the human syndrome, the lab has significantly contributed to the field of Alzheimer’s disease research. Specifically, the lab generated transgenic rats that over-express two mutant human transgenes that are each independently causative of familial early-onset Alzheimer’s disease: “Swedish” mutant amyloid precursor protein and deltaE9 mutant presenilin-1. Unlike their transgenic mouse cousins that develop ‘senile’ plaques but fail to manifest ‘tangles’ and frank neuronal loss, these transgenic rats for the first time develop the full spectrum of Alzheimer pathologies. This year, the town group deployed the latest cutting-edge imaging techniques alongside advanced mathematical models to show longitudinally progression of Alzheimer’s disease in this exciting new rat model (see Fick et al., 2017). This makes these animals an invaluable tool for understanding Alzheimer’s disease etiology and for testing cutting- edge therapeutics—all in living animals. Using this new Alzheimer rat model, Dr. Town is actively pursuing collaborations with academics and industry partners to understand basic mechanisms of Alzheimer’s. To date, they have already bred rats for over 30 labs around the world.

Tobias Ulmer The Ulmer lab has revealed how the coupling of extracellular and membrane-embedded protein domains sets the activation threshold of integrin cell-adhesion receptors. Faulty control of the activation state of integrins leads to cancer, cardiovascular and autoimmune disease. Moreover, the sequence motif responsible for modulating this coupling was predicted in 21% of all single- pass human transmembrane proteins, making it a universal motif involved in the signaling of a wide range of cell surface receptors. In a separate study, the Ulmer group addressed how membrane proteins efficiently pack into bundles of helices. Specifically, the amino acid proline is known to facilitate this assembly by introducing kinks into helix geometry. The study showed how such kinks can be introduced in a manner that does not destabilize the entire protein and render it non-functional. Finally, the function of membrane proteins, which represent the targets of most pharmaceutical drugs, relies on a defined orientation in the membrane. Contacts between membrane lipids and membrane proteins were examined by NMR spectroscopy to compile a picture of the immersion of integrin in synthetic model membranes.

30 Scientific Advancements Image credit: Tobias Ulmer Tobias credit: Image

Right: Membrane anchoring of integrin transmembrane helices. Left: Immersion of integrin transmembrane helices in lipids.

Kai Wang The Wang lab has developed several bioinformatics tools for genome analysis, including iCAGES and iMEGES for prioritizing causal variants in cancer and psychiatric diseases, respectively.

Gabriel Zada The Zada lab conducts translational research pertaining to genomics and targeted, precision molecular therapies for brain tumors. The lab focuses on a variety of brain tumors including pituitary adenoma, meningioma, glioma, cerebral metastases, chordoma, and craniopharyngioma, among others. Research in 2016-2017 has focused on performing genome- wide DNA methylation and gene expression analysis of surgically-resected pituitary adenomas and meningiomas. Based on this research and prior work, several promising candidate gene targets have been identified that are now being incorporated into tumor cell line models to test the effects of modulated gene expression on cell survival, invasion, and hormone production.

Previous collaborations include leading a nationwide group called the Pituitary Adenoma Genomic and Epigenetic (PAGE) consortium and applying for national support for a consortium- based, multi-institutional study focusing on these tumors. In addition, Dr. Zada and his team launched a collaborative research study with Dr. Joshua Neman-Ebrahim (Neurological Surgery, USC) focusing on meningioma research. Additional collaborations have been established with the laboratory of Peggy Farnham (Biochemistry and Molecular Medicine, USC).

Scientific Advancements 31 Li Zhang The Zhang Lab continued their multiple-aspect investigation of the neural circuits at different auditory processing stages along the central auditory pathway. By integrating a series of cutting-edge techniques, they were able to reveal some new computational mechanisms exploited by the auditory circuits to process acoustic information. In particular, they recently explored the neural circuitry underlying an auditory- motor behavior, and revealed that sensory cortex can directly drive innate defense behavior through corticofugal projections, a previously unrecognized neural pathway mediated by the inferior colliculus.

Berislav Zlokovic Utilizing loss-of-function pericyte-deficient mice, the Zlokovic lab has demonstrated that pericyte degeneration diminishes global and individual capillary cerebral blood flow (CBF) responses to neuronal stimulus resulting in neurovascular uncoupling, reduced oxygen supply to brain and metabolic stress, which leads to impaired neuronal excitability and neurodegeneration (Kisler, Nelson…Zlokovic, Nature Neuroscience 20, 406-416, 2017). Thus, pericyte degeneration as seen in neurological disorders such as Alzheimer’s disease (AD) may contribute to neurovascular dysfunction and neurodegeneration associated with human disease. The topic of CBF regulation and dysfunction in Alzheimer’s disease was reviewed by Kisler, Nelson, Montagne and Zlokovic (Nature Reviews Neuroscience 18, 419-434, 2017). For these studies, the group also developed a set of standardized in vivo protocols for measurements of cerebrovascular hemodynamic responses and tissue oxygenation in the mouse brain (currently in review with Nature Protocols).

Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, behavior and tissue analysis, the Zlokovic lab also showed that pericyte degeneration disrupts white matter microcirculation causing accumulation of toxic blood-derived fibrin(ogen) deposits and blood flow reductions, which triggers loss of myelin, axons and oligodendrocytes. This disrupts brain circuits leading to white matter functional deficits before neuronal loss occurs, suggesting that pericytes control white matter structure and function (Montagne, Nikolakopoulou …Zlokovic, Nature Medicine, accepted). These findings have implications for the pathogenesis and treatment of human white matter disease associated with small vessel disease of the brain.

Deploying their advanced dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI, Montagne…Zlokovic, Neuron 85, 296-302, 2015), the Zlokovic team continues to evaluate blood-brain barrier integrity in individuals with no or mild cognitive impairment but at genetic risk for AD, i.e., APOE4 gene for sporadic AD, and PSEN1 mutations for autosomal dominant AD.

32 Scientific Advancements Academic and Community Activities

Frank Attenello Dr. Campbell’s contributions to the understanding of Dr. Attenello was the Recipient of an NIH CTSI KL2 the role of noncoding RNAs in psychiatric disorders Clinical Translational Research Scholar Award were recognized by invitations to give lectures at a dozen prestigious universities. Dr. Campbell was Alexandre Bonnin also appointed to the editorial boards of the journals Dr. Bonnin taught in the USC Neuroscience Graduate Developmental Neuroscience and Behavioral and Program as well as Pharmacology to first year USC Psychiatric Genetics. He was also the co-Chair medical students. In 2017, Dr Bonnin was invited as for Genetics on the Program Committee for the reviewer on the NIH (NIAID) Special Emphasis Review International Meeting For Autism Research. He Panel: Partnerships for Countermeasures Against served on NIH study sections and on the Integration Select Pathogens (R01). Additionally, Dr. Bonnin was Panel for the Department of Defense Congressionally an invited speaker and session co-chair at national Directed Medical Research Programs Autism Research and international symposia (including those held in Program. Paris, France and Milan, Italy). Dr. Bonnin is also a member of the USC Institutional Biosafety Committee. Jeannie Chen He serves on the editorial board of Translational Dr. Chen served on the Scientific Advisory Board of the Developmental Psychiatry and MOJ Anatomy & Karl Kirchgessner Foundation. Physiology. Recent talks include: • International Society for Serotonin Research, Dr. Chen participated in a scientific review panel to Seattle, WA. review predoctoral (F30 and F31) and postdoctoral • Molecular Toxicology IDP at UCLA, Los Angeles, (F32) fellowship applications submitted to NIH CA. CSR Special Emphasis Panel (SEP) “Fellowship: Cell • Michigan State University (Dr Racicot), Grand Biology, Developmental Biology, and Bioengineering Rapids, MI. (F05-U). • Florida Atlantic University (Dr Blakely), Jupiter, FL. • Distinguished Speaker, Los Angeles Zika Virus Robert Chow Awareness Symposium, USC School of Medicine Dr. Chow served as a mentor for the following (organized by Dr Jung, USC). programs: • Dept of Cell Biology & Anatomy, U of Calgary, • CIRM summer internship Canada. • CIRM Bridges internship • Division of Reproductive Sciences, U Colorado, • Bridging the Gaps: Bench to Bedside Summer USA. Research Program • Keystone Symposia on Molecular & Cellular Biology, Park City, Utah, USA. Daniel Campbell

Academic and Community Activities 33 David Conti Russell Jacobs Dr. Conti was appointed Interim Division Chief, Dr. Jacobs established and serves as director of the Biostatistics Division, Department of Preventive Functional Biological Imaging core. Dr. Jacobs gave Medicine. He served as Statistical Editor for the talks at the following events: Journal of the National Cancer Institute (JNCI) and • Bridge @ USC Scientific Retreat 2016 at the editorial board member for Genetic Epidemiology Michelson Center for Convergent Bioscience. and Cancer Research. • Canadian Association of Physicists 2016 Annual Meeting Plenary Session Hong Wei Dong • ZNI Seminar Series Dr. Dong served as an associate editor for Brain Informatics. Radha Kalluri Dr. Kalluri served on the editorial board of Otology He was an invited speaker to several events, and Neurotology; the Executive Committee of including: the Neuroscience Graduate Program, and was a • Gordon Research Conference, Molecular and founding member of the a networking group for Cellular Neurobiology, Hong Kong, entitled: Early Career Investigators in Auditory Neuroscience. “Assembling global neural networks of the mouse brain.” Ralf Langen • The 2nd Annal da Vinci Convergence Dr. Langen gave numerous invited lectures at Symposium: A Scientific Summit on international meetings. At USC he has been serving Computational Modeling Across the Scale, on the curriculum committee, the seminar series Invitated talk, “Assembling Neural Networks of committee and the admissions committee. He the Mammalian Brain”. also serves as a permanent member of an NIH • USC 2017 Pathology Conference, Key note study section (BPNS), a panel that evaluates grant speaker, “Assembling Neural Networks of the applications for NIH funding. Mammalian Brain” • Korea Center for Functional Connectomics, Brian Lee “Assembling global neural networks of the Dr. Lee was a recipient of an NIH SC CTSI KL2 Career mouse brain. Development Award; as well as a Neurosurgery • University of Pennsylvania, Center for Research and Education Foundation (NREF) Young Neurodegenerative Disease Research, Annual Clinician Investigator Award. retreat, Invited talk, “Genetic architecture and neural networks of the mouse hippocampus.” William Mack • Gordon Research Conference, Molecular and Dr. Mack was elected to the Society of Cellular Neurobiology, Hong Kong, entitled: Neurointerventional Surgeons Board of Directors “The hippocampal wiring diagram and its (Secretary) and served as associate editor for molecular signature” Journal of Neurointerventional Surgery and on the editorial board of World Neurosurgery as the Book Review Section Editor. Dr. Mack also served on the Neuroscience Graduate Program Admissions Committee.

34 Academic and Community Activities Janos Peti-Peterdi Dr. Peti-Peterdi served as the director of the USC Tobias Ulmer Multiphoton Microscopy Core. He also serves on Dr. Ulmer gave talks at Vanderbilt University (Nashville, the KSOM Faculty Research Council, and the Faculty TN); and the National Institutes of Health (Bethesda, Appointments, Promotion, and Tenure Committee. He MD) Bax Symposium. is core director of the RCLD Cell and Tissue Imaging Core. He is an elected member of the European Kai Wang Academy of Sciences and Arts, and the American Dr. Wang participated in the Program Committee and Society for Clinical Investigation. chaired one session for the International Conference on Intelligent Biology and Medicine. Ansgar Siemer Dr. Siemer continued to serve on USC’s PIBBS Gabriel Zada (Programs in Biomedical and Biological Sciences) Dr. Zada participated in the USC Pituitary Symposium admission committee. He co-organized the retreat of and Chordoma Foundation Community Conferences, the Department of Biochemistry and Molecular Biology both hosted here at the USC Norris Comprehensive in Spring 2017. Further, together with Dr. Ralf Langen, Cancer Center. Dr. Siemer organized a new PhD program in Medical Biophysics, which began accepting students in the Li Zhang summer 2017. Dr. Zhang was invited to speak at an International Workshop at the Weizmann Institute of Science Huizhong Tao (Israel); Winter Conference on Brain Research Dr. Tao served as director of a graduate level (WCBR, Breckenridge, Colorado) where he was advanced seminar course “Optogenetics and Circuit also an organizer; University of Virginia; Frontiers Mapping”. in Interdisciplinary Neuroscience and Technology (Hangzhou, China); Peking University (China); and the Terrence Town Annual meeting of neuroscience in China (Tianjin) Dr. Town gave talks at the University of California, Irvine and Genentech and was a plenary speaker at the American Federation for Aging Research (Santa Barbara, CA); and Southern California Alzheimer’s Disease Centers Research Symposium (Irvine, CA).

The nerve damage Multiple sclerosis (MS) is a chronic causes many different neurological condition where the immune symptoms, including system attacks myelin, a protective vision loss, pain, substance that covers nerves. fatigue, and impaired coordination.

Academic and Community Activities 35 Berislav Zlokovic Association International Conference, Invited Dr. Zlokovic was included in Thomson Reuters list Speaker (Toronto, Canada); The Gordon Research of ‘The World’s Most Influential Scientific Minds’ Conference Neurology of Brain Disorders as one the most cited authors in the field of Conference (Girona, Spain); Sahlgrenska Neurosciences and Behavior in 2016. Academy Seminar (Gothenburg, Sweden); Sol He was asked by the Nobel Assembly at Sherry distinguished lecture in Thrombosis Karolinska Institutet to nominate one or more with John H Griffin; TETRA Seminar Rockefeller candidate for the Nobel Prize in Physiology and University; New York Academy of Sciences AD Medicine 2017. He gave the plenary lecture on NeuroVascular Inflammation, Keynote Speaker Alzheimer’s disease and Parkinson’s disease (Manhattan); Cold Spring Harbor BBB meeting, International meeting in Vienna, 2017, and Keynote Speaker (New York); 23rd Annual blood- delivered the prestigious Del Monte Lecture in brain barrier consortium (Stevenson, WA); 13th Neuroscience at the University of Rochester NY, International Conference on Alzheimer’s and 2017. He was installed as initial holder of the Mary Parkinson’s Diseases: Mechanisms, Clinical Hayley and Selim K. Zilkha endowed Chair for Strategies and Promising Treatments of Alzheimer’s disease research. Neurodegenerative Diseases, Plenary Speaker (Vienna, Austria); 28th Symposium on Cerebral In March 2016, he organized USC Vision and Blood Flow, Metabolism and Function, 13th Voices, KSOM, to examine with students how Conference on Quantification of Brain Function music affects brain functions. In 2016, he with PET (Berlin, Germany); Symposium on was a member of the Strategic Plan Steering Small Vessel Disease of the Brain, NovoNordisk Committee for Keck School of Medicine of Foundation Symposia (Copenhagen); Del Monte USC, and a member of USC Honorary degree Neuroscience Lecture, University of Rochester, committee. (NY).

In November 2016, he organized at ZNI the prestigious annual Zach Hall lecture with Eric R. Kandel, Nobel Prize winner, and Denise Kandel. In April 2017, he organized and held at ZNI the Annual Zilkha International Symposium on Alzheimer Disease and Related Disorders, From Investigation to Integration: New Basic, Translational & Clinical Efforts in Alzheimer’s Disease & Related Disorders.

Dr. Zlokovic was an invited speaker at the following workshop/conferences: The Alzheimer’s

36 Academic and Community Activities Collaborations

Frank Attenello • Berislav Zlokovic of USC, my NIH KL2 mentor, studying the effects of host pericyte modulation on glioma tumor growth • William Mack, Caleb Finch, Constantinos Sioutas, Todd Morgan, USC, studying effects of nanoparticulate matter on neural stem cell behavior following ischemic stroke

Alexandre Bonnin • Irina Burd, Johns Hopkins University; collaborating on fetal brain imaging studies following maternal exposure to stress and antidepressant drugs • Anne Andrews, UCLA; collaborating on fast microdialysis studies to measure offspring neurochemical activity following prenatal exposure to stress and antidepressant drugs • Gerard Karsenty, Columbia University, NY; collaborating on a study related to the role of a bone- derived molecule in fetal brain development • George Anderson, Yale University; collaborating on fetal, placental and maternal measures of biogenic amines • Robert Schwarcz, University of Maryland; collaborating on fetal, placental, and maternal measures of specific biogenic amines. • Jae Jung, USC; collaboration on the study of Zika virus maternal-fetal transmission during pregnancy • Thierry Fournier and Sophie Gil, University of Paris, France; collaborating on transplacental drug transfer in human pregnancies • Tracy Bale, University of Pennsylvania; collaborating on studies of placental metabolism impact on fetal brain development • Karen Racicot, Michigan State University; collaborating on studying the impact of maternal CMV infection during pregnancy on fetal brain development

Collaborations 37 Daniel Campbell • Wange Lu, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, USC; studying the impact of autism-related genetic variants on neuronal differentiation • James Knowles, ZNI, USC; studying gene expression changes caused by non-coding RNAs • Heather Volk, Johns Hopkins University; investigating gene-environment interactions in autism • Kevin V. Morris, Scripps Research Institute; studying the molecular mechanisms of non-coding RNAs • Judy Van de Water, University of California, Davis; studying the genetic basis of altered immune sensitivities in autism • Lisa Croen, Kaiser Permanente; studying the genetic basis of altered immune sensitivities in autism

Karen Chang • Tai Min, UNIST, Korea; investigating common molecular pathways altered in Down syndrome and Fragile X syndrome, two of the most common genetic causes of mental retardation • Dion Dickman, Department of Neurobiology, USC; studying the role of a novel synaptic kinase in regulating synaptic growth and function • Ralf Langen, ZNI, USC; examining the effects of post-translational modification on membrane protein functions • Sergey Nuzhdin, Department of Molecular Biology, USC: mechanisms regulating learning and memory

Jeannie Chen • Alapakkam Sampath, UCLA; investigating the signal transfer from the photoreceptor sensory neurons to bipolar cells during retinal degeneration and during recovery from degeneration • Greg Field, Duke University; investigating how changes in retinal ganglion cell receptive fields during retinal degeneration and during recovery from degeneration • Ralf Langen, ZNI, USC; investigating amyloid structures in eyes affected with macular degeneration and exploring therapeutic agents to dissolve these structures • M. Carter Cornwall, Boston University; collaborating on the molecular mechanisms that regulate recovery of light sensitivity following bright light exposure • King-Wai Yau, Johns Hopkins University School of Medicine; collaborating on the role of calcium- feedback to the olfactory sensory neurons in sensitivity adjustment during odorant adaptation. • Vsevolod Gurevich, Vanderbilt University; studying function of visual arrestins in the physiology of the photoreceptor cell • Gordon Fain, UCLA; collaborating on mechanisms that regulate phototransduction in rod and cone photoreceptors • Vladimir Kefalov, Washington University; investigating proteins that regulate calcium concentration in rod and cone photoreceptors

Robert Chow • James Knowles, ZNI, USC; We are collaborating to correlate physiology and transcriptomics of single adult and fetal brain neurons • Oleg Evgrafov, ZNI, USC; We have developed a novel 3D culture of differentiated nasal neuroepithelial biopsy cells, in order to test hypothesis that such cells will form synapses, and, if derived from schizophrenic patients, the synapses will be abnormal • Cheng-Ming Chuong, Pathology, USC; We have tested the role of electrical and calcium signaling in development of chick feather bud morphology

38 Collaborations Robert Chow (cont.) • Ralf Langen, ZNI, USC; investigating the potentiating effect of free fatty acids and monophthalates (plasticisers) in potentiating amyloid peptide cytotoxicity in the setting of obesity in type 2 diabetes and Alzheimer’s • Jeannie Chen, ZNI, USC; We are applying our new genetically encoded ratiometric calcium indicator to study cytoplasmic calcium of photoreceptors in vivo and in vitro in mouse models of photoreceptor degeneration • Mark Humayun and James Weiland, Department of Ophthalmology, USC. We are collaborating on two projects: 1) improving performance of the Argus II retinal prosthesis, and 2) development of a novel photovoltaic nanoswitch for remote optical control of neuron activity • Koping Kirk Shung, Viterbi School of Engineering, USC; collaborating on a project to distinguish highly invasive breast cancer cells from less invasive cancer cells, using high-frequency ultrasound stimulation of cytoplasmic calcium elevation • I-Chueh Huang, Department of Molecular Microbiology and Immunology, USC: studying the cellular tropism of Zika virus in fetal brain tissue, and mechanisms to prevent Zika virus replication • Michael Bonaguidi (Stem Cell & Regenerative Medicine), Jonathan Russin, Charles Liu, William Mack (Neurological Surgery), USC. We have created an interdisciplinary team to study the mechanism of epilepsy

Marcelo Coba • Guoping Feng, Stanley Center for Psychiatric Research, Broad Institute, Boston; studying of SHANK3 mutations in psychiatric disorders, and their role in postsynaptic signaling • Justin Ichida, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC; collaborating on hiPSC cells for the study of neurodevelopmental processes in psychiatric disease • James Knowles SUNY downstate NY; studying the role of synaptic signaling complexes in Obsessive compulsive disorder and Schizophrenia • Ted Abel, University of Iowa; studying the role of Shank3, Fmr1 and AKAP signaling mechanisms associated to neurological disease • Marco Bortolato, Utah University; collaborating on the role of NMDAR signaling in the pathophysiological processes underlying impulsive aggression and related neurodevelopmental disorders (autism-spectrum disorder, ADHD, Tourette syndrome) • Thomas O’Dell, UCLA; collaborating on the role of TNiK and Dlgap1 signaling in synaptic plasticity, learning and memory • Chao Zhang, USC; investigating the chemical genomics approaches to the study of protein kinase signaling • Fengzhu Sun, Department of Computational Biology and Bioinformatics at USC; analyzing of protein domains and their role in synaptic signaling complexes associated to Schizophrenia • Pat Levitt, USC-CHLA; working to determine of the Autism Risk factor MET interactome and its role in the developing synapse • Fowzan S Alkuraya, MD, Head, Developmental Genetics Unit, King Faisal Specialist Hospital and Research Center. Saudi Arabia. Studying the role of mutations in the protein kinase TNIK, found in patients with intellectual disability and their function in neuronal development • Benjamin M. Neale, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Analysis of de novo coding mutations on exome-sequenced parent–proband trio cohorts for complex brain disorders and their role in synaptic protein networks • Stephanie Dulawa, UCSD. Role of Dlgap1 in obsessive compulsive disorder and schizophrenia

Collaborations 39 David Conti • Sylvia Richardson and Paul Newcombe, MRC Biostatistics Unit, Cambridge, UK; developing of Bayesian model selection for functional integration in genetic association studies • Chris Haiman, Department of Preventive Medicine, USC; investigating the role of genetic variants in prostate cancer • Marc Tischkowitz, University of Cambridge, Department of Medical Genetics, Jonine Bernstein, Dept. of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center; collaborating on WECARE Study (Women’s Environmental, Cancer, and Radiation Epidemiology) which examines genetic susceptibility and radiation exposure in breast cancer • Frank Gilliland and Jim Gauderman, Department of Preventive Medicine, USC; examining the role of genetic variation and pollution in asthma and lung function development in over 10,000 children followed for over 10 years in Los Angeles • Wendy Cozen, Department of Preventive Medicine, USC; through genetic association studies, they are investigating the role genes play in multiple myeloma and Hodgkin’s lymphoma • Duncan Thomas, Department of Preventive Medicine, USC; developing new statistical approaches to the analysis of genes and environmental factors that interact via biological pathways • Kiros Berhane, Department of Preventive Medicine, USC; developing new statistical methods that incorporate both age and sex related changes in the dynamic relationship between weight, height and obesity as well as the complex multi-level relationships of determinants of obesity • Lilyana Amescua, Department of Neurology, USC; investigating the impact of genetics in Multiple Sclerosis using a Hispanic population sampled in Los Angeles and novel statistical methods • Danieli Salinas, Department of Pediatrics, USC; estimating clinical outcomes and classifying CFTR variants of unknown significance in children with a positive newborn screening for Cystic Fibrosis • Duncan Thomas, Jim Gauderman, Juan Pablo Lewinger, Paul Marjoram, Kim Sigmund, Paul Thomas, Josh Millstein, Haiyu Mi, Department of Preventive Medicine, USC; Program Project to develop statistical methods for integrative genomics in cancer • Jim Gauderman, USC and Riki Peters of the Fred Hutch Cancer Center: Using functional Genomics to Inform Gene Environment Interactions for Colorectal Cancer

Hong Wei Dong • Jean Shih, Department of Pharmacology, USC. We collaborate on characterizing disruption of cortico- striatal pathways in the mouse models of Autism • X William Yang, Department of Neuropsychiatry, UCLA. We collaborate on characterizing connectopathies in the mouse models of Huntington’s disease • Peyman Golshani, Department of Neurology, UCLA. Collaborative project: Optogenetic treatment of social behavior in autism

Russell Jacobs • Terrence Town, ZNI, USC: Longitudinal MRI is used to assay in vivo effects of aging and Alzheimer’s Disease pathogenesis in the TgF344-AD rat model developed in Prof. Town’s lab with special emphasis on changes in brain vascular • Alan Epstein, Pathology, USC: Examine efficacy & mechanisms of CAR T- and NK-cell immunotherapies in mouse models of cancer • Danny JJ Wang, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, USC: MR imaging of a muscarinic acetylcholine receptor DREADD (designer receptor exclusively activated by designer drugs) introduced in the rodent brain, which can be activated by chemogenetic stimulation with chlozapine N oxide

40 Collaborations Russell Jacobs (cont.) • Yonggang Shi, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, USC; Developing high resolution MRI for modeling the mouse connectome with multi-shell diffusion imaging • Andrew Raubitschek, CHO Pharma, Inc.: Mechanisms of immunotherapies based on glycosolated antibodies using MRI and PET imaging • Roberta Brinton, College of Medicine University of Arizona: Using high resolution 3D MRI to detail changes in the brain anatomy of the aging female brain in rodent model systems • Elaine Bearer, University of New Mexico: We use systems-wide longitudinal strategies to explore the brain’s response to unconditioned fear (predator stress) and its progression or resolution over time in a rodent model system • Kristi Clark, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, USC: Comparison of 3D MRI anatomy with “clarified” histo-pathogy of the human hippocampus • Berislav Zlokovic, ZNI, USC: Longitudinal in vivo MRI studies involving DTI, T2*weighted scans, DCE MRI scans of in rodent models of stroke and cerebrovascular ß-amyloidosis • Erkki Ruoslahti, Sanford Burnham Prebys Medical Discovery Institute, UC Santa Barbara: Using Positron Emission Tomography (PET) to examine the biology of a series of small cyclic peptides that recognize the vasculature in the hippocampus of Alzheimer’s mouse model • Angelique Louie, UC Davis: Simultaneous PET & MR imaging of multimodal probes of vascular plaque

Radha Kalluri, • Ruth Anne Eatock, University of Chicago; working on a computational model for defining information transfer in the vestibular sensory periphery • Neil Segil, Takahiro Ohyama, Justin Ichida, Departments of Otolaryngology and Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, USC; studying the molecular basis of neuronal differentiation in directly differentiated neurons • Carolina Abdala, Department of Otolaryngology at USC; using otoacoustic emissions to non-invasively probe the status of mechanical transduction in hearing impaired humans • Christopher Shera, Department of Otolaryngology at USC; collaborating on understanding the mechanical basis of low-frequency hearing • Jason Zevin, Department of Psychology at USC; collaborating on understanding individual variability in speech perception ability • Raymond Goldsworthy, Department of Otolaryngology of USC; linking behavioral and physiological measures of frequency resolution in humans

Hearing loss affects 48 million people in the US. 1 out of 3 people over the age of 65 have some degree of hearing loss, with 2 out of every 3 people over the age of 75 affected.

Collaborations 41 James Knowles The Knowles lab is highly collaborative. Projects range from investigations of animal models of human anxiety disorders to large scale international efforts to identify genetic risk factors for complex neuropsychiatric disorders (e.g., schizophrenia, bipolar disorder, depression, autism, and obsessive- compulsive disorder) to smaller studies of genetic predisposition to congenital disorders (e.g., congenital heart disease; non-syndromic hearing loss) to projects that build computer workflow pipelines to handle petabytes of genetic data. The following are either ongoing collaborations or newly established alliances that were formed to further these research projects: • Oleg Evgrafov, Robert Chow, Derek Sieburth, Li Zhang, Marcelo Coba, David Conti, Dan Campbell, Chris Haiman, William Mack, Rick Friedman, and Russell Jacobs, ZNI, USC. Various projects with ZNI investigators on studies of genetic expression and genetic variation in health and disease (e.g., autism, schizophrenia) • Ewa Deelman, Jonathan Buckley, Colin Dias, Mike Kahn, Carl Kesselman, Jerold Shinbane, Justin Ichida, Arthur Toga, Paul Thompson, Yonggang Shi, Peggy Farnham and Brad Peterson, USC; collaborating on various projects including the identification of susceptibility genes for complex diseases • Dan Stein, University of Capetown, Gerry Nestadt and Jack Samuels of Johns Hopkins University, Abby Fyer, Columbia University, Ben Greenberg and Steve Rasmussen, Brown University, James McCracken and John Piacentini, UCLA, David Pauls, Scott Rauch and Dan Geller, Harvard University, Dennis Murphy and Yin Shugart, NIH, Carol Matthews, UCSF, and Stephanie Dulawa, University of California San Diego; studying Obsessive compulsive disorder (OCD) • Steven McCarroll, Harvard University/Broad Institute, Mike Boehnke and Goncalo Abecasis of the University of Michigan; Ayman Fanous of the Veterans Administration, Washington DC; Mohammad Ayub, Queens University, Kingston, ONT; studying Schizophrenia • Ned Kalin, Pat Rosebloom, Jonathan Oler, and Drew Fox, the University of Wisconsin, Madison; genetic studies of anxiety in primates

Ralf Langen • Alasdair Steven, NIH; using a cryo electron microscopy to look at mechanisms of membrane curvature and protein misfolding in neurodegenerative diseases • Tobias Ulmer, ZNI; combining NMR and EPR-based approaches to determine structures of amyloidogenic proteins involved in neurodegeneration • Ansgar Siemer, ZNI; combining solid state and NMR and EPR-based approaches to determine structures of amyloidogenic proteins involved in neurodegeneration • Martin Kast, Department of Molecular Microbiology & Immunology, USC; investigating membrane- bound annexin A2 complexes as receptors for HPV entry • Ian Hawaorth, School of Pharmacy, USC; combining EPR and computational methods for determining protein structures • Oliver Daumke, University of Berlin; investigating control of membrane curvature by EHD-2. • Robert Chow, ZNI, USC; investigating membrane-mediated toxicity of amyloidogenic proteins in Alzheimer’s disease and type-2 diabetes • Songi Han, University of California, Santa Barbara; using novel EPR and NMR-based methods to monitor water exposure and its application to protein misfolding and membrane interaction • Pinchas Cohen, School of Gerontology, USC; investigating the misfolding inhibition of mitochondrially derived peptide

42 Collaborations Ralf Langen (cont.) • Ali Koshnan, Caltech; huntingtin antibody interactions • Rohit Pappu, Washington University; interaction of huntingtin with profilin, a potential misfolding inhibitor

Brian Lee • Richard Andersen, the California Institute of Technology; to develop a brain-machine interface (BMI) system in patients with spinal cord injury

William Mack • Caleb Finch, Gerontology and Constantinos Sioutas and Environmental Engineering, USC; collaborating on studies of the effects of particulate matter exposure from vehicular exhaust on the progression of stroke and cerebral hypoperfusion • James Knowles, ZNI, USC; working on a large study designed to evaluate cellular heterogeneity of temporal and cerebellar cells using patchclamp and RNA-Seq of single cells • Robert Chow, ZNI, USC; collaborating on a large study designed to evaluate cellular heterogeneity of temporal and cerebellar cells using patchclamp and RNA-Seq of single • Frank Attenello, ZNI, USC; collaborating to study the effect of particulate matter on neural stem cells in the setting of stroke

Takahiro Ohyama • Neil Segil and Justin Ichida, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, USC; researching factors that directly transform somatic cells into auditory sensory cells • Pinchas Cohen, USC Davis School of Gerontology; testing protective effects of mitochondria-derived peptides on drug-induced hair cell damage • Rick Friedman, ZNI, USC; testing molecular functions of genes identified through genetic screening of mouse hearing disease model

Janos Peti-Peterdi • Matthias Kretzler, Wenjun Ju, and Markus Bitzer, University of Michigan; collaborating on the development of urinary CCN1 as a novel biomarker of kidney and cardiovascular diseases. • Andrew McMahon, USC; analysis of the macula densa cell molecular fingerprint • Genevieve Nguyen, College de France, Paris; studying the role of the prorenin receptor in macula densa cells • Dominique Eladari and Regine Cambrey, INSERM, France; working novel electrolyte transport mechanisms in the distal nephron • Paola Romagnani, University of Florence, Italy; studying Intrarenal stem cells • Matthew Butler, University of Bristol, UK; studying the role of the glomerular glycocalyx • John Mullins, University of Edinburgh, UK; studying the role of renin cells in vascular remodeling. • Wilhelm Kriz, University of Heidelberg, Germany; studying the structure/function features of the glomerular filtration barrier • Peter Deen, University of Nijmegen, Netherlands; investigating the role of GPR91 in distal nephron ion transport

Collaborations 43 Janos Peti-Peterdi (cont.) • Laszlo Rosivall, Semmelweis University, Budapest, Hungary; studying novel intrarenal mechanisms of body fluid and electrolyte balance • Naoki Kashihara, Kawasaki University, Okayama, Japan; studying the role of podocytes in glomerular diseases • Laura Perin, Children’s Hospital Los Angeles; studying the role of amniotic fluid-derived stem cells in kidney repair • Valter Longo, School of Gerontology, USC; studying the mechanism of kidney and liver regeneration. • Alicia McDonough, Integrative Anatomical Sciences, USC; studying the role of the intra-renal renin- angiotenisn system • Rudy Ortiz, University of California, Merced; studying the role of mitochondrial factors in cell and tissue metabolism. • Stuart Shankland, University of Washington, Seattle; studying the mechanisms of glomerular dysfunction and repair • Giuseppe Remuzzi, University of Bergamo, Italy; collaborating on a clinical study of a new therapeutic approach to kidney regeneration. • Jochen Reiser (Rush University) and Sanja Sever (Harvard University); studying the effects of suPAR on the glomerular filter • Inderbir Gill, Department of Urology, USC; human translational studies on the macula densa renal tissue repair mechanism • Chaim Jacob, Department of Medicine, USC; studying the role of glomerular immune cells in lupus nephritis • Berislav Zlokovic, ZNI, USC; studying a new mechanism of kidney-to-brain crosstalk and its role in the maintenance and repair of cerebral blood vessels in neurodegenerative diseases • Lon Schneider, Department of Neurology, USC; collaborating on the development of urinary CCN1 as a novel biomarker of cognitive impairment in aging and Alzheimer’s disease

Derek Sieburth • James Knowles, ZNI, USC; sequencing entire genomes of the nematode C. elegans to identify mutations that cause defects in synaptic transmission and profiling changes in gene expression patters in the nematode C. elegans in response to oxidative stress • Robert Chow, ZNI, USC; examining how calcium regulates the release of neurotransmitters in real time from living tissue (using Total Internal Reflection Fluorescence Microscopy)

Ansgar Siemer • Ralf Langen, ZNI, USC; studying the structure and dynamic of toxic huntingtin fibril • Kausik Si of Stowers Institute for Medical Research; studying the structure of the functional amyloid Orb2 responsible for long-term memory • Martin Kast, Department of Molecular, Microbiology, and Immunology, USC; Human papillomavirus membrane interaction • Janine Kirstein, FMP Berlin; huntingtin-chaperone interaction

44 Collaborations Huizhong Tao • Xiaohui Zhang, State Key Laboratory of Cognitive Neuroscience & Learning and IDG/McGovern Institute for Brain Research, Beijing Normal University, China; studying mechanisms underlying critical period dependent cortical plasticity • Jeannie Chen, ZNI, USC; studying cortical responses after reversal of retinal degeneration • Li Zhang, ZNI, USC; studying common inhibitory mechanisms underlying visual and auditory cortical processing • Ying Xiong, Chongqing Key Laboratory, Neurobiology, Third Military Medical University, China; studying synaptic mechanisms for functional heterogeneity of cortical neurons

Terrence Town • John Breitner and Judes Poirier, McGill University, Canada; We are working as a contractual group to determine efficacy and mechanism of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease • Tarek Fahmy, Yale University Department of Biomaterials; We have an R01 grant together to evaluate a next-generation nanoparticle drug delivery system for prevention and treatment of Alzheimer’s disease and pediatric brain cancer • Li-Huei Tsai, Harvard University HHMI Investigator; Collaboration to investigate aberrant cyclin- dependent kinase activation in our novel transgenic Alzheimer rat model • Erol Fikrig, Yale University HHMI Investigator; Collaboration to interrogate neuro-immune mechanisms of West Nile encephalitis • Richard A. Flavell, Yale University HHMI Investigator and National Academy member; Collaboration on developing mouse models with human immune systems as a critical tool to examine stem cell graft tolerance vs. rejection • Caleb ‘Tuck’ Finch, School of Gerontology, USC; working together to understand the role of pollution on brain inflammation and Alzheimer’s disease pathology in pre-clinical animal models • Helena Chui, Department of Neurology, USC; collaboratively validating observations that my group has made in mouse models using human Alzheimer patient samples • Paul Thompson, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, USC; we have an R01 grant together to collaboratively evaluate our TgF344-AD rat model using next-generation MRI- based imaging approaches • Russell Jacobs, ZNI, USC; we have an R01 grant together to perform both MRI and micro-PET imaging approaches to establish a “natural history” of disease evolution in our TgF344-AD rat model of Alzheimer’s disease • Berislav Zlokovic, ZNI, USC; collaborating to extend his findings with the blood-brain-barrier into our novel Alzheimer transgenic rat model

Collaborations 45 Tobias Ulmer • Woojin An, Biochemistry & Molecular Medicine, USC; collaborating on histone protein structure and interactions • Ralf Langen, ZNI, USC; collaborating on the role of huntingtin in Huntington’s disease • Chungho Kim, Korea University in Seoul; collaborating on integrin receptor cell biology

Kai Wang • James Knowles, ZNI, USC; evaluating biological and technical noises of single-neuron RNA-Seq data and benchmarking different bioinformatics algorithms on these data • Jiang Zhong, USC Dental School; evaluating variant calling and quantification of gene expression from RNA-Seq data

Li Zhang • Hongwei Dong, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, USC; studying corticostriatal projection and movement control • Huizhong Whit Tao, ZNI, USC; investigating imaging processing in the visual cortex • Qilong Ying, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, USC, generating transgenic rats • Pin Wang, Chemical Engineering, USC, engineering new AAV virus for circuit tracing • Andrew Hires, Biological Sciences, USC, neuromodulator function on sensory processing

Berislav Zlokovic • Arthur Toga, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, USC; imaging living human brain cerebrovascular system, BBB and structural connectivity • Paul Thompson, Departments of Neurology, Psychiatry & Behavioral Sciences and Engineering, USC; imaging in animal models of human diseases with vascular deficits • Helena Chui, Department of Neurology, USC: collaboration within USC Alzheimer’s Research Disease Center • Lon C. Schneider, Department of Psychiatry, USC; collaboration within Alzheimer’s Research Disease Center • Terrence Town, ZNI, USC; collaboration on BBB functions in the rat model of AD • Hong-Wei Dong, ZNI, USC; collaboration on effects of pericytes on mouse brain circuits • Russell Jacobs, ZNI, USC; collaboration on BBB and blood flow studies in models of neurological disorders • David M. Holtzman, Washington University in St. Louis; working on amyloid-beta metabolism and clearance in brain via LDLR receptors and role of apoE in amyloid-beta clearance • John Griffin, Scripps Institute; working on APC mechanisms in stroke • William Mack, ZNI, USC; collaborating on hypoperfusion injury to white matter • Meng Law, Department of Neuroradiology and Helena Chui, Department of Neurology, USC; working on MRI imaging of blood-brain barrier permeability in neurologically normal and MS patients and patients at risk for Alzheimer’s disease • Scott Fraser, Departments of Biological Sciences and Biomedical Engineering, USC and Andy McMahon, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, USC; working on systemis biology comparisons from Zebra fish to rodent models. • Justin Ichida, USC, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research; working on in vitro trial with 3K3A-APC in human C9-derived iMN as well as on iPSC-derived PICALM mutations in AD

46 Collaborations Berislav Zlokovic (cont.) • Rudy Tanzi, MGH Harvard Medical School; working on PICALM mutations in AD • Washington University Alzheimer’s Disease Research Center; collaborating on CSF biomarkers in individuals at risk for Alzheimer’s with and without mild cognitive impairment including APOE4 carriers and non-carriers, and PSEN1 carriers and non-carriers • Nunzio Pomara, New York Medical Center; examining CSF biomarkers of blood-brain barrier injury in cognitively normal and depressed individuals • Pat Lyden, Cedars Sinai; working on preparation for Phase 3 clinical trial for stroke with 3K2A-APC. • Caleb Finch of USC; examining the blood-brain barrier permeability by imaging in animal models exposed to environmental pollution • Jae Jung, Molecular, Microbiology, and Immunology, USC; working on brain-specific TRIpartite Motif protein 9 in stroke and brain trauma models and Zika virus and BBB • Ruchi Bajpai, School of Dentistry, USC, using stem cell technology working on pericyte dysfunction in Alzheimer’s disease • Michael Harrington, Huntington Medical Research Institute Pasadena; collaborating on CSF biomarkers and imaging blood-brain barrier integrity in APOE4 carriers and non-carriers • Daniel Nation, Department of Psychology, USC; working on CSF and imaging biomarkers in individuals at high risk for hypertension and effects of apoE genotype • John Morris, Washington University in St. Louis; collaborating on imaging and CSF biomarkers and APOE and PSEN1 genotype • Anne Fagan, Washington University in St. Louis; collaborating on CSF biomarkers and APOE and PSEN1 genotype • Tammie Benzinger, Washington University in St. Louis; working on imaging vascular biomarkers in mild cognitive impairment • Judy Pa, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, USC; working on structural and functional connectivity, neuroimaging, AD and MCI. • John Ringman, Neurology, USC; collaborating on AD, PSEN1, ADAD, imaging and biomarkers • Eric Reiman, Banner Alzheimer’s Institute, AZ; collaborating on neuroimaging, genomics, biomarkes, APOE genotype • Richard Caselli, Mayo Clinic, AZ; collaborating on neuroimaging, genomics and biomarkers • Anne Joutel, University of Paris, France; collaborating on imaging ColIV mutant mice • Joanna Wardlaw, University of Edinburgh, Scotland; collaborating on small vessel disease of the brain • Sandra Black, University of Toronto, Canada; collaborating on small vessel disease of the brain

Collaborations 47 Faculty Publications

The primary method for communicating scientific advancements is to document one’s research by writing a paper outlining the methods and resources applied to an experimental problem, reporting the findings and submitting this work to a journal whose audience is comprised of other researchers working in the same or similar field.

A typical scholarly, scientific journal article is peer-reviewed by a group of researchers who examine thoroughly the approach and techniques deployed, validate the data and ensure the conclusions are empirically sound. Most papers contain citations of previous work, upon which the current paper is Image credit: Jeannie Chen credit: Image based, building upon sometimes generations of scientists who have led the field to our current state of knowledge.

A journal’s impact factor is a measure of the frequency with which the average article in a journal has been cited in a particular year. The impact factor is calculated by dividing the number of citations in the current year to articles published in the two previous years by the total number of articles published in the two previous years. While the expectation is that all peer-reviewed publications move science forward, in some areas of study coverage is not as widespread and thus the impact factor of a journal in a highly specialized field will not necessarily have the same impact factor as the broader journals like Science and Nature. The number of papers an institution publishes in high-impact journals is one of several measures of productivity.

During the reporting period of 2017, ZNI researchers published 153 papers, with 12% in high impact journals.

Liu SJ, Horlbeck MA, Cho SW, Birk HS, Malatesta M, He D, Attenello F, Villalta JE, Cho MY, Chen Y, Mandegar MA, Olvera MP, Gilbert LA, Conklin BR, Chang HY, Weissman JS, Lim DA. CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells. Science. 2017 Jan 06; 355(6320). PMID: 27980086.

Bakhsheshian J, Jin DL, Chang KE, Strickland BA, Donoho DA, Cen S, Mack WJ, Attenello F, Christian EA, Zada G. Risk factors associated with the surgical management of craniopharyngiomas in pediatric patients: analysis of 1961 patients from a national registry database. Neurosurg Focus. 2016 Dec; 41(6):E8. PMID: 27903117.

48 Faculty Publications Attenello F, Mack WJ. Pitfalls of administrative database analysis are evident when assessing the ‘weekend effect’ in stroke. Evid Based Med. 2016 Nov 4. PMID: 27815303.

Attenello F, Tuchman A, Christian EA, Wen T, Chang KE, Nallapa S, Cen SY, Mack WJ, Krieger MD, McComb JG. Infection rate correlated with time to repair of open neural tube defects (myelomeningoceles): an institutional and national study. Childs Nerv Syst. 2016 Sep; 32(9):1675-81. doi: 10.1007/s00381-016-3165 PMID: 27444296.

Strickland BA, Attenello F, Russin JJ. Extracranial to intracranial bypass for the treatment of cerebral aneurysms in the pediatric population. J Clin Neurosci. 2016 Dec; 34:6-10. PMID: 27430415.

Fujii T, Moriel G, Kramer DR, Attenello F, Zada G. Prognostic factors of early outcome and discharge status in patients undergoing surgical intervention following traumatic intracranial hemorrhage. J Clin Neurosci. 2016 Sep; 31:152-6. doi: 10.1016/j.jocn.2016.03.007. Epub 2016 Jul 14. PMID: 27424129.

King JR, Velasquez JC, Torii M, Bonnin A. Effect of Maternal ±Citalopram Exposure on P11 Expression and Neurogenesis in the Mouse Fetal Brain. ACS Chem Neurosci. 2017 May 17;8(5):1019-1025. doi: 10.1021/ acschemneuro.6b00339. Epub 2017 Jan 13. PMID: 28076682

Muller CL, Anacker AM, Rogers TD, Goeden N, Keller EH, Forsberg CG, Kerr TM, Wender C, Anderson GM, Stanwood GD, Blakely RD, Bonnin A, Veenstra-VanderWeele J. Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment. Neuropsychopharmacology. 2017 Jan;42(2):427-436. doi: 10.1038/npp.2016.166. Epub 2016 Aug 23. PMID: 27550733

Brummelte S, Mc Glanaghy E, Bonnin A, Oberlander TF. Developmental changes in serotonin signaling: Implications for early brain function, behavior and adaptation. Neuroscience. 2017 Feb 7;342:212-231. doi: 10.1016/j.neuroscience.2016.02.037. Epub 2016 Feb 22. Review. PMID: 26905950

DeWitt JJ, Hecht PM, Grepo N, Wilkinson B, Evgrafov OV, Morris KV, Knowles JA, Campbell DB. Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells. Dev Neurosci. 2016;38(5):375-383. doi: 10.1159/000453258. Epub 2016 Dec 29.

DeWitt JJ, Grepo N, Wilkinson B, Evgrafov OV, Knowles JA, Campbell DB. Impact of the Autism- Associated Long Noncoding RNA MSNP1AS on Neuronal Architecture and Gene Expression in Human Neural Progenitor Cells. Genes (Basel). 2016 Sep 28;7(10). pii: E76. PMID: 27690106

Beversdorf, D.Q., Missouri Autism Summit Consortium (Wang, P., Barnes, G., Weisskopf, M., Hardan, A., Hu, V., Mazurek, M.O., Talebedizah, Z., Goldberg, W., Jones, K.L., Campbell, D.B., Feliciano, P., Spence, S., Muller, R.A., Brown, R.M.A., Kanne, S.M., Sohl, K., Smith, D.G. London, E., Bauman, M.L., and Amaral, D.G). Phenotyping, etiological factors, and biomarkers: toward precision medicine in autism spectrum disorder. Journal of Developmental & Behavioral Pediatrics. 37: 659-673. 2016. PMID: 27676697.

Geng, J., Wang, L., Lee, J, Chen, C-K., and Chang, K.T. Phosphorylation of Synaptojanin differentially regulates synaptic vesicle endocytosis of distinct vesicle pools. J Neurosci, 36(34):8882-94, 2016. PMCID:PMC4995302.

Faculty Publications 49 Lee, J.Y., Geng, J., Lee, J., and Chang, K.T. Activity-induced synaptic structural modifications by an activator of integrin signaling at the Drosophila neuromuscular junction. J Neurosci, 37(12):3246-3263. PMCID:PMC5373117.

Vinberg F, Wang T, De Maria A, Zhao H, Bassnett S, Chen J, Kefalov VJ. The Na+/Ca2+, K+ exchanger NCKX4 is required for efficient cone-mediated vision. Elife. 2017 Jun 26;6. pii: e24550. doi: 10.7554/ eLife.24550. [Epub ahead of print] PMID: 28650316

Rose K, Walston ST, Chen J. Separation of photoreceptor cell compartments in mouse retina for protein analysis. Mol Neurodegener. 2017 Apr 11;12(1):28. doi: 10.1186/s13024-017-0171-2. PMID: 28399904

Wang T, Tsang SH, Chen J. Two pathways of rod photoreceptor cell death induced by elevated cGMP. Hum Mol Genet. 2017 Jun 15;26(12):2299-2306. doi: 10.1093/hmg/ddx121. PMID: 28379353

Cho JH, Swanson CJ, Chen J, Li A, Lippert LG, Boye SE, Rose K, Sivaramakrishnan S, Chuong CM, Chow RH. The GCaMP-R Family of Genetically Encoded Ratiometric Calcium Indicators. ACS Chem Biol. 2017 Apr 21;12(4):1066-1074. doi: 10.1021/acschembio.6b00883. Epub 2017 Mar 1. PMID: 28195691

Lee AS, Brandhorst S, Rangel DF, Navarrete G, Cohen P, Longo VD, Chen J, Groshen S, Morgan TE, Dubeau L. Effects of Prolonged GRP78 Haploinsufficiency on Organ Homeostasis, Behavior, Cancer and Chemotoxic Resistance in Aged Mice. Sci Rep. 2017 Feb 1;7:40919. doi: 10.1038/srep40919. PMID: 28145503

Sakurai K, Vinberg F, Wang T, Chen J, Kefalov VJ. The Na(+)/Ca(2+), K(+) exchanger 2 modulates mammalian cone phototransduction. Sci Rep. 2016 Sep 1;6:32521. doi: 10.1038/srep32521. PMID: 27580676

Chang YC, Walston ST, Chow RH, Weiland JD. In vivo characterization of genetic expression of virus- transduced calcium indicators in retinal ganglion cells using a low-cost funduscope. Conf Proc IEEE Eng Med Biol Soc. 2016 Aug;2016:1316-1319. doi: 10.1109/EMBC.2016.7590949. PMID: 28261004

Lim HG, Li Y, Lin MY, Yoon C, Lee C, Jung H, Chow RH, Shung KK. IEEE Trans Ultrason Ferroelectr Freq Control. 2016 Aug 16. PMID: 27541791

Dueck HR, Ai R, Camarena A, Ding B, Dominguez R, Evgrafov OV, Fan JB, Fisher SA, Herstein JS, Kim TK, Kim JM, Lin MY, Liu R, Mack WJ, McGroty S, Nguyen JD, Salathia N, Shallcross J, Souaiaia T, Spaethling JM, Walker CP, Wang J, Wang K, Wang W, Wildberg A, Zheng L, Chow RH, Eberwine J, Knowles JA, Zhang K, Kim J. Assessing characteristics of RNA amplification methods for single cell RNA sequencing. BMC Genomics. 2016 Nov 24;17(1):966. PMID: 27881084

Okada AK, Teranishi K, Isas JM, Bedrood S, Chow RH (co-senior author), Langen R. Diabetic Risk Factors Promote Islet Amyloid Polypeptide Misfolding by a Common, Membrane-mediated Mechanism. Sci Rep. 2016 Aug 17; 6:31094. doi: 10.1038/srep31094. PMID: 27531121

50 Faculty Publications Li J, Wilkinson B, Clementel VA, Hou J, O’Dell TJ, Coba MP. Long-term potentiation modulates synaptic phosphorylation networks and reshapes the structure of the postsynaptic interactome. Sci Signal. 2016 Aug 9;9(440):rs8. doi: 10.1126/scisignal.aaf6716. PMID: 27507650

Xie Z, Li J, Baker J, Eagleson KL, Coba MP, Levitt P. Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse. Biol Psychiatry. 2016 Dec 15;80(12):933-942. doi: 10.1016/j.biopsych.2016.02.022. Epub 2016 Feb 26. PMID: 27086544

Rodriguez-Broadbent H, Law PJ, Sud A, Palin K, Tuupanen S, Gylfe A, Hänninen UA, Cajuso T, Tanskanen T, Kondelin J, Kaasinen E, Sarin AP, Ripatti S, Eriksson JG, Rissanen H, Knekt P, Pukkala E, Jousilahti P, Salomaa V, Palotie A, Renkonen-Sinisalo L, Lepistö A, Böhm J, Mecklin JP, Al-Tassan NA, Palles C, Martin L, Barclay E, Farrington SM, Timofeeva MN, Meyer BF, Wakil SM, Campbell H, Smith CG, Idziaszczyk S, Maughan TS, Kaplan R, Kerr R, Kerr D, Passarelli MN, Figueiredo JC, Buchanan DD, Win AK, Hopper JL, Jenkins MA, Lindor NM, Newcomb PA, Gallinger S, Conti D, Schumacher F, Casey G, Aaltonen LA, Cheadle JP, Tomlinson IP, Dunlop MG, Houlston RS. Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer. Int J Cancer. 2017 Jun 15;140(12):2701-2708. doi: 10.1002/ijc.30709. Epub 2017 Apr 6. PubMed PMID: 28340513.

Wang H, Schmit SL, Haiman CA, Keku TO, Kato I, Palmer JR, van den Berg D, Wilkens LR, Burnett T, Conti DV, Schumacher FR, Signorello LB, Blot WJ, Zanetti KA, Harris C, Pande M, Berndt SI, Newcomb PA, West DW, Haile R, Stram DO, Figueiredo JC; Hispanic Colorectal Cancer Study., Le Marchand L. Novel colon cancer susceptibility variants identified from a genome-wide association study in African Americans. Int J Cancer. 2017 Jun 15;140(12):2728-2733. doi: 10.1002/ijc.30687. Epub 2017 Mar 28. PubMed PMID: 28295283; PubMed Central PMCID: PMC5505639.

Ng MCY, Graff M, Lu Y, Justice AE, Mudgal P, Liu CT, Young K, Yanek LR, Feitosa MF, Wojczynski MK, Rand K, Brody JA, Cade BE, Dimitrov L, Duan Q, Guo X, Lange LA, Nalls MA, Okut H, Tajuddin SM, Tayo BO, Vedantam S, Bradfield JP, Chen G, Chen WM, Chesi A, Irvin MR, Padhukasahasram B, Smith JA, Zheng W, Allison MA, Ambrosone CB, Bandera EV, Bartz TM, Berndt SI, Bernstein L, Blot WJ, Bottinger EP, Carpten J, Chanock SJ, Chen YI, Conti DV, Cooper RS, Fornage M, Freedman BI, Garcia M, Goodman PJ, Hsu YH, Hu J, Huff CD, Ingles SA, John EM, Kittles R, Klein E, Li J, McKnight B, Nayak U, Nemesure B, Ogunniyi A, Olshan A, Press MF, Rohde R, Rybicki BA, Salako B, Sanderson M, Shao Y, Siscovick DS, Stanford JL, Stevens VL, Stram A, Strom SS, Vaidya D, Witte JS, Yao J, Zhu X, Ziegler RG, Zonderman AB, Adeyemo A, Ambs S, Cushman M, Faul JD, Hakonarson H, Levin AM, Nathanson KL, Ware EB, Weir DR, Zhao W, Zhi D; Bone Mineral Density in Childhood Study (BMDCS) Group., Arnett DK, Grant SFA, Kardia SLR, Oloapde OI, Rao DC, Rotimi CN, Sale MM, Williams LK, Zemel BS, Becker DM, Borecki IB, Evans MK, Harris TB, Hirschhorn JN, Li Y, Patel SR, Psaty BM, Rotter JI, Wilson JG, Bowden DW, Cupples LA, Haiman CA, Loos RJF, North KE. Discovery and fine-mapping of adiposity loci using high density imputation of genome- wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium. PLoS Genet. 2017 Apr 21;13(4):e1006719. doi: 10.1371/journal.pgen.1006719. eCollection 2017 Apr. PubMed PMID: 28430825; PubMed Central PMCID: PMC5419579.

Faculty Publications 51 Amos CI, Dennis J, Wang Z, Byun J, Schumacher FR, Gayther SA, Casey G, Hunter DJ, Sellers TA, Gruber SB, Dunning AM, Michailidou K, Fachal L, Doheny K, Spurdle AB, Li Y, Xiao X, Romm J, Pugh E, Coetzee GA, Hazelett DJ, Bojesen SE, Caga-Anan C, Haiman CA, Kamal A, Luccarini C, Tessier D, Vincent D, Bacot F, Van Den Berg DJ, Nelson S, Demetriades S, Goldgar DE, Couch FJ, Forman JL, Giles GG, Conti DV, Bickeböller H, Risch A, Waldenberger M, Brüske-Hohlfeld I, Hicks BD, Ling H, McGuffog L, Lee A, Kuchenbaecker K, Soucy P, Manz J, Cunningham JM, Butterbach K, Kote-Jarai Z, Kraft P, FitzGerald L, Lindström S, Adams M, McKay JD, Phelan CM, Benlloch S, Kelemen LE, Brennan P, Riggan M, O’Mara TA, Shen H, Shi Y, Thompson DJ, Goodman MT, Nielsen SF, Berchuck A, Laboissiere S, Schmit SL, Shelford T, Edlund CK, Taylor JA, Field JK, Park SK, Offit K, Thomassen M, Schmutzler R, Ottini L, Hung RJ, Marchini J, Amin Al Olama A, Peters U, Eeles RA, Seldin MF, Gillanders E, Seminara D, Antoniou AC, Pharoah PD, Chenevix-Trench G, Chanock SJ, Simard J, Easton DF. The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers. Cancer Epidemiol Biomarkers Prev. 2017 Jan;26(1):126-135. doi: 10.1158/1055-9965.EPI-16-0106. Epub 2016 Oct 3. PubMed PMID: 27697780; PubMed Central PMCID: PMC5224974.

Rand KA, Song C, Dean E, Serie DJ, Curtin K, Sheng X, Hu D, Huff CA, Bernal-Mizrachi L, Tomasson MH, Ailawadhi S, Singhal S, Pawlish K, Peters ES, Bock CH, Stram A, Van Den Berg DJ, Edlund CK, Conti DV, Zimmerman T, Hwang AE, Huntsman S, Graff J, Nooka A, Kong Y, Pregja SL, Berndt SI, Blot WJ, Carpten J, Casey G, Chu L, Diver WR, Stevens VL, Lieber MR, Goodman PJ, Hennis AJ, Hsing AW, Mehta J, Kittles RA, Kolb S, Klein EA, Leske C, Murphy AB, Nemesure B, Neslund-Dudas C, Strom SS, Vij R, Rybicki BA, Stanford JL, Signorello LB, Witte JS, Ambrosone CB, Bhatti P, John EM, Bernstein L, Zheng W, Olshan AF, Hu JJ, Ziegler RG, Nyante SJ, Bandera EV, Birmann BM, Ingles SA, Press MF, Atanackovic D, Glenn MJ, Cannon-Albright LA, Jones B, Tricot G, Martin TG, Kumar SK, Wolf JL, Deming Halverson SL, Rothman N, Brooks-Wilson AR, Rajkumar SV, Kolonel LN, Chanock SJ, Slager SL, Severson RK, Janakiraman N, Terebelo HR, Brown EE, De Roos AJ, Mohrbacher AF, Colditz GA, Giles GG, Spinelli JJ, Chiu BC, Munshi NC, Anderson KC, Levy J, Zonder JA, Orlowski RZ, Lonial S, Camp NJ, Vachon CM, Ziv E, Stram DO, Hazelett DJ, Haiman CA, Cozen W. A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci. Cancer Epidemiol Biomarkers Prev. 2016 Dec;25(12):1609-1618. Epub 2016 Sep 1. PubMed PMID: 27587788; PubMed Central PMCID: PMC5524541.

Multiple sclerosis (MS) is a chronic The nerve damage causes neurological condition many different symptoms, where the immune including vision loss, pain, system attacks myelin, fatigue, and impaired a protective substance coordination. that covers nerves.

52 Faculty Publications Brooks JD, John EM, Mellemkjaer L, Lynch CF, Knight JA, Malone KE, Reiner AS, Bernstein L, Liang X, Shore RE, Stovall M; WECARE Study Collaborative Group., Bernstein JL. Body mass index, weight change, and risk of second primary breast cancer in the WECARE study: influence of estrogen receptor status of the first breast cancer. Cancer Med. 2016 Nov;5(11):3282-3291. doi: 10.1002/cam4.890. Epub 2016 Oct 3. PubMed PMID: 27700016; PubMed Central PMCID: PMC5119984.

Yang B, Thrift AP, Figueiredo JC, Jenkins MA, Schumacher FR, Conti DV, Lin Y, Win AK, Limburg PJ, Berndt SI, Brenner H, Chan AT, Chang-Claude J, Hoffmeister M, Hudson TJ, Marchand LL, Newcomb PA, Slattery ML, White E, Peters U, Casey G, Campbell PT. Common variants in the obesity-associated genes FTO and MC4R are not associated with risk of colorectal cancer. Cancer Epidemiol. 2016 Oct;44:1-4. doi: 10.1016/j. canep.2016.07.003. Epub 2016 Jul 21. PubMed PMID: 27449576; PubMed Central PMCID: PMC5125024.

Fehringer G, Kraft P, Pharoah PD, Eeles RA, Chatterjee N, Schumacher FR, Schildkraut JM, Lindström S, Brennan P, Bickeböller H, Houlston RS, Landi MT, Caporaso N, Risch A, Amin Al Olama A, Berndt SI, Giovannucci EL, Grönberg H, Kote-Jarai Z, Ma J, Muir K, Stampfer MJ, Stevens VL, Wiklund F, Willett WC, Goode EL, Permuth JB, Risch HA, Reid BM, Bezieau S, Brenner H, Chan AT, Chang-Claude J, Hudson TJ, Kocarnik JK, Newcomb PA, Schoen RE, Slattery ML, White E, Adank MA, Ahsan H, Aittomäki K, Baglietto L, Blomquist C, Canzian F, Czene K, Dos-Santos-Silva I, Eliassen AH, Figueroa JD, Flesch-Janys D, Fletcher O, Garcia-Closas M, Gaudet MM, Johnson N, Hall P, Hazra A, Hein R, Hofman A, Hopper JL, Irwanto A, Johansson M, Kaaks R, Kibriya MG, Lichtner P, Liu J, Lund E, Makalic E, Meindl A, Müller-Myhsok B, Muranen TA, Nevanlinna H, Peeters PH, Peto J, Prentice RL, Rahman N, Sanchez MJ, Schmidt DF, Schmutzler RK, Southey MC, Tamimi R, Travis RC, Turnbull C, Uitterlinden AG, Wang Z, Whittemore AS, Yang XR, Zheng W, Buchanan DD, Casey G, Conti DV, Edlund CK, Gallinger S, Haile RW, Jenkins M, Le Marchand L, Li L, Lindor NM, Schmit SL, Thibodeau SN, Woods MO, Rafnar T, Gudmundsson J, Stacey SN, Stefansson K, Sulem P, Chen YA, Tyrer JP, Christiani DC, Wei Y, Shen H, Hu Z, Shu XO, Shiraishi K, Takahashi A, Bossé Y, Obeidat M, Nickle D, Timens W, Freedman ML, Li Q, Seminara D, Chanock SJ, Gong J, Peters U, Gruber SB, Amos CI, Sellers TA, Easton DF, Hunter DJ, Haiman CA, Henderson BE, Hung RJ; Ovarian Cancer Association Consortium (OCAC).; PRACTICAL Consortium.; Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON).; Colorectal Transdisciplinary (CORECT) Study.; African American Breast Cancer Consortium (AABC) and African Ancestry Prostate Cancer Consortium (AAPC).. Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations. Cancer Res. 2016 Sep 1;76(17):5103-14. doi: 10.1158/0008-5472.CAN-15-2980. Epub 2016 Apr 20. PubMed PMID: 27197191; PubMed Central PMCID: PMC5010493.

Baurley JW, Edlund CK, Pardamean CI, Conti DV, Krasnow R, Javitz HS, Hops H, Swan GE, Benowitz NL, Bergen AW. Genome-Wide Association of the Laboratory-Based Nicotine Metabolite Ratio in Three Ancestries. Nicotine Tob Res. 2016 Sep;18(9):1837-1844. doi: 10.1093/ntr/ntw117. Epub 2016 Apr 25. PubMed PMID: 27113016; PubMed Central PMCID: PMC4978985.

Jarvis D, Mitchell JS, Law PJ, Palin K, Tuupanen S, Gylfe A, Hänninen UA, Cajuso T, Tanskanen T, Kondelin J, Kaasinen E, Sarin AP, Kaprio J, Eriksson JG, Rissanen H, Knekt P, Pukkala E, Jousilahti P, Salomaa V, Ripatti S, Palotie A, Järvinen H, Renkonen-Sinisalo L, Lepistö A, Böhm J, Meklin JP, Al-Tassan NA, Palles C, Martin L, Barclay E, Farrington SM, Timofeeva MN, Meyer BF, Wakil SM, Campbell H, Smith CG, Idziaszczyk S, Maughan TS, Kaplan R, Kerr R, Kerr D, Buchanan DD, Win AK, Hopper JL, Jenkins MA, Lindor NM, Newcomb PA, Gallinger S, Conti D, Schumacher F, Casey G, Taipale J, Aaltonen LA, Cheadle JP, Dunlop MG, Tomlinson IP, Houlston RS. Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer. Br J Cancer. 2016 Jul 12;115(2):266-72. doi: 10.1038/bjc.2016.188. Epub 2016 Jun 23. PubMed PMID: 27336604; PubMed Central PMCID: PMC4947703.

Faculty Publications 53 Zhang P, Lewinger JP, Conti D, Morrison JL, Gauderman WJ. Detecting Gene-Environment Interactions for a Quantitative Trait in a Genome-Wide Association Study. Genet Epidemiol. 2016 Jul;40(5):394-403. doi: 10.1002/gepi.21977. Epub 2016 May 27. PubMed PMID: 27230133; PubMed Central PMCID: PMC5108681.

Han Y, Rand KA, Hazelett DJ, Ingles SA, Kittles RA, Strom SS, Rybicki BA, Nemesure B, Isaacs WB, Stanford JL, Zheng W, Schumacher FR, Berndt SI, Wang Z, Xu J, Rohland N, Reich D, Tandon A, Pasaniuc B, Allen A, Quinque D, Mallick S, Notani D, Rosenfeld MG, Jayani RS, Kolb S, Gapstur SM, Stevens VL, Pettaway CA, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, John EM, Murphy AB, Signorello LB, Carpten J, Leske MC, Wu SY, Hennis AJM, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Zheng SL, Witte JS, Casey G, Lubwama A, Pooler LC, Sheng X, Coetzee GA, Cook MB, Chanock SJ, Stram DO, Watya S, Blot WJ, Conti DV, Henderson BE, Haiman CA. Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. J Natl Cancer Inst. 2016 Jan 27;108(7). doi: 10.1093/jnci/djv431. Print 2016 Jul. PubMed PMID: 26823525; PubMed Central PMCID: PMC4948565.

Hintiryan H, Foster NN, Bowman I, Bay M, Song MY, Gou L, Yamashita S, Bienkowski MS, Zingg B, Zhu M, Yang XW, Shih JC, Toga AW, Dong HW. The mouse cortico-striatal projectome. Nat Neurosci. 2016 Aug;19(8):1100- 14. doi: 10.1038/nn.4332. Epub 2016 Jun 20. PMID: 27322419

Condro MC, Matynia A, Foster NN, Ago Y, Rajbhandari AK, Van C, Jayaram B, Parikh S, Diep AL, Nguyen E, May V, Dong HW, Waschek JA. High-resolution characterization of a PACAP-EGFP transgenic mouse model for mapping PACAP-expressing neurons. J Comp Neurol. 2016 Dec 15;524(18):3827-3848. doi: 10.1002/ cne.24035. Epub 2016 Jun 3.PMID: 27197019

Miller C, Sepehrband F, Williams C, Talishinsky A, Mehta S, Bienkowski M, Gonzalez-Zacarias C, Barnes S, Jacobs R, Toga A, Dong HW, Clark K. ZOom^ 3: A three-dimensional super-resolution technique to map brain connectivity from millimeters to molecules. Journal of Neuropathology and Experimental Neurology. 75 (6), 567-616, 2016.

Kari E, Schrauwen I, Llaci L, Fisher LM, Go JL, Naymik M, Knowles JA, Huentelman MJ, Friedman RA. Compound heterozygous mutations in MASP1 in a deaf child with absent cochlear nerves. Neurol Genet. 2017 May 11;3(3):e153. doi: 10.1212/NXG.0000000000000153. eCollection 2017 Jun. PMID: 28534045

Lavinsky J, Aaron KA, Christian E, Go JL, Hurth K, Giannotta SL, Friedman RA. Solitary Plasmacytoma in the Internal Auditory Canal and Cerebellopontine Angle Mimicking Meningioma. Otol Neurotol. 2016 Dec;37(10):e400-e401. PMID: 26457817

Lavinsky J, Ge M, Crow AL, Pan C, Wang J, Salehi P, Myint A, Eskin E, Allayee H, Lusis AJ, Friedman RA. The Genetic Architecture of Noise-Induced Hearing Loss: Evidence for a Gene-by-Environment Interaction. G3 (Bethesda). 2016 Oct 13;6(10):3219-3228. doi: 10.1534/g3.116.032516.PMID: 27520957

Salehi P, Myint A, Kim YJ, Ge MX, Lavinsky J, Ho MK, Crow AL, Cruz C, Monges-Hernadez M, Wang J, Hartiala J, Zhang LI, Allayee H, Lusis AJ, Ohyama T, Friedman RA. Genome-Wide Association Analysis Identifies Dcc as an Essential Factor in the Innervation of the Peripheral Vestibular System in Inbred Mice. J Assoc Res Otolaryngol. 2016 Oct;17(5):417-31. doi: 10.1007/s10162-016-0578-4. Epub 2016 Aug 18. PMID: 27539716

Thylur DS, Jacobs RE, Go JL, Toga AW, Niparko JK. Ultra-High-Field Magnetic Resonance Imaging of the Human Inner Ear at 11.7 Tesla. Otol Neurotol. 2017;38(1):133-8. Epub 2016/10/19. doi: 10.1097/ mao.0000000000001242. PubMed PMID: 27755367; PMCID: PMC5154835.

54 Faculty Publications Santos R, Kawauchi S, Jacobs RE, Lopez-Burks ME, Choi H, Wikenheiser J, Hallgrimsson B, Jamniczky HA, Fraser SE, Lander AD, Calof AL. Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects. Plos Biol. 2016;14(9):e2000197. Epub 2016/09/09. doi: 10.1371/journal.pbio.2000197. PubMed PMID: 27606604; PMCID: PMC5016002.

Kalluri R, Monges-Hernandez M. Spatial Gradients in the Size of Inner Hair Cell Ribbons Emerge Before the Onset of Hearing in Rats. J Assoc Res Otolaryngol. 2017 Jun;18(3):399-413. doi: 10.1007/s10162-017- 0620-1. Epub 2017 Mar 30. PMID: 28361374

Hight AE, Kalluri R. A biophysical model examining the role of low-voltage-activated potassium currents in shaping the responses of vestibular ganglion neurons. J Neurophysiol. 2016 Aug 1;116(2):503-21. doi: 10.1152/jn.00107.2016. Epub 2016 Apr 27. PMID: 27121577

Huang AY, Yu D, Davis LK, Sul JH, Tsetsos F, Ramensky V, Zelaya I, Ramos EM, Osiecki L, Chen JA, McGrath LM, Illmann C, Sandor P, Barr CL, Grados M, Singer HS, Nöthen MM, Hebebrand J, King RA, Dion Y, Rouleau G, Budman CL, Depienne C, Worbe Y, Hartmann A, Müller-Vahl KR, Stuhrmann M, Aschauer H, Stamenkovic M, Schloegelhofer M, Konstantinidis A, Lyon GJ, McMahon WM, Barta C, Tarnok Z, Nagy P, Batterson JR, Rizzo R, Cath DC, Wolanczyk T, Berlin C, Malaty IA, Okun MS, Woods DW, Rees E, Pato CN, Pato MT, Knowles JA, Posthuma D, Pauls DL, Cox NJ, Neale BM, Freimer NB, Paschou P, Mathews CA, Scharf JM, Coppola G; Tourette Syndrome Association International Consortium for Genetics (TSAICG); Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI). Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. Neuron. 2017 Jun 21;94(6):1101-1111.e7. doi: 10.1016/j.neuron.2017.06.010.PMID: 28641109

Samuels J, Bienvenu OJ, Krasnow J, Wang Y, Grados MA, Cullen B, Goes FS, Maher B, Greenberg BD, McLaughlin NC, Rasmussen SA, Fyer AJ, Knowles JA, Nestadt P, McCracken JT, Piacentini J, Geller D, Pauls DL, Stewart SE, Murphy DL, Shugart YY, Kamath V, Bakker A, Riddle MA, Nestadt G. An investigation of doubt in obsessive-compulsive disorder. Compr Psychiatry. 2017 May;75:117-124. doi: 10.1016/j.comppsych.2017.03.004. Epub 2017 Mar 12. PMID: 28359017

Bigdeli TB, Ripke S, Peterson RE, Trzaskowski M, Bacanu SA, Abdellaoui A, Andlauer TF, Beekman AT, Berger K, Blackwood DH, Boomsma DI, Breen G, Buttenschøn HN, Byrne EM, Cichon S, Clarke TK, Couvy-Duchesne B, Craddock N, de Geus EJ, Degenhardt F, Dunn EC, Edwards AC, Fanous AH, Forstner AJ, Frank J, Gill M, Gordon SD, Grabe HJ, Hamilton SP, Hardiman O, Hayward C, Heath AC, Henders AK, Herms S, Hickie IB, Hoffmann P, Homuth G, Hottenga JJ, Ising M, Jansen R, Kloiber S, Knowles JA, Lang M, Li QS, Lucae S, MacIntyre DJ, Madden PA, Martin NG, McGrath PJ, McGuffin P, McIntosh AM, Medland SE, Mehta D, Middeldorp CM, Milaneschi Y, Montgomery GW, Mors O, Müller-Myhsok B, Nauck M, Nyholt DR, Nöthen MM, Owen MJ, Penninx BW, Pergadia ML, Perlis RH, Peyrot WJ, Porteous DJ, Potash JB, Rice JP, Rietschel M, Riley BP, Rivera M, Schoevers R, Schulze TG, Shi J, Shyn SI, Smit JH, Smoller JW, Streit F, Strohmaier J, Teumer A, Treutlein J, Van der Auwera S, van Grootheest G, van Hemert AM, Völzke H, Webb BT, Weissman MM, Wellmann J, Willemsen G, Witt SH, Levinson DF, Lewis CM, Wray NR, Flint J, Sullivan PF, Kendler KS. Genetic effects influencing risk for major depressive disorder in China and Europe. Transl Psychiatry. 2017 Mar 28;7(3):e1074. doi: 10.1038/tp.2016.292. PMID: 28350396

Faculty Publications 55 Ritter ML, Guo W, Samuels JF, Wang Y, Nestadt PS, Krasnow J, Greenberg BD, Fyer AJ, McCracken JT, Geller DA, Murphy DL, Knowles JA, Grados MA, Riddle MA, Rasmussen SA, McLaughlin NC, Nurmi EL, Askland KD, Cullen B, Piacentini J, Pauls DL, Bienvenu J, Stewart E, Goes FS, Maher B, Pulver AE, Mattheisen M, Qian J, Nestadt G, Shugart YY. Genome Wide Association Study (GWAS) between Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD). Front Mol Neurosci. 2017 Mar 23;10:83. doi: 10.3389/fnmol.2017.00083. eCollection 2017. PMID: 28386217

McLaughlin RL, Schijven D, van Rheenen W, van Eijk KR, O’Brien M, Kahn RS, Ophoff RA, Goris A, Bradley DG, Al-Chalabi A, van den Berg LH, Luykx JJ, Hardiman O, Veldink JH; Project MinE GWAS Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nat Commun. 2017 Mar 21;8:14774. doi: 10.1038/ ncomms14774. PMID: 28322246

Chen D, Bienvenu OJ, Krasnow J, Wang Y, Grados MA, Cullen B, Goes FS, Maher B, Greenberg BD, McLaughlin NC, Rasmussen SA, Fyer AJ, Knowles JA, McCracken JT, Piacentini J, Geller D, Pauls DL, Stewart SE, Murphy DL, Shugart YY, Riddle MA, Nestadt G, Samuels J. Parental bonding and hoarding in obsessive-compulsive disorder. Compr Psychiatry. 2017 Feb;73:43-52. doi: 10.1016/j. comppsych.2016.11.004. Epub 2016 Nov 14. PMID: 27915218

Ding SL, Royall JJ, Sunkin SM, Ng L, Facer BA, Lesnar P, Guillozet-Bongaarts A, McMurray B, Szafer A, Dolbeare TA, Stevens A, Tirrell L, Benner T, Caldejon S, Dalley RA, Dee N, Lau C, Nyhus J, Reding M, Riley ZL, Sandman D, Shen E, van der Kouwe A, Varjabedian A, Write M, Zollei L, Dang C, Knowles JA, Koch C, Phillips JW, Sestan N, Wohnoutka P, Zielke HR, Hohmann JG, Jones AR, Bernard A, Hawrylycz MJ, Hof PR, Fischl B, LeinReference ES. Comprehensive cellular-resolution atlas of the adult human brain. J Comp Neurol. 2017 Feb 1;525(2):407. doi: 10.1002/cne.24130. PMID: 27917481

Diagram showing a role the Sieburth lab has recently identified for electrical synapses formed by the GAP junction protein INX-1/Cx36 in electrically coupling two neurons to promote neurotransmitter release in an ultradian circuit. Image credit: Derek Sieburth Derek credit: Image

56 Faculty Publications Charney AW, Ruderfer DM, Stahl EA, Moran JL, Chambert K, Belliveau RA, Forty L, Gordon-Smith K, Di Florio A, Lee PH, Bromet EJ, Buckley PF, Escamilla MA, Fanous AH, Fochtmann LJ, Lehrer DS, Malaspina D, Marder SR, Morley CP, Nicolini H, Perkins DO, Rakofsky JJ, Rapaport MH, Medeiros H, Sobell JL, Green EK, Backlund L, Bergen SE, Juréus A, Schalling M, Lichtenstein P, Roussos P, Knowles JA, Jones I, Jones LA, Hultman CM, Perlis RH, Purcell SM, McCarroll SA, Pato CN, Pato MT, Craddock N, Landén M, Smoller JW, Sklar P. Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Transl Psychiatry. 2017 Jan 10;7(1):e993. doi: 10.1038/tp.2016.242. PMID: 28072414

Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, Antaki D, Shetty A, Holmans PA, Pinto D, Gujral M, Brandler WM, Malhotra D, Wang Z, Fajarado KVF, Maile MS, Ripke S, Agartz I, Albus M, Alexander M, Amin F, Atkins J, Bacanu SA, Belliveau RA Jr, Bergen SE, Bertalan M, Bevilacqua E, Bigdeli TB, Black DW, Bruggeman R, Buccola NG, Buckner RL, Bulik-Sullivan B, Byerley W, Cahn W, Cai G, Cairns MJ, Campion D, Cantor RM, Carr VJ, Carrera N, Catts SV, Chambert KD, Cheng W, Cloninger CR, Cohen D, Cormican P, Craddock N, Crespo-Facorro B, Crowley JJ, Curtis D, Davidson M, Davis KL, Degenhardt F, Del Favero J, DeLisi LE, Dikeos D, Dinan T, Djurovic S, Donohoe G, Drapeau E, Duan J, Dudbridge F, Eichhammer P, Eriksson J, Escott-Price V, Essioux L, Fanous AH, Farh KH, Farrell MS, Frank J, Franke L, Freedman R, Freimer NB, Friedman JI, Forstner AJ, Fromer M, Genovese G, Georgieva L, Gershon ES, Giegling I, Giusti-Rodríguez P, Godard S, Goldstein JI, Gratten J, de Haan L, Hamshere ML, Hansen M, Hansen T, Haroutunian V, Hartmann AM, Henskens FA, Herms S, Hirschhorn JN, Hoffmann P, Hofman A, Huang H, Ikeda M, Joa I, Kähler AK, Kahn RS, Kalaydjieva L, Karjalainen J, Kavanagh D, Keller MC, Kelly BJ, Kennedy JL, Kim Y, Knowles JA, Konte B, Laurent C, Lee P, Lee SH, Legge SE, Lerer B, Levy DL, Liang KY, Lieberman J, Lönnqvist J, Loughland CM, Magnusson PKE, Maher BS, Maier W, Mallet J, Mattheisen M, Mattingsdal M, McCarley RW, McDonald C, McIntosh AM, Meier S, Meijer CJ, Melle I, Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V, Mokrab Y, Morris DW, Müller-Myhsok B, Murphy KC, Murray RM, Myin-Germeys I, Nenadic I, Nertney DA, Nestadt G, Nicodemus KK, Nisenbaum L, Nordin A, O’Callaghan E, O’Dushlaine C, Oh SY, Olincy A, Olsen L, O’Neill FA, Van Os J, Pantelis C, Papadimitriou GN, Parkhomenko E, Pato MT, Paunio T; Psychosis Endophenotypes International Consortium, Perkins DO, Pers TH, Pietiläinen O, Pimm J, Pocklington AJ, Powell J, Price A, Pulver AE, Purcell SM, Quested D, Rasmussen HB, Reichenberg A, Reimers MA, Richards AL, Roffman JL, Roussos P, Ruderfer DM, Salomaa V, Sanders AR, Savitz A, Schall U, Schulze TG, Schwab SG, Scolnick EM, Scott RJ, Seidman LJ, Shi J, Silverman JM, Smoller JW, Söderman E, Spencer CCA, Stahl EA, Strengman E, Strohmaier J, Stroup TS, Suvisaari J, Svrakic DM, Szatkiewicz JP, Thirumalai S, Tooney PA, Veijola J, Visscher PM, Waddington J, Walsh D, Webb BT, Weiser M, Wildenauer DB, Williams NM, Williams S, Witt SH, Wolen AR, Wormley BK, Wray NR, Wu JQ, Zai CC, Adolfsson R, Andreassen OA, Blackwood DHR, Bramon E, Buxbaum JD, Cichon S, Collier DA, Corvin A, Daly MJ, Darvasi A, Domenici E, Esko T, Gejman PV, Gill M, Gurling H, Hultman CM, Iwata N, Jablensky AV, Jönsson EG, Kendler KS, Kirov G, Knight J, Levinson DF, Li QS, McCarroll SA, McQuillin A, Moran JL, Mowry BJ, Nöthen MM, Ophoff RA, Owen MJ, Palotie A, Pato CN, Petryshen TL, Posthuma D, Rietschel M, Riley BP, Rujescu D, Sklar P, St Clair D, Walters JTR, Werge T, Sullivan PF, O’Donovan MC, Scherer SW, Neale BM, Sebat J; CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017 Jan;49(1):27-35. doi: 10.1038/ng.3725. Epub 2016 Nov 21. PMID: 27869829

Faculty Publications 57 Park JM, Samuels JF, Grados MA, Riddle MA, Bienvenu OJ, Goes FS, Cullen B, Wang Y, Krasnow J, Murphy DL, Rasmussen SA, McLaughlin NC, Piacentini J, Pauls DL, Stewart SE, Shugart YY, Maher B, Pulver AE, Knowles JA, Greenberg BD, Fyer AJ, McCracken JT, Nestadt G, Geller DA. ADHD and executive functioning deficits in OCD youths who hoard. J Psychiatr Res. 2016 Nov;82:141-8. doi: 10.1016/j.jpsychires.2016.07.024. Epub 2016 Jul 30. PMID: 27501140

Melo AA, Hegde BG, Shah C, Larsson E, Isas JM, Kunz S, Lundmark R, Langen R, Daumke O.Structural insights into the activation mechanism of dynamin-like EHD ATPases. Proc Natl Acad Sci U S A. 2017 May 30;114(22):5629-5634. doi: 10.1073/pnas.1614075114. Epub 2017 Feb 22. PMID: 28228524

Cervantes, S.A., Bajakian, T.H., Conrad-Soria, M.A., Falk, A.S., Service, R.J., Langen, R., Siemer, A.B. Identification and Structural Characterization of the N-terminal Orb2A Amyloid Core. (2016) Scientific Reports, 6, 38265, PMID: 27922050

Fisette O, Päslack C, Barnes R, Isas JM, Langen R, Heyden M, Han S, Schäfer LV. Hydration Dynamics of a Peripheral Membrane Protein. J Am Chem Soc. 2016 Sep 14;138(36):11526-35. doi: 10.1021/ jacs.6b07005. Epub 2016 Sep 2. PMID: 27548572

Donoho DA, Wen T, Liu J, Zarabi H, Christian E, Cen S, Zada G, McComb JG, Krieger MD, Mack WJ, Attenello FJ. The effect of NACHRI children’s hospital designation on outcome in pediatric malignant brain tumors. J Neurosurg Pediatr. 2017 Jun 2:1-9. doi: 10.3171/2017.1.PEDS16527. [Epub ahead of print] PMID: 28574315

Babadjouni RM, Hodis DM, Radwanski R, Durazo R, Patel A, Liu Q, Mack WJ. Clinical effects of air pollution on the central nervous system; a review. J Clin Neurosci. 2017 May 18. pii: S0967- 5868(17)30228-X. doi: 10.1016/j.jocn.2017.04.028. [Epub ahead of print] Review. PMID: 28528896

Strickland BA, Pham MH, Bakhsheshian J, Russin JJ, Mack WJ, Acosta FL. Bow Hunter’s Syndrome: Surgical Management (Video) and Review of the Literature. World Neurosurg. 2017 Apr 24. pii: S1878- 8750(17)30609-5. doi: 10.1016/j.wneu.2017.04.101. [Epub ahead of print] PMID: 28450231

Ho L, Kramer DR, Wen T, Moalem AS, Millett D, Heck CN, Mack WJ, Liu CY. Potentially preventable complications in epilepsy admissions: The “weekend effect”. Epilepsy Behav. 2017 May;70(Pt A):50- 56. doi: 10.1016/j.yebeh.2017.03.008. Epub 2017 Apr 12. PMID: 28410465

Mack WJ, Kim LJ, Lopes DK, Mocco J. Introduction: New techniques and technologies in the management of ischemic stroke. Neurosurg Focus. 2017 Apr;42(4):E1. doi: 10.3171/2017.1.FOCUS1730. No abstract available. PMID: 28366068

Babadjouni RM, Walcott BP, Liu Q, Tenser MS, Amar AP, Mack WJ. Neuroprotective delivery platforms as an adjunct to mechanical thrombectomy. Neurosurg Focus. 2017 Apr;42(4):E4. doi: 10.3171/2017.1.FOCUS16514. Review. PMID: 28366053

58 Faculty Publications Buchanan IA, Mack WJ. Minimally Invasive Surgical Approaches for Chronic Subdural Hematomas. Neurosurg Clin N Am. 2017 Apr;28(2):219-227. doi: 10.1016/j.nec.2016.11.004. Epub 2017 Jan 16. Review. PMID: 28325456

Ramirez L, Kim-Tenser MA, Sanossian N, Cen S, Wen G, He S, Mack WJ, Towfighi A. Trends in Transient Ischemic Attack Hospitalizations in the United States. J Am Heart Assoc. 2016 Sep 24;5(9). pii: e004026. PMID: 27664805

James RF, Kramer DR, Aljuboori ZS, Parikh G, Adams SW, Eaton JC, Abou Al-Shaar H, Badjatia N, Mack WJ, Simard JM. Novel Treatments in Neuroprotection for Aneurysmal Subarachnoid Hemorrhage. Curr Treat Options Neurol. 2016 Aug;18(8):38. doi: 10.1007/s11940-016-0421-6. Review. PMID: 27325362

Inouye S, Jin D, Cen S, Nguyen P, Renda N, Amar AP, Mack WJ, Kim-Tenser MA. Trends in the use of pulmonary artery catheterization in the aneurysmal subarachnoid hemorrhage population. J Clin Neurosci. 2016 Sep;31:133-6. doi: 10.1016/j.jocn.2016.02.025. Epub 2016 Apr 8. PMID: 27068011

Hartiala J, Zhang LI, Allayee H, Lusis AJ, Ohyama T, Friedman RA. Genome-Wide Association Analysis Identifies Dcc as an Essential Factor in the Innervation of the Peripheral Vestibular System in Inbred Mice. J Assoc Res Otolaryngol. 2016 Oct;17(5):417-31. doi: 10.1007/s10162-016-0578-4. Epub 2016 Aug 18. PMID: 27539716

Shibata S, Miwa T, Wu HH, Levitt P, Ohyama T. Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing. J Neurosci. 2016 Aug 3;36(31):8200-9. doi: 10.1523/JNEUROSCI.4410-15.2016. PMID: 27488639

Shirokova V, Biggs LC, Jussila M, Ohyama T, Groves AK, Mikkola ML. Foxi3 Deficiency Compromises Hair Follicle Stem Cell Specification and Activation. Stem Cells. 2016 Jul;34(7):1896-908. doi: 10.1002/ stem.2363. Epub 2016 Apr 4. PMID: 26992132

Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects neurons There is currently no responsible for controlling voluntary treatment or cure for ALS. muscle movements like chewing, walking, breathing and talking.

Faculty Publications 59 Kaverina NV, Kadoya H, Eng DG, Rusiniak ME, Sequeira-Lopez ML, Gomez RA, Pippin JW, Gross KW, Peti-Peterdi J, Shankland SJ. Tracking the stochastic fate of cells of the renin lineage after podocyte depletion using multicolor reporters and intravital imaging. PLoS One. 2017 Mar 22;12(3):e0173891. doi: 10.1371/journal.pone.0173891. eCollection 2017. PMID: 28329012

Zhang Y, Peti-Peterdi J, Brandes AU, Riquier-Brison A, Carlson NG, Müller CE, Ecelbarger CM, Kishore BK. Prasugrel suppresses development of lithium-induced nephrogenic diabetes insipidus in mice. Purinergic Signal. 2017 Jun;13(2):239-248. doi: 10.1007/s11302-017-9555-6. Epub 2017 Feb 23. PMID: 28233082

Choi D, Park E, Jung E, Seong YJ, Hong M, Lee S, Burford J, Gyarmati G, Peti-Peterdi J, Srikanth S, Gwack Y, Koh CJ, Boriushkin E, Hamik A, Wong AK, Hong YK. ORAI1 Activates Proliferation of Lymphatic Endothelial Cells in Response to Laminar Flow Through Krüppel-Like Factors 2 and 4. Circ Res. 2017 Apr 28;120(9):1426-1439. doi: 10.1161/CIRCRESAHA.116.309548. Epub 2017 Feb 6. PMID: 28167653

Choi D, Park E, Jung E, Seong YJ, Yoo J, Lee E, Hong M, Lee S, Ishida H, Burford J, Peti-Peterdi J, Adams RH, Srikanth S, Gwack Y, Chen CS, Vogel HJ, Koh CJ, Wong AK, Hong YK. Laminar flow downregulates Notch activity to promote lymphatic sprouting. J Clin Invest. 127(4):1225-1240, 2017.

Peti-Peterdi J. A practical new way to measure kidney fibrosis. Kidney Int. 2016 Nov;90(5):941-942. doi: 10.1016/j.kint.2016.07.036. PMID: 27742198

Lemos DR, Marsh G, Huang A, Campanholle G, Aburatani T, Dang L, Gomez I, Fisher K, Ligresti G, Peti- Peterdi J, Duffield JS. Maintenance of vascular integrity by pericytes is essential for normal kidney function. Am J Physiol Renal Physiol. 2016 Dec 1;311(6):F1230-F1242. doi: 10.1152/ajprenal.00030.2016. Epub 2016 Jun 22. PMID:27335372

Raynes R, Juarez C, Pomatto LC, Sieburth D, Davies KJ. Aging and SKN-1-dependent Loss of 20S Proteasome Adaptation to Oxidative Stress in C. elegans. J Gerontol A Biol Sci Med Sci. 2017 Feb;72(2):143-151. doi: 10.1093/gerona/glw093. Epub 2016 Jun 23. PMID: 27341854

Falk AS, Siemer AB (2016) Dynamic Domains of Amyloid Fibrils can be Site-specifically Assigned with Proton Detected 3D NMR Spectroscopy J. Biomol. NMR 66(3), 159–162

Fang Q, Tao HW. Direction selectivity starts early. Nat Neurosci. 2017 Jun 27;20(7):899-901. doi: 10.1038/nn.4585. No abstract available. PMID: 28653688

Li YT, Fang Q, Zhang LI, Tao HW. Spatial Asymmetry and Short-Term Suppression Underlie Direction Selectivity of Synaptic Excitation in the Mouse Visual Cortex. Cereb Cortex. 2017 May 11:1-12. doi: 10.1093/cercor/bhx111. [Epub ahead of print] PMID: 28498898

Tao C, Zhang G, Zhou C, Wang L, Yan S, Tao HW, Zhang LI, Zhou Y, Xiong Y. Diversity in Excitation- Inhibition Mismatch Underlies Local Functional Heterogeneity in the Rat Auditory Cortex. Cell Rep. 2017 Apr 18;19(3):521-531. doi: 10.1016/j.celrep.2017.03.061. PMID: 28423316

60 Faculty Publications Zingg B, Chou XL, Zhang ZG, Mesik L, Liang F, Tao HW, Zhang LI. AAV-Mediated Anterograde Transsynaptic Tagging: Mapping Corticocollicular Input-Defined Neural Pathways for Defense Behaviors. Neuron. 2017 Jan 4;93(1):33-47. doi: 10.1016/j.neuron.2016.11.045. Epub 2016 Dec 15. PMID: 27989459

Mori T, Koyama N, Tan J, Segawa T, Maeda M, Town T. Combination Therapy with Octyl Gallate and Ferulic Acid Improves Cognition and Neurodegeneration in a Transgenic Mouse Model of Alzheimer Disease. J Biol Chem. 2017 May 16. pii: jbc.M116.762658. doi: 10.1074/jbc.M116.762658. [Epub ahead of print] PMID: 28512130

Fick RHJ, Daianu M, Pizzolato M, Wassermann D, Jacobs RE, Thompson PM, Town T, Deriche R. Comparison of biomarkers in transgenic Alzheimer rats using multi-shell diffusion MRI. Mathematics and Visualization, “Computational Diffusion MRI” pp 187-199; 2017 Jan 01; Springer: Dordrecht Netherlands; doi: 10.1007/978-3-319-54130-3_16.

Guillot-Sestier MV, Weitz TM, Town T. Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer’s Disease. J Vis Exp. 2016 Dec 26;(118). doi: 10.3791/54868. PMID: 28060279

Breunig JJ, Levy R, Antonuk CD, Molina J, Dutra-Clarke M, Park H, Akhtar AA, Kim GB, Town T, Hu X, Bannykh SI, Verhaak RG, Danielpour M. Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma. Cell Rep. 2016 Dec 20;17(12):3407. doi: 10.1016/j.celrep.2016.12.026.

Acharya D, Wang P, Paul AM, Dai J, Gate D, Lowery JE, Stokic DS, Leis AA, Flavell RA, Town T, Fikrig E, Bai F. Interleukin-17A Promotes CD8+ T Cell Cytotoxicity To Facilitate West Nile Virus Clearance. J Virol. 2016 Dec 16;91(1). pii: e01529-16. Print 2017 Jan 1. PMID: 27795421

Paul AM, Acharya D, Le L, Wang P, Stokic DS, Leis AA, Alexopoulou L, Town T, Flavell RA, Fikrig E, Bai F. TLR8 Couples SOCS-1 and Restrains TLR7-Mediated Antiviral Immunity, Exacerbating West Nile Virus Infection in Mice. J Immunol. 2016 Dec 1;197(11):4425-4435. Epub 2016 Oct 21. PMID: 27798161

Weitz TM, Town T. Amyloid Cascade into Clarity. Immunity. 2016 Oct 18;45(4):717-718. doi: 10.1016/j. immuni.2016.10.006. PMID: 27760336

Matundan HH, Mott KR, Allen SJ, Wang S, Bresee CJ, Ghiasi YN, Town T, Wechsler SL, Ghiasi H. Interrelationship of Primary Virus Replication, Level of Latency, and Time to Reactivation in the Trigeminal Ganglia of Latently Infected Mice. J Virol. 2016 Sep 29;90(20):9533-42. doi: 10.1128/JVI.01373- 16. Print 2016 Oct 15. PMID: 27512072

Andreasson KI, Bachstetter AD, Colonna M, Ginhoux F, Holmes C, Lamb B, Landreth G, Lee DC, Low D, Lynch MA, Monsonego A, O’Banion MK, Pekny M, Puschmann T, Russek-Blum N, Sandusky LA, Selenica ML, Takata K, Teeling J, Town T, Van Eldik LJ. Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem. 2016 Sep;138(5):653-93. doi: 10.1111/jnc.13667. Review.

Schmidt T, Situ AJ, Ulmer TS. Direct Evaluation of Protein-Lipid Contacts Reveals Protein Membrane Immersion and Isotropic Bicelle Structure. J Phys Chem Lett. 2016 Nov 3;7(21):4420-4426. Epub 2016 Oct 26. PMID: 27776216

Faculty Publications 61 Zou M, Bhatia A, Dong H, Jayaprakash P, Guo J, Sahu D, Hou Y, Tsen F, Tong C, O’Brien K, Situ AJ, Schmidt T, Chen M, Ying Q, Ulmer TS, Woodley DT, Li W. Evolutionarily conserved dual lysine motif determines the non-chaperone function of secreted Hsp90alpha in tumour progression. Oncogene. 2017 Apr;36(15):2160-2171. doi: 10.1038/onc.2016.375. Epub 2016 Oct 10. PMID: 27721406

Schmidt T, Situ AJ, Ulmer TS. Structural and thermodynamic basis of proline-induced transmembrane complex stabilization. Sci Rep. 2016 Jul 20;6:29809. doi: 10.1038/srep29809. PMID: 27436065

Schmidt T, Ye F, Situ AJ, An W, Ginsberg MH, Ulmer TS. A Conserved Ectodomain-Transmembrane Domain Linker Motif Tunes the Allosteric Regulation of Cell Surface Receptors. J Biol Chem. 2016 Aug 19;291(34):17536-46. doi: 10.1074/jbc.M116.733683. Epub 2016 Jun 30. PMID: 27365391

Dong C, Guo Y, Yang H, He Z, Liu X, Wang K. iCAGES: integrated CAncer GEnome Score for comprehensively prioritizing driver genes in personal cancer genomes, Genome Medicine, 8:135, 2016

He KY, Zhao Y, McPherson EW, Li Q, Xia F, Weng C, Wang K, He MM Pathogenic Mutations in Cancer- Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records, PLoS ONE, 11: e0167847, 2016

Zhao J, Song X, Wang K. lncScore: alignment-free identification of long noncoding RNA from assembled novel transcripts. Scientific Reports, 6:34838, 2016

Tafti AP, Ye Z, He KY, Wang K, He MM. SparkText: biomedical text mining on big data framework. PLoS ONE, 11:e0162721, 2016

Kleyner R, Malcolmson J, Tegay D, Ward K, Maughan A, Maughan G, Nelson L, Wang K, Robison R, Lyon GJ. KBG syndrome involving a single nucleotide duplication in ANKRD11. Molecular Case Studies, 2:a001131, 2016

Malcolmson J, Kleyner R, Tegay D, Adams W, Ward K, Coppinger J, Nelson L, Meisler MH, Wang K, Robison R, and Lyon GJ. SCN8A mutation in child presenting with seizures and developmental delays. Molecular Case Studies, 2:a001073, 2016

Germanwala AV, Hofler R, Lagman C, Chung LK, Khalessi AA, Zada G, Smith ZA, Dahdaleh NS, Bohnen AM, Cho JM, Colen CB, Duckworth E, Kan P, Lam S, Kim CY, Li G, Lim M, Sherman JH, Wang VY, Yang I. Neurosurgery concepts: Key perspectives on endoscopic versus microscopic resection for pituitary adenomas, surgical decision-making in tuberculum sellae meningiomas, optic nerve mobilization during resection of craniopharyngiomas, and evaluation of headache and quality of life after endoscopic transphenoidal surgery for pituitary adenomas. Surg Neurol Int. 2017 Apr 5;8:52. doi: 10.4103/sni. sni_17_17. eCollection 2017. No abstract available. PMID: 28480114

Bakhsheshian J, Strickland BA, Patel NN, Jakoi AM, Minneti M, Zada G, Acosta FL, Hsieh PC, Wang JC, Liu JC, Pham MH. The use of a novel perfusion-based cadaveric simulation model with cerebrospinal fluid reconstitution comparing dural repair techniques: a pilot study. Spine J. 2017 Apr 12. pii: S1529- 9430(17)30141-9. doi: 10.1016/j.spinee.2017.04.007. [Epub ahead of print] PMID: 28412565

62 Faculty Publications Bonney PA, Fujii T, Zada G. Recruitment of Medical Students in Neurosurgery. World Neurosurg. 2017 Feb;98:859. doi: 10.1016/j.wneu.2016.10.121. No abstract available.PMID: 28235351

Lagman C, Chung LK, Macyszyn L, Choy W, Smith ZA, Dahdaleh NS, Bohnen AM, Cho JM, Colen CB, Duckworth E, Germanwala AV, Kan P, Khalessi AA, Kim CY, Lam S, Li G, Lim M, Sherman JH, Wang VY, Zada G, Yang I. Neurosurgery concepts: Key perspectives on imaging characteristics of spinal metastases, surgery for low back pain, anesthesia for disc surgery, and laminectomy versus laminectomy and fusion for lumbar spondylolisthesis. Surg Neurol Int. 2017 Jan 19;8:9. doi: 10.4103/2152-7806.198736. eCollection 2017. No abstract available. PMID: 28217388

Nagasawa DT, Lagman C, Sun M, Yew A, Chung LK, Lee SJ, Bui TT, Ooi YC, Robison RA, Zada G, Yang I. Pineal germ cell tumors: Two cases with review of histopathologies and biomarkers. J Clin Neurosci. 2017 Apr;38:23-31. doi: 10.1016/j.jocn.2016.12.024. Epub 2017 Feb 8. Review. PMID: 28189312

Donoho DA, Bose N, Zada G, Carmichael JD. Management of aggressive growth hormone secreting pituitary adenomas. Pituitary. 2017 Feb;20(1):169-178. doi: 10.1007/s11102-016-0781-7. Review. PMID: 27987061

Ziu M, Dunn IF, Hess C, Fleseriu M, Bodach ME, Tumialan LM, Oyesiku NM, Patel KS, Wang R, Carter BS, Chen JY, Chen CC, Patil CG, Litvack Z, Zada G, Aghi MK. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Posttreatment Follow-up Evaluation of Patients With Nonfunctioning Pituitary Adenomas. Neurosurgery. 2016 Oct;79(4):E541-3. doi: 10.1227/ NEU.0000000000001392. PMID: 27635964

Bian SX, Routman D, Liu J, Yang D, Groshen S, Zada G, Trakul N, Wong MK, Yu C, Chang EL. Prognostic factors for melanoma brain metastases treated with stereotactic radiosurgery. J Neurosurg. 2016 Dec;125(Suppl 1):31-39. PMID: 27903181

A stroke is a “brain attack” that can happen to anyone at any time. Every year, more than 795,000 people in the US have a stroke and about 140,000 people die from stroke each year.

Faculty Publications 63 Sheehan J, Lee CC, Bodach ME, Tumialan LM, Oyesiku NM, Patil CG, Litvack Z, Zada G, Aghi MK. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline for the Management of Patients With Residual or Recurrent Nonfunctioning Pituitary Adenomas. Neurosurgery. 2016 Oct;79(4):E539-40. doi: 10.1227/NEU.0000000000001385. PMID: 27635963

Kuo JS, Barkhoudarian G, Farrell CJ, Bodach ME, Tumialan LM, Oyesiku NM, Litvack Z, Zada G, Patil CG, Aghi MK. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Surgical Techniques and Technologies for the Management of Patients With Nonfunctioning Pituitary Adenomas. Neurosurgery. 2016 Oct;79(4):E536-8. doi: 10.1227/NEU.0000000000001390. PMID: 27635962

Lucas JW, Bodach ME, Tumialan LM, Oyesiku NM, Patil CG, Litvack Z, Aghi MK, Zada G. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Primary Management of Patients With Nonfunctioning Pituitary Adenomas. Neurosurgery. 2016 Oct;79(4):E533-5. doi: 10.1227/ NEU.0000000000001389. PMID: 27635961

Newman SA, Turbin RE, Bodach ME, Tumialan LM, Oyesiku NM, Litvack Z, Zada G, Patil CG, Aghi MK. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Pretreatment Ophthalmology Evaluation in Patients With Suspected Nonfunctioning Pituitary Adenomas. Neurosurgery. 2016 Oct;79(4):E530-2. doi: 10.1227/NEU.0000000000001388. PMID: 27635960

Fleseriu M, Bodach ME, Tumialan LM, Bonert V, Oyesiku NM, Patil CG, Litvack Z, Aghi MK, Zada G. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline for Pretreatment Endocrine Evaluation of Patients With Nonfunctioning Pituitary Adenomas. Neurosurgery. 2016 Oct;79(4):E527-9. doi: 10.1227/NEU.0000000000001387. PMID: 27635959

Chen CC, Carter BS, Wang R, Patel KS, Hess C, Bodach ME, Tumialan LM, Oyesiku NM, Patil CG, Litvack Z, Zada G, Aghi MK. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Preoperative Imaging Assessment of Patients With Suspected Nonfunctioning Pituitary Adenomas. Neurosurgery. 2016 Oct;79(4):E524-6. doi: 10.1227/NEU.0000000000001391. PMID: 27635958

An estimated 700,000 people in Nearly 17,000 people the US are living with a primary die of a brain tumor brain tumor and nearly 80,000 each year. more will be diagnosed next year.

64 Faculty Publications Matsushima K, Inaba K, Cho J, Mohammed H, Herr K, Leichtle S, Zada G, Demetriades D. Therapeutic anticoagulation in patients with traumatic brain injury. J Surg Res. 2016 Sep;205(1):186-91. doi: 10.1016/j. jss.2016.06.042. Epub 2016 Jun 21. PMID: 27621017

Mittelstein D, Deng J, Kohan R, Sadeghi M, Maarek JM, Zada G. Novel technique of a multifunctional electrosurgical system for minimally invasive surgery. J Neurosurg. 2017 Mar;126(3):997-1002. doi: 10.3171/2016.2.JNS15763. Epub 2016 Apr 29. PMID: 27128589

Shilian P, Zada G, Kim AC, Gonzalez AA. Overview of Intraoperative Neurophysiological Monitoring During Spine Surgery. J Clin Neurophysiol. 2016 Aug;33(4):333-9. doi: 10.1097/ WNP.0000000000000132. PMID: 25233250

Tao C, Zhang G, Zhou C, Wang L, Yan S, Zhang LI, Zhou Y, Xiong Y. Synaptic Basis for the Generation of Response Variation in Auditory Cortex. Sci Rep. 2016 Aug 3;6:31024. doi: 10.1038/srep31024.

Nikolakopoulou AM, Zhao Z, Montagne A, Zlokovic BV (2017) Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet- derived growth factor receptor beta signaling. Plos One Apr 25;12(4):e0176225. doi: 10.1371/journal. pone.0176225. eCollection 2017.

Ochocinska MJ, Zlokovic BV, Searson PC, Searson PC, Crowder AT, Kraig RP, Ljubimova JY, Mainprize TG, Banks WA, Warren RQ, Kindzelski A, Timmer W, Liu CH (2017) NIH workshop report on the trans-agency blood-brain interface workshop 2016: exploring key challenges and opportunities associated with the blood, brain and their interface. Fluids Barriers CNS 14 (1): 12.

Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang Y, Ahuja A, Lazic D, Tsai PS, Zhao Z, Zhou Y, Boas DA, Sakadžić S, Zlokovic BV (2017) Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nature Neuroscience 20, 406-416.

Griffin JH, Mosnier LO, Fernández JA, Zlokovic BV. (2016) Thrombotic stroke: neuroprotective therapy by recombinant activated protein C. Arteriosclerosis, Thromb. Vasc. Biol. 36(11):2143-2151.

Qiming Liang Q, Luo Z, Zeng J, Chen W, Foo S-S, Lee S-A, Ge J, Wang S, Goldman SA, Zlokovic BV, Zhao Z, Jung JU (2016) Zika Virus NS4A-NS4B inhibition of Akt-mTOR pathway contributes to deficient neurogenesis and dysregulated autophagy by human fetal neural stem cells. Cell Stem Cells 19: 663-671

Wang Y, Zhao Z, Rege S, Griffin JH, Goldman SA, Zlokovic BV (2016) 3K3A-APC stimulates post-ischemic neuronal repair by human neural progenitor cells in mice. Nature Medicine 22 (9): 1050-1055.

Akassoglou K, Agalliu D, Chang CJ, Davalos D, Grutzendler J, Hillman E, Khakh BS, Kleinfeld D, McGavern DB, Nelson SJ, Zlokovic BV (2016) Neurovascular and Immuno-imaging: From mechanisms to therapies. Frontiers in Neuroscience 10: 46.

Faculty Publications 65 Teaching

Despite maintaining comprehensive research programs, ZNI faculty also contribute to teaching in a variety of ways: undergraduate lectures, graduate courses and seminars, medical student curricula and individual mentoring of junior scientists.

Frank Attenello Lecturer: Keck School of Medicine, Neurosciences Section: Traumatic Brain Injury Lecturer: Keck School of Medicine, Neurosciences Section: Ruptured Cerebral Aneurysms and Treatment Disparities Alexandre Bonnin NEUR524, NGP – “Specificity of wiring” KSOM Neuroscience 100 – Neuroscience systems: created and gave 2 pharmacology lectures to 1st year USC MED students: • “Sedatives, hypnotics and anxiolytics” • “Antipsychotic drugs”

Daniel Campbell Dr. Campbell taught in the Neuroscience Graduate Program Core Course.

Karen Chang Peroxisome and Mitochondria lecture (Medical Microanatomy) Liver and Gallbladder lecture (Medical Microanatomy) Oral cavity lecture (Medical Microanatomy) Medical Microanatomy labs: cardiovascular, renal, respiratory, endocrine, GI tract, and reproductive biology.

Jeannie Chen Lecturer, INTD 550, Introduction to Pathology. Lecturer, MPTX 500, Molecular Pharmacology and Signal Transduction. Lecturer, INTD 549, Protein Chemistry: Structure & Function Neuroscience Graduate Program Grant Writing Workshop Lecturer and laboratory instructor for Microanatomy, Year 1 and Year 2 Medical Students curriculum.

66 Teaching Robert Chow • Cell Biology INTD531 (3x2-hr lectures/yr, 60 students) • Advanced Neuroscience NEUR524 (3x2-hr lectures/yr, 25 students) • Methods in Experimental Path. PATH552A (3x2-hr lectures/yr, 25 students) David Conti PM 534: Statistical Genetics

Hong-Wei Dong Designed, organized, and taught NIIN 560 Advanced Microscopic Technology in Animal Models. This is a core course for a Master Program (Master’s of Science in Neuroimaging and Informatics) at USC Keck School of Medicine.

Radha Kalluri • Neuroscience Graduate Program Core Course • Hearing and Communications Neuroscience Core Course

Ralf Langen Dr. Langen lectured in a number of courses, including INTD-549 (Protein Chemistry and Structure), Gero 666 (Free Radical Chemistry, Biology & Medicine), INTD-531 (Cell Biology), PSCI 557 (Introduction to Tools and Techniques for Chemical Biology starting). In addition, he also lectured to medical students. Dr. Langen is also the director of the Medical Biophysics PhD program.

Janos Peti-Peterdi • Year 2 medical students, renal block, Renal microanatomy, 4 lectures, +2 lab practice • INTD572, Renal physiology, 4 lectures • INTD660, Ion transport, 1 lecture • Nephrology residents and fellows, 1 lecture

Ansgar Siemer • Co-organizing “Protein Chemistry” INTD 549 • 1 lecture in “Protein Chemistry” INTD 549 • 3 lectures in “Molecular Biology” INTD 561 • 4 lectures in “Biochemistry” INTD 571 Huizhong Tao • Neuroscience Graduate Program core course Neur524 • Neuroscience Graduate Course NSCI-540 Advanced Seminars in Neuroscience:”Optogenetics and Circuit Mapping”

Teaching 67 Terrence Town Dr. Town continues to be Course Director for PHBI 550: “Seminars in Physiology & Biophysics.” The goal of this class is to teach students the essential scientific presentation skills that they will find invaluable for presenting their work. He has lectured in NEUR 524: “Advanced Neuroscience,” which is one of the core courses for the USC Neuroscience Graduate Program. The goal of his lectures is to introduce neuroscience students to the field of neuroimmunology; particularly as related to neurodegenerative diseases. He has lectured in FMS-3: “Alertin,” where he lectured to medical students on the neuroendocrine system.

Tobias Ulmer • “Protein Chemistry: Structure & Function” (INTD-549) • Course coordinator (joint with Dr. Ansgar Siemer) • Three lectures • Three student seminars • “Biochemistry” (INTD-571), annual course • Two lectures Berislav Zlokovic • Mentoring: 5 Postdoctoral Fellows • Mentoring: 3 Neurosurgery Faculty, 2 Neurology Faculty, 2 Neuroimaging Faculty, 1 Stem Cell Faculty, 1 Engineering Faculty, 4 PHBI Faculty, 2 Graduate Students • Gave lectures for CME credit at Dornsife College (USC), the Society for Neuroscience, the Alzheimer’s Association, the National Institute of Health, the National Institute of Neurological Disorders and Stroke, the National Institute of Aging, the New York Academy of Sciences, the National Heart, Blood and Lung Institute, Cold Spring Harbor Laboratory

More than 5 million Americans are living with Alzheimer’s. Every 66 seconds, someone in the US develops the disease.

68 Teaching ZNI Postdoctoral fellows

A postdoctoral researcher is a person professionally conducting research after the completion of their doctoral studies, typically after obtaining a PhD. The ultimate goal of a postdoctoral researcher, or fellow, is to pursue additional research, training, or teaching in order to have better skills to pursue a career in academia, research or industry. Generally, postdocs work independently but under the supervision of an established principal investigator with a complementary funded research program. Listed below are ZNI’s postdoctoral trainees, (their mentors), and the titles of their research projects. ZNI had 34 postdoctoral fellows in FY17.

Yingxi Wu (Frank Attenello) “Differential Tumor-Host Pericyte Modulations in the Repression of Growth and Angiogenesis in Glioblastoma”

Yen Chan, MD (Alexandre Bonnin ) “Maternal Stress and Antidepressants Effects on Fetal Brain Development”

Qiuying Zhao (Alexandre Bonnin) “Maternal Stress and Antidepressants Effects on Fetal Brain Development”

Junhua Geng (Karen Chang) “Mechanisms Regulating Bulk Vesicle Retrieval”

Joo-Yen Lee (Karen Chang) “A Novel DnaJ Domain Protein Regulates Synaptic Development and Maintains Stem Cell Niche in Drosophilia”

Yao-Chuan Chang (Robert Chow) “Optimizing Stimulation Strategies for Cortical Visual Prosthesis”

Yuan Zhao (Robert Chow) “Optimizing Stimulation Strategies for Cortical Visual Prosthesis”

Zhao Yang (David Conti) “Integrated Analysis of Germline, Omic and Disease Data”

ZNI Postdoctoral Fellows 69 Lilit Chemenyan (David Conti) “Bayesian model selection for functional integration in genetic association studies”

Kan Wang (David Conti) “Multiethnic fine-mapping in genetic association studies”

Nicholas Foster (Hong Wei Dong) “Mouse Brain Connectome Mapping of Cortical and Striatal Long- distance Axon Projection Deficits in Huntington’s Disease Mouse Models”

Michael Bienkowski (Hong Wei Dong) “The Mouse Connectome Project”

Naomi Sta Maria (Russell Jacobs) “Development of MRI/PET Technologies to Track Cancer Immunotherapies and Elucidate Brain Dysfunctions”

Nitin Pandey (Ralf Langen) “Huntingtin Folding and Misfolding”

Jose Bravo Arrendondo (Ralf Langen) “Protein Dynamics in Amyloid Diseases”

Awoop Rawat (Ralf Langen) “Neurodegenerative Diseases”

Baishali Mukherjee (Ralf Langen) “Protein-Membrane Interaction in Neurodegenerative Diseases”

Hank Chang (William Mack) “Particulate Matter Exposure/Cerebral Hypoperfusion”

Dorinne Desposito (Janos Peti-Peterdi) “Novel Regulatory Mechanisms of the Glomerular Endothelium”

Balint Der (Janos Peti-Peterdi) “Role of Macula Densa Cells in Kidney Development and Remodeling in the Adult”

Sungjin Kim (Derek Sieburth) “Regulation of Synaptic Function by Stress Signaling”

Mingxi Hu (Derek Sieburth) “Control of Rhythmic Behaviors by Neuropeptide Signaling”

Li Shen (Huizhong Tao and Li Zhang) “Sensory Responses in a Basal Forebrain Structure”

Marie-Victoire Guillot-Sestier, Ph.D. (Terrence Town) “Role of the Anti-Inflammatory IL-10 Pathway in Evolution of Alzheimer’s Disease”

Tara M. Weitz, Ph.D. (Terrence Town) “Blocking TGF-beta-Smad 2/3 Signaling in Peripheral Macrophages to Mitigate Alzheimer-like Pathology”

Kevin Doty (Terrence Town) “STAT3 Signaling as a Critical Mediator of Alzheimer’s Pathogenesis”

Marie-Victoire Guillot-Sestier, Ph.D. (Terrence Town) “Role of the Anti-Inflammatory IL-10 Pathway in Evolution of Alzheimer’s Disease”

70 ZNI Postdoctoral Fellows Tara M. Weitz, Ph.D. (Terrence Town) “Blocking TGF-beta-Smad 2/3 Signaling in Peripheral Macrophages to Mitigate Alzheimer-like Pathology”

Leandro Lima (Kai Wang) “Development of Copy Number Variation Calling Tools”

Qian Liu (Kai Wang) “Long-Read Sequencing for Diagnosing Trinucleotide Repeat Expansion Syndrome”

Atlas Khan (Kai Wang) “Neural Network for Analysis of Genetic Variants”

Axel Montagne (Berislav Zlokovic) “Quantitative Dynamic Contrast-Enhanced Magnetic Resonance Imaging to Evaluate Blood-Brain Barrier Integrity in Alzheimer’s Disease and Related Disorders”

Amy Nelson (Berislav Zlokovic) “The Role of Pericytes in Capillary Contractility Using Otogenetic Models”

Mikko Huuskonen (Berislav Zlokovic) “Cerebrovascular MRI Imaging in Models of Stroke and APOE Transgenic Mice” Photo credit: Steve Cohn Steve credit: Photo

Members of Dr. Zlokovic’s lab pose with Drs. Berislav Zlokovic and Helena Chui.

ZNI Postdoctoral Fellows 71 ZNI Graduate Students

For an institute our size, ZNI has a relatively large graduate student population of 54 individuals who are pursuing advanced degrees from a variety of USC programs and departments: Neuroscience, Preventive Medicine, Biostatistics and Physiology & Biophysics, and PIBBS (Programs in Biomedical and Biological Sciences), which includes degrees in Cancer Biology & Genomics; Development, Stem Cells & Regenerative Medicine; Medical Biology; and Molecular Structure & Signaling). Each graduate student works with a ZNI faculty mentor for up to 5 years before defending their thesis and being awarded a Ms or PhD, depending upon the program. Below is the list of students working at ZNI, (their mentors), and their projects.

Nick Goeden (Alexandre Bonnin) “Placental Tryptophan Metabolic Dysfunction: A Potential Pathway for the Developmental Programming of Mental Disorders”.

Juan Velasquez (Alexandre Bonnin ) “Effects of Maternal Depression and Antidepressant Treatments on Fetal Neurodevelopment”

Jessica DeWitt (Daniel Campbell) “Genetics and the Environment: Examining the Role of Noncoding RNA in Autism Spectrum Disorder”

Gurleen Chadha (Daniel Campbell) “Molecular Mechanisms that Contribute to Autism Spectrum Disorder”

Andres Camarena (Jeannie Chen) “Molecular Crowding by Rrhodopsin/Arrestin Complex as a Mechanism of Photoreceptor Light Damage”

Madison Zitting (Robert Chow) “Calcium Sensitivity of Large-dense Core Vesicle Exocytosis in Complexin 2 Knock-out Mouse Chromaffin Cells”

Alejandra Gonzalez Calle (Robert Chow) “Strategy to improve retinal prosthesis function”

Brent Wilkinson (Marcelo Coba) “Synaptic Signaling Networks”

Zhao Yang (David Conti) “Integrated Analysis of Germline, Omic and Disease Data”

Lilit Chemenyan (David Conti) “Bayesian model selection for functional integration in genetic association studies”

72 ZNI Graduate Students Muye Zhou (Hong Wei Dong) “The Mouse Connectome Project”

Monica Song (Hong Wei Dong) “The Mouse Connectome Project”

Nora Benavidez (Hong Wei Dong) “The Mouse Connectome Project”

Christopher Ventura (Radha Kalluri) “The Role of Hyperpolarization-Activated Inward Currents in Shaping Neuronal Function in The Vestibular Nerve”

Alex Markowitz (Radha Kalluri) “The Biophysical Development of Spiral Ganglion Neurons”

Shayna Cooperman (Radha Kalluri) “3-D Reconstructions of Neuronal Fibers”

JaeMun (Hugo) Kim (James Knowles) “Single Cell RNA Sequencing”

Edder Lopez (James Knowles) “Differentiation of Neural Progenitors to Cortical Neurons in 2D and 3D Cultures”

Chris Armoskus (James Knowles and Kai Wang) “Statistical Analysis of Genetic Variation Predisposing to Schizophrenia”

Meixin Tao (Ralf Langen) “Protein-Membrane Interaction in Neurodegenerative Diseases”

Baishali Mukherjee (Ralf Langen) “Protein-Membrane Interaction in Neurodegenerative Diseases”

Hank Chang (William Mack) “Particulate Matter Exposure/ Cerebral Hypoperfusio”

Matt Butler (Janos Peti-Peterdi) “The Role of the Endothelial Glycocalyx in Glomerular Injury”

Hiroyuki Kadoya (Janos Peti-Peterdi) “The Role of Glomerular Glycocalyx and T cells in Lupus Nephritis”

Ina Schiessl (Janos Peti-Peterdi) “Intravital Imaging of Cell Death Dynamics in the Kidney”

Toshiki Doi (Janos Peti-Peterdi) “Macula Densa-Mediated Tissue Remodeling in Renovascular Hypertension”

Urvi Shroff (Janos Peti-Peterdi) “A New View of Macula Densa Cell Biology”

Qi Jia (Derek Sieburth) “Regulation of Oxidative Stress Response by Neuroendocrine Signaling”

Ukjin Choi (Derek Sieburth) “Regulation of Neuronal Excitability by Gap Junctions”

Silvia Cervantes (Ansgar Siemer) “Structural Investigation of Huntingtin Fibrils with Solid-State NMR and EPR”

Sandy Falk (Ansgar Siemer) “Interaction of Orb2 isoforms A and B”

ZNI Graduate Students 73 Maria Conrad (Ansgar Siemer) “Oligomer Formation and Membrane Interaction of Orb2A”

Brian Zingg (Huizhong Tao and Li Zhang) “Using viral Tools and Optogenetics to Dissect Functional Neural Circuits for Defensive Behaviors”

Xiaolin Chou (Huizhong Tao) “Fear Conditioning Induced Cortical Synaptic Plasticity”

Wen Zhong (Huizhong Tao and Li Zhang) “Microcircuits in the Midbrain Dr. Li Zhang observes a student’s experiment. Structures Involved in Defensive Behaviors”

Haifu Li (Huizhong Tao and Li Zhang) “Synaptic Mechanisms for Bandwidth Tuning”

Linqing Yan (Huizhong Tao and Li Zhang) “Modulation of Receptive Field Properties by Higher Order Thalamic Inputs”

Guangwei Zhang (Huizhong Tao and Li Zhang) “Function of a Non-Canonical Auditory Pathway”

Yuan Zhang (Huizhong Tao) “Visual Cortical Responses in Awake Mice”

Lukas Mesik (Huizhong Tao) “Functional Characterization of Inhibitory Interneurons During Development”

Ahyun Jung (Huizhong Tao and Li Zhang) “Neural Circuits Underlying Feeding Behavior”

Brian P. Leung (Terrence Town) “TREM2/C1q Signaling in Alzheimer’s Pathogenesis”

Kwok (Chris) Im (Terrence Town) “Role of T Helper 17 Cells in Learning and Memory and Neurodegeneration”

Alicia Quihuis (Terrence Town) “Brain Sexual Dimorphism in the TgF344-AD Rat Model of Alzheimer’s Disease”

Mariana Figueiredo Uchoa (Terrence Town) “The Role of IL-10/STAT3 Signaling in Age-Dependent Learning and Memory Impairment”

Rachel Oseas (Terrence Town) “Role of Brain Sexual Dimorphism in Age-Dependent Learning and Memory Impairment”

74 ZNI Graduate Students ChengLiang Dong (Kai Wang) “iCAGES: Genome-Guided Precision Medicine for Cancer Treatment”

Yunfei Guo (Kai Wang) “SeqMule: An Automated Pipeline for Whole Genome/Exome Analysis on Mendelian Diseases”

Hui Yang (Kai Wang) “Phenotype-based Detection of Causal SNPs and CNVs From Next-Generation Sequencing Data”

Young Joo Kim( Li Zhang) “Molecular Mechanisms for the Development of Auditory Cochlear Innervation Pattern”

Lukas Mesik (Li Zhang) “Functional Characterization of Inhibitory Interneurons During Development”

Qi Fang (Li Zhang ) “Visual Cortical Processing in Awake Mice”

Divna Lazic (Berislav Zlokovic) “Understanding the Role of Endothelial and Neuronal PICALM and its Novel Mutations Brain Functions”

Melanie Sweeney (Berislav Zlokovic) “Single cell RNAseq Analysis During Angiogenesis and in Pericyte-Defcient Models”

Conditions such as age-related Nearly 24 million macular degeneration (AMD), people in the US cataracts, glaucoma, diabetic experience vision retinopathy, and optic nerve disease are common in people loss. age 65 years and older.

ZNI Graduate Students 75 Zach Hall Travel Award Winners

For many years, Dr Zach Hall served as Senior Associate Dean for Academic Development at the Keck School of Medicine of USC and was a contributing founder of the Zilkha Neurogenetic Institute. Named in his honor and funded in part with a donation by Dr Hall and his wife Julie Giacobassi, ZNI is pleased to offer each year, travel awards to qualified graduate students working with ZNI Investigators. The grants allow students to attend a scientific meeting, collaborative trip or research training opportunity that they otherwise might not afford, thereby making a positive difference in their training. The competitive application process requires students to submit a mini-grant proposal, including a description of their research project, CV and letter of nomination from their mentor. Photo credit: Steve Cohn Steve credit: Photo

In 2016, four students received funds to attend meetings with an international crowd of researchers in their respective fields. Nobel prize winner Eric Kandel reviews a poster with graduate student Melanie Alicia Quihuis (laboratory of Terrence Town) presented an abstract Sweeney. at The Endocrine Society’s 99th Annual Meeting & Expo in Orlando, FL, “Female biased spatial memory and cognitive deficits in the novel TgF344-Alzheimer’s disease rat model.”

Chris Ventura (laboratory of Radha Kalluri) attended the annual meeting for the Association for Research in Otolaryngology in Baltimore, MD. Chris’s dissertation work focuses on understanding the role of two prominent groups of ion channels in shaping the response properties of primary vestibular afferents. These neurons are the primary conduits for transmitting sensory information about head movements to several other sensory and autonomic systems.

Xiaolin Chou (laboratory of Huizhong Tao) presented a poster at the annual Society for Neuroscience meeting in San Diego, CA. Xiaolin’s research is focused on understanding the state-dependent sensory cortical activity changes and underlying mechanisms in primary visual and auditory cortex with in vivo electrophysiology recording and optogenetics and identifying neural pathways for regulating defensive behaviors with anatomical tracing, in vivo electrophysiology recording, optogenetics and various kinds of behavioral tests.

Melanie Sweeney (laboratory of Berislav Zlokovic) presented a poster at the annual Society for Neuroscience meeting in San Diego, CA and additionally she was selected to give a Nanosymposium talk “ Impact of APOE4 genetic risk on CSF and MRI biomarkers of the neurovascular unit in preclinical Alzheimer’s disease.”

After returning from their travels, each graduate student participates in a poster session held at ZNI, in association with the annual Zach Hall lecture, sharing their work with colleagues in and around USC. In addition, all recipients attend a celebratory lunch with Dr Zach Hall on the day of the event. ZNI is proud to contribute to the growth of all the awardees and praise their successes.

76 ZNI Graduate Students NRSA Grant Training

Partnering with the USC Graduate Program in Neuroscience, ZNI again in FY17 co-organized workshops for graduate students who could benefit from applying for and receiving a fellowship under the National Institute of Health (NIH)’s Ruth L. Kirchstein National Research Service Awards (NRSA) program. The NRSAs are a family of grants provided by the NIH for training researchers in the behavioral sciences and health sciences. They are highly selective and a very prestigious source of funding for doctoral and postdoctoral trainees, as the grants are notably difficult to obtain. Only applications with very good impact scores are funded, based on budget cutoffs determined by each individual NIH institute.

The two-day workshops are team taught at ZNI by M. Carter Cornwall MD PhD, Professor of Physiology & Biophysics at the University of Utah; Jeannie Chen PhD, ZNI member and Professor of Cell & Neurobiology; and Kathie Eagleson PhD, Associate Professor of Research in Pediatrics, USC/Childrens Hospital of Los Angeles. The workshops are built around the idea of having students submit their draft applications for an in-depth and critical review. The instructors share sample successful applications, provide writing critiques but also cover tips and tricks from a reviewer’s point of view. Individuals who avail themselves to this opportunity dramatically increase their success rate when submitting final NRSA grant applications.

The impact on new awards to USC has been measurable, with 19 new NRSAs issued during the reporting period. Most grants run for three years and beyond, covering the fellow’s stipend while also providing funds for laboratory supplies.

Parkinson’s disease is a degenerative Parkinson’s disease disorder of the central nervous system that affects approximately affects nerve cells in the brain and makes 1 million people movement difficult. in the US.

ZNI Graduate Students 77 Grants and Contracts ZNI ACTIVE GRANTS FY12 to FY17 DC 30 million F&A

25 million

20 million

15 million

10 million

5 million

0 2012 2013 2014 2015 2016 2017

When it comes to submitting and securing grants, PIs at ZNI are very active and successful. For the current reporting period, ZNI received 27 awards out of 79 proposals submitted, roughly 34% average or 2 out of every 7 grants per month. ZNI PIs held 90 sponsored projects during FY17, with the majority from 12 different NIH institutes.

Significantly, the amount of total dollars in active grants jumped from $23M in FY16 to nearly $30M in FY17.

7812 GrantGRANTSs ANDand CONTRACTSContracts 2017 ZNI SPONSORED PROJECTS BY NIH INSTITUTE OR FEDERAL AGENCY OD 1% DoD 1% NINDS NSF 13% 2% NIDCD 2%

NCI NIMH 5% 13% NEI 5% NIEHS 4% NIA 8%

NHGRI 1% NIGMS NIDDK 2% 2% NIBIB 3%

DoD - Department of Defense NCI - National Cancer Institute NEI - National Eye Institute NHGRI - National Human Genome Research Institute NIA - National Institute on Aging NIBIB - National Institute of Biomedical Imaging & Bioengineering NIDCD - National Institute on Deafness and Other Communication Disorders NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases NIEHS - National Institute of Environmental Health Sciences NIGMS - National Institute of General Medical Sciences NIMH - National Institute of Mental Health NINDS - National Institute of Neurological Disorders and Stroke NSF - National Science Foundation OD - NIH Office of the Director

Grants and Contracts 79 ZNI FUNDED VS SUBMITTED PROJECTS FY12 to FY17

Funded 2012 Submitted 2013

2014

2015

2016

2017

0306090 120 150

Number of Projects

ZNI NEW GRANTS FY12 to FY17

Direct Costs (DC) 2012 Facilities & Administrative Costs (F&A) 2013

2014

2015

2016

2017 0510 15 20 25 30

Dollars in Millions

80 Grants and Contracts ZNI Investigator Funding Agency Direct Costs F&A Total Project Title Costs Costs Attenello, Frank National Institute $41,030 $26,670 $67,700 Effects of particulate of Environmental matter on neural stem cell- Health Sciences P30 mediated proliferation and (Preventive Med response to hypoxic injury Satellite) Bonnin, Childrens Hospital $15,303 $9,947 $25,250 Enduring Effects of Early- Alexandre of Los Angeles SubK Life Serotonin Signaling (National Institute of Mental Health R01) Bonnin, University of $30,418 $19,582 $50,000 Kynurenic Acid and Alexandre Maryland SubK Cognitive Abnormalities (National Institute of Mental Health R01) Bonnin, National Institute of $309,150 $122,867 $432,017 Prenatal stress and Alexandre Mental Health R01 antidepressants effects on offspring brain development Campbell, Daniel National Institute of $252,636 $164,214 $416,850 Biology of Non-Coding Mental Health R01 RNAs Associated with Psychiatric Disorders Campbell, Daniel Johns Hopkins $18,930 $12,304 $31,234 Prospective Evaluation of University SubK Air Pollution, Cognition, and (National Institue of Autism from Birth Onward Environmental Health Science R01) Chang, Karen Lejeune Foundation $47,974 $4,796 $52,770 Systematic analysis of genes contributing to synaptic defects in Down Syndrome Chang, Karen National Institute $218,750 $142,188 $360,938 Role of DYRK1A/MNB of Neurological in Synaptic growth and Disorders and Stroke function R01 Chang, Karen Alzheimer's $272,730 $27,270 $300,000 Functional Protein Association Interactions in Alzheimer's Disease and Down Syndrome Chang, Karen National Cancer $120,000 $78,000 $198,000 (PQ#9): Altered Institute R21 mitochondrial transport and chemotherapy-induced peripheral neuropathy Chen, Jeannie National Eye Institute $401,813 $224,023 $625,836 Phototransduction in Dark R01 Adaptation and Retinal Degeneration Chen, Jeannie National Eye Institute $421,159 $141,903 $563,062 Analyses of retinal circuits R01 after rod rescue in a mouse model of human blindness

Grants and Contracts 81 ZNI Investigator Funding Agency Direct Costs F&A Costs Total Project Title Costs Chow, Robert National Science $135,308 $87,517 $222,825 Retinal Nanophotoswitch Foundation (Ophthalmology Satellite) Chow, Robert National Institute $27,453 $17,844 $45,297 A Resource on Medical of Biomedical Ultrasonic Transducer Imaging and Technology Bioengineering (BMES Satellite) Chow, Robert Whittier $25,000 - $25,000 The Mechanism of Foundation Thapslgargin-mediated Zika Virus Inhibition Chow, Robert National Institute $187,267 $121,723 $308,990 Evaluation of Cellular of Mental Health Heterogeneity Using U01 Patchclamp and RNA-Seq of Single Cells Chow, Robert U.S. Army $201,385 $130,900 $332,285 Optimizing Stimulation Medical Research Strategies for Cortical Visual Acquisition Prostheses Activity Chow, Robert University of $174,846 $113,650 $288,496 Experimental and Clinical Michigan SubK Investigations of Retinal (National Eye Stimulation Institute R01 ) Coba, Marcelo University of Utah $148,974 $96,833 $245,807 Deciphering gene- SubK (National environment interactions Institute of in pathological reactive Mental Health aggression R01) Conti, David National Cancer $136,543 $88,753 $225,296 Incorporating Intermediate Institute R01 Biomarkers of folate with colorectal cancer Conti, David University of $17,259 $11,218 $28,477 Biology of colorectal cancer Virginia SubK risk enhancers (National Cancer Institute R01) Conti, David University of $22,975 $14,934 $37,909 MD-CPHG Inherited Virginia SubK colorectal cancer risk (National Cancer variants: from association to Institute R01) biology Evgrafov, Oleg Brain and $92,592 $7,408 $100,000 In Vitro Modeling of Altered Behavior Brain Development in Research Schizophrenia Foundation Evgrafov, Oleg National Institute $404,134 $244,983 $649,117 Transcriptome sequencing of Mental Health of neuronal cell lines from R01 patients with Schizophrenia

82 Grants and Contracts ZNI Investigator Funding Agency Direct Costs F&A Costs Total Costs Project Title Jacobs, Russell National Institute $65,310 $42,452 $107,762 Activated protein C system of Neurological in Stroke Models Disorders and Stroke R01 (Dr. Zlokovic) Jacobs, Russell National Institute $52,576 $34,174 $86,750 Cerebrovascular beta- on Aging R01 (Dr. Amyloidosis: A-beta CNS Zlokovic) Transport Pathways Jacobs, Russell National Institute $113,117 $73,525 $186,642 Vascular Contributions to on Aging P01 (Dr. Dementia and Genetic Risk Zlokovic's P01- Factors for Alzheimer's Project 3) Disease Jacobs, Russell National Institute $87,380 $56,797 $144,177 The Role of Pericytes in of Neurological White Matter Disease Disorders and Stroke R01 (Dr. Zlokovic) Jacobs, Russell National Institute of $4,500 $2,925 $7,425 Computational Tools for Biomedical Imaging Modeling Human and and Bioengineering Mouse Connectome with R01 (INI Satellite) Multi-Shell Diffusion Imaging Knowles, James International OCD $43,629 - $43,629 Replication of Genome- Foundation Wide Association Findings of Obsessive-Compulsive Disorder Knowles, James National Institute of $393,830 $255,990 $649,820 The USC PsychENCODE Mental Health U01 Project

Knowles, James National Institute $97,000 $63,050 $160,050 The USC PsychENCODE of Mental Health Project (Administrative supplement) Knowles, James National Institute of $808,638 $510,990 $1,319,628 Evaluation of Cellular Mental Health U01 Heterogeneity Using Patchclamp and RNA-Seq of Single Cells Knowles, James National Institute of $404,437 $262,884 $667,321 Addition of OCD to the Mental Health R01 Genomic Psychiatry Cohort

Knowles, James University of $12,680 $8,242 $20,922 Brain Mechanisms Mediating Wisconsin Subk Genetic Risk for Anxiety and (National Institute of Depression Mental Health R01) Knowles, James Suny Downstate $333,638 $216,865 $550,503 African Ancestry Genomic Medical Center Subk Psychiatry Cohort (National Institute of Mental Health R01)

Grants and Contracts 83 ZNI Investigator Funding Agency Direct Costs F&A Costs Total Costs Project Title Knowles, James National Institute of $10,814 $7,029 $17,843 Computational Tools for Biomedical Imaging Modeling Human and and Bioengineering Mouse Connectome with R01 (INI Satellite) Multi-Shell Diffusion Imaging Langen, Ralf National Institute $204,372 $132,829 $337,201 Molecular Mechanisms of of Neurological Huntingtin Misfolding Disorders and Stroke R01 Langen, Ralf National Institute $38,641 $25,117 $63,758 Molecular mechanism of of Neurological huntingtin misfolding - Disorders and Diversity Supplement Stroke R01 Diversity Supplement (Cervantes) Langen, Ralf National Institute $197,500 $128,375 $325,875 Membrane remodeling of General Medical by alpha-synuclein: Sciences R01 implications for function and disease Langen, Ralf Washington $96,938 $63,009 $159,947 Mechanism of modulation University In of huntington exon 1 St. Louis SubK aggregation by profilin (National Institute of Neurological Disorders and Stroke R01) Langen, Ralf Virginia Polytechnic $67,883 $44,124 $112,007 Virus-host interactions in Institute State the assembly of positive- University SubK strand RNA virus replication (National Science complexes Foundation) Mack, William National Institute of $294,680 $177,373 $472,053 Neurotoxicity of Airborne Environmental Health Particles: Role of Chronic Sciences R01 Cerebral Hypoperfusion Peti-Peterdi, French Diabetes $31,587 - $31,587 New mechanisms of tissue Janos Society Fellowship remodeling in diabetic (Desposito) nephropathy Peti-Peterdi, National Institute $225,000 $146,250 $371,250 Novel imaging approach to Janos of Diabetes and study podocyte function in Digestive and Kidney vivo Disease R01 Peti-Peterdi, Amgen, Incorporated $137,931 $62,069 $200,000 Validation of Prodocyte Janos TRPC6 as a Target in Glomerular Pathology Peti-Peterdi, American Heart $127,272 $12,728 $140,000 The role of macula densa Janos Association cells in renovascular disease

84 Grants and Contracts ZNI Investigator Funding Agency Direct Costs F&A Costs Total Costs Project Title Peti-Peterdi, American Diabetes $100,000 $15,000 $115,000 Novel tissue remodeling Janos Association mechanisms in diabetic kidney disease Peti-Peterdi, National Institute $269,015 $174,860 $443,875 Multiphoton imaging of the Janos of Diabetes and juxtaglomerular apparatus Digestive and Kidney Disease R01 Peti-Peterdi, Amgen, Incorporated $110,319 $71,707 $182,026 Validation of GPR91 as a Janos target in diabetic nepropathy

Peti-Peterdi, Eli Lilly & Company $253,269 $164,625 $417,894 Multiphoton imaging of the Janos renal hemodynamic effects of Compound X Peti-Peterdi, Amgen, Incorporated $149,094 $96,911 $246,005 Multiphoton imaging of Janos the effects novel TRPC6 antagonists in glomerular injury Peti-Peterdi, Office of the $599,808 - $599,808 Multiphoton Microscope Janos Director, National Replacement for Shared Institutes of Health Resource S10 Sieburth, Derek National Institute $6,822 $4,434 $11,256 Oxygen Radical Toxicity and of Neurological Protein Degradation Disorders and Stroke R01 (Gerontology Satellite) Sieburth, Derek National Institute $250,000 $162,500 $412,500 Stress Regulation of Synaptic of Neurological Transmission Disorders and Stroke R56 Sieburth, Derek National Institute $40,000 $26,000 $66,000 Environmental Exposures, of Environmental Host Factors and Human Health Sciences P30 Disease (Preventive Medicine Satellite) Sieburth, Derek American Heart $140,000 $14,000 $154,000 Neuronal control of the Association, Western Oxidative Stress Response: States Genetic Analysis of SKN- 1/Nrf2 Activation by Neuroendocrine Signaling Sieburth, Derek National Institute $218,750 $142,188 $360,938 Stress Regulation of Synaptic of Neurological Transmission Disorders and Stroke R01 Siemer, Ansgar Whitehall Foundation $200,143 $24,857 $225,000 The Funtion of Amyloid Proteins in Long-Term Memory

Grants and Contracts 85 ZNI Investigator Funding Agency Direct Costs F&A Total Project Title Costs Costs Siemer, Ansgar National Institute $211,424 $114,451 $325,875 Orb2 a functional amyloid of General Medical in long-term memory: Its Sciences R01 structure and how it forms Siemer, Ansgar National Institute $41,446 $26,953 $68,399 Molecular Mechanisms of of Neurological Huntingtin Misfolding Disorders and Stroke R01 (Dr. Langen) Huizhong Tao Karl Kirchgessner $50,000 - $50,000 Development of Visual Foundation Synaptic Circuitry

Huizhong Tao National Eye Institute $294,845 $188,701 $483,546 Cortical Synaptic Circuitry R01 Underlying Visual Processing

Huizhong Tao National Eye Institute $250,000 $162,500 $412,500 Synaptic circuitry R01 mechanisms underlying functional development of visual cortex Terrence Town National Institute $218,750 $142,188 $360,938 Peripheral TGF-beta of Neurological Pathway Inhibitor Therapy in Disorders and Stroke Alzheimer's Rats R01 Terrence Town National Institute $30,303 $19,697 $50,000 Peripheral TGF-beta of Neurological Pathway Inhibitor Therapy in Disorders and Stroke Alzheimer's Rats R01 (Administrative supplement) Terrence Town National Cancer $108,750 $70,688 $179,438 T cell TGF-beta signaling Institute R21 as a therapeutic target for pediatric brain tumors Terrence Town Cure Alzheimer's $150,000 - $150,000 Targeting Beneficial Innate Fund Immunity in Alzheimer's by IRAK-M deletion Terrence Town National Institute on $150,000 $97,500 $247,500 Rebalancing Innate Immunity Aging R21 in Alzheimer's Disease by Deleting IRAK-M Terrence Town Alzheimer's $227,265 $22,725 $249,990 Brain Sexual Dimorphism Association and Aging Interact in Development of AD Terrence Town Bright Focus $74,190 - $74,190 AB clearance by Central Foundation (Gulliot- vs. Peripheral IL-10R-/- Sestier) monocytes

86 Grants and Contracts ZNI Investigator Funding Agency Direct Costs F&A Costs Total Project Title Costs Terrence Town Douglas Hospital $200,000 - $200,000 Readying cerebrospinal fluid Research Centre and plasma measurements by MSD assay for Douglas Hospital Research Centre Terrence Town National Institute $160,906 $104,589 $265,495 Vascular Contributions to on Aging P01 (Dr. Dementia and Genetic Risk Zlokovic's P01- Factors for Alzheimer's Project 3) Disease Tobias Ulmer Spastic Paraplegia $150,000 - $150,000 Structural basis Foundation, Inc. of brain carnitine palmitoyltransferase 1 function Tobias Ulmer American Heart $127,272 $12,728 $140,000 Ectodomain-Transmembrane Association Domain Coupling in Integrin Receptor Signaling

Wang, Kai National Human $220,000 $143,000 $363,000 Integrated variation Enome Research detection annotation and Institute R01 analysis for high-throughout sequencing Wang, Kai National Institute of $250,000 $146,250 $396,250 Understanding the Mental Health R01 functional impacts of genetic variants in mental disorders

Zhang, Li National Institute $250,035 $162,523 $412,558 Synaptic circuitry mechanism on Deafness and for auditory cortical other Communicative processing Disorders R01 Zhang, Li National Institute $43,576 - $43,576 Functional Properties on Deafness and of Subclasses of Layer other Communicative 5 Projection Neurons in Disorders F31 (Zingg) Auditory Cortex Zhao, Zhen Alzheimer's $90,888 $9,088 $99,976 PICALM mediated Association autophagic A-beta clearance and toxicity mitigation in pericyte Zhao, Zhen National Institute $19,333 $12,566 $31,899 Alzheimer Disease Research on Aging P50 Center - Pilot 32.2 Zhao (Neurology Satellite )

Grants and Contracts 87 ZNI Investigator Funding Agency Direct Costs F&A Total Costs Project Title Costs Zhao, Zhen Whittier Foundation $50,000 - $50,000 Combination Therapy with Human Neural Stem Cells and 3K3A-APC for Ischemic Stroke Zlokovic, Berislav National Institute on $51,604 $6,305 $57,909 Caloric Restriction and Aging R01 Alzheimers ABeta Clearance Pathway Zlokovic, Berislav National Institute $412,491 $186,609 $599,100 Alzheimer's Abeta. of Neurological Apoliproteins and Blood- Disorders and Stroke Brain Barrier R01 Zlokovic, Berislav National Institute on $198,850 $129,252 $328,102 The Role of Pericytes in the Aging R01 Adult and the Aging Brain

Zlokovic, Berislav National Institute $396,194 $132,122 $528,316 Activated protein C system of Neurological in stroke models Disorders and Stroke R01 Zlokovic, Berislav Cedars Sinai Medical $11,932 $7,756 $19,688 ZZ-3K3A-201: Safety Center SubK evaluation of 3K3A-APC in (National Institute ischemic stroke of Neurological Disorders and Stroke U01) Zlokovic, Berislav National Institute on $342,436 $163,754 $506,190 Cerebrovascular Beta- Aging R01 Amyloidosis: A-beta CNS Transport Pathways Zlokovic, Berislav National Institute $30,233 $19,651 $49,884 Alzheimer Disease Research on Aging P50 Center, Biomarkers Core - (Neurology Satellite) Zlokovic Zlokovic, Berislav National Institute $93,125 $60,531 $153,656 Alzheimer Disease Research on Aging P50 Center, Project 1 - Zlokovic (Neurology Satellite) Zlokovic, Berislav Cure Alzheimer's $375,170 - $375,170 PICALM gene therapy and Fund drug screening for Abeta Clearance Zlokovic, Berislav Cure Alzheimer's $300,000 - $300,000 The role of PICALM Fund mutations in Alzheimer's disease Zlokovic, Berislav National Institute on $1,518,373 $614,945 $2,133,318 Vascular Contributions to Aging P01 Dementia and Genetic Risk Factors for Alzheimer's Disease

88 Grants and Contracts ZNI Investigator Funding Agency Direct Costs F&A Costs Total Costs Project Title Zlokovic, Berislav National Institute $412,620 $177,658 $590,278 The Role of Pericytes in of Neurological White Matter Disease Disorders and Stroke R01 Zlokovic, Berislav National Institute $12,767 $8,298 $21,065 Imaging Cerebral and of Neurological Retinal Microvasculature Disorders and in Cerebral Small Vessel Stroke R01 (INI Disease Satellite) Zlokovic, Berislav Cure Alzheimer's $225,000 - $225,000 PICALM gene therapy and Fund drug screening for Abeta clearance

Zlokovic, Berislav Alzheimer's $3,000,000 - $3,000,000 VASCULAR Association CONTRIBUTIONS TO DEMENTIA in APOE4 CARRIERS Zlokovic, Berislav Fondation Leducq $639,390 $63,939 $703,329 Understanding the roleof the perivascular space in cerebral small vessel disease $21,299,370 $8,140,373 $29,439,743

Total number of Active Grants FY17 Federal Grants 61 $21,395,601 Federal Fellowships 1 $43,576 Foundation/Private Grants 22 $6,848,864 Non-Federal Fellowships 2 $105,777 Industry 4 $1,045925

Total 90 $29,439,743

Grants and Contracts 89 ZNI Events ZNI hosts an extensive number of academic activities throughout the year, ranging from our regular seminar series to interactive workshops and meetings as well as chalk talks and journal clubs. ZNI also initiates special lectures and symposia, collaborative offerings, and community programs. We pride ourselves in inviting some of the best minds in the field to come and share their expertise and latest findings in the community through these events. Some of the offerings from FY 17 are below.

ZNI Seminar Series

7/27/2016 “A Search for The Molecular Causes of Vascular Cognitive Impairment and Dementia” Zhen Zhao PhD, Research Assistant Professor, Department of Physiology and Biophysics, Keck School of Medicine of USC Hosted by: Berislav Zlokovic

9/14/2016 “Sequence This: Applications of Next Generation Sequencing in Biology and Medicine” Oleg V. Evgrafov PhD, DSc Associate Professor of Research, Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine of USC Hosted by: Berislav Zlokovic

9/21/2016 “Brain Circuits Mediating Negative Emotions” Xiaoke Chen PhD, Assistant Professor, Department of Biology, Stanford University Hosted by: Li Zhang

10/12/2016 “G-WiZ: Genome-Wide Zeitgeist: Moving from Etiology to Pathophysiology Based Animal Models of Schizophrenia” Steven Siegel MD PhD, Professor and Chair, Department of Psychiatry and Behavioral Sciences, Keck School of Medicine of USC Hosted by: Berislav Zlokovic

10/26/2016 “Structure Biology Center for USC Labs: A Cheap, Fast and Efficient Way to Extend Your Research into Structure Biology” Fariborz Nasertorabi PhD, Research Scientist, Head of USC Structural Biology Center, USC Hosted by: Berislav Zlokovic

90 ZNI Events 11/2/2016 “A Mesoscopic View: Connecting the Micro and Macro” Russell Jacobs PhD Professor of Research, Department of Physiology and Biophysics Zilkha Neurogenetic Institute, Keck School of Medicine of USC Hosted by: Berislav Zlokovic Chu Emily credit: Photo

11/10/2016 “Communicating Your Research: Demystifying the Editorial and Peer Review Processes at Nature Research Journals” Brett Benedetti PhD, Associate Editor, Nature Medicine Dr. Bingwei Lu describes part of his research Hosted by: Berislav Zlokovic

12/7/2016 “Perinatal Infection and Inflammation: Effects on Fetal Brain Development” Irina Burd MD PhD, Director, Integrated Research Center for Fetal Medicine, Director of Research, Division of Maternal Fetal Medicine, Associate Professor of Gyn/OB and Neurology, Johns Hopkins University Hosted by: Alex Bonnin

1/11/2017 “From Concussion to Dementia: Targeting Dysregulated Brain Inflammation” Linda J. Van Eldik PhD, Professor & Chair of Neuoscience, University of Kentucky, Co-Director of Kentucky Neuroscience Institute, Director of Sanders-Brown Center of Aging and Alzheimer’s Disease Center, University of Kentucky Hosted by: Berislav Zlokovic

1/25/2017 “Postsynaptic Plasticity Following Temporally-Controlled Presynaptic Neuron Ablation in the Adult Retina” Felice A. Dunn PhD, Assistant Professor, Department of Ophthalmology, University of California, San Francisco Hosted by: Jeannie Chen

2/1/2017 “Neuroethology of Prosocial Communication and Learning in Rodents” Robert C. Liu PhD, Associate Professor, Department of Biology, Emory University Hosted by: Li Zhang

3/1/2017 “Novel Signaling Mechanisms for Glutamatergic Synapse Formation” Yimin Zou PhD, Professor & Chair, Neurobiology Section, Division of Biological Sciences University of California, San Diego Hosted by: Hong Wei Dong

3/22/2017 “Probing Neural Circuits with Shaped Light” Na Ji PhD, Group Leader, Janelia Research Campus, Janelia Farm, Howard Hughes Medical Institute Hosted by: Whit Tao

ZNI Events 91 3/29/2017 “The Development of Dendrites and Axons: The Mechanisms and Relevance to Neurodevelopmental Diseases” Bing Ye PhD, Associate Professor, Burton L. Baker Collegiate Professor of the Life Sciences, Department of Cell and Developmental Biology, University of Michigan Medical School Hosted by: Karen Chang

4/19/2017 “Parental Stress and Epigenetic Programming of the Developing Brain” Tracy L. Bale PhD, Professor of Neuroscience in Psychiatry, Department of Psychiatry, Perelman School of Medicine, Director, Neuroscience Center, School of Veterinary Medicine, University of Pennsylvania Hosted by: Alex Bonnin

4/26/2017 “Understanding the Role of Mitochondria in Neuronal Development and Disease” Bingwei Lu PhD, Professor, Department of Pathology, Stanford University School of Medicine Hosted by: Karen Chang

5/10/2017 “From Intuitive to Quantitative Understanding of the Mouse, Mammalian and Vertebrate Brain” Pavel Osten MD PhD, Associate Professor, Cold Spring Habor Laboratory, Cold Spring Harbor, New York Hosted by: Hong Wei Dong

5/24/2017 “Wiring Up a Circuit to Perform Computations: Development of Direction Selectivity” Marla B. Feller PhD, Professor & Head, Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley Hosted by: Jeannie Chen

5/31/2017 “Visual Responses in the Mouse Superior Colliculus” Jianhua Cang PhD, Professor, Department of Neurobiology, Northwestern University Hosted by: Whit Tao

6/7/2017 “Connecting Transmembrane Signaling to the Lonization Properties of Protein Functional Groups in Bilayer Membranes.” Roger E. Koeppe II PhD, Distinguished Professor, Department of Chemistry and Biochemistry, University of Arkansas Hosted by: Tobias Ulmer

6/27/2017 “Blood-Derived Neuronal Exosomes in the Prediction and Pathogenicity of Alzheimer’s Disease” Robert Rissman PhD, Associate Professor, Department of Neurosciences, University of California, San Diego Hosted by: Berislav Zlokovic

92 ZNI Events 7th Annual Zach Hall Lecture

On Friday, November 18, 2016, the Zilkha Neurogenetic Institute was honored to host Drs Eric R. Kandel and Denise Kandel as the keynote speakers for the 7th Annual Zach Hall Lecture.

Dr Eric Kandel is Professor at Columbia University, Kavli Professor and Director at the Kavli Institute for Brain Science, Co-Director at the Mortimer B. Zuckerman Mind Brain Behavior Institute and a Senior Investigator at the Howard Hughes Medical Institute. He has been recognized with many notable awards, including the Nobel Prize for Physiology or Medicine (2000). Dr Denise Kandel is Professor of Sociomedical Sciences in Psychiatry at the Department of Psychiatry at the College of Physicians and Surgeons, Professor at the Mailman School of Public Health at Columbia University, and Head of the Department of the Epidemiology of Substance Abuse at the New York State Psychiatric Institute.

Their joint talk, entitled “The Gateway Hypothesis of Substance Abuse: Developmental, Biological and Societal Perspectives,” described how tobacco or alcohol use precedes marijuana and other illicit drug use and included a roundtable discussion with Dr Berislav Zlokovic and the two speakers fielding questions from the audience. USC Provost Michael Quick provided introductory remarks while Zach Hall and Julie Giacobassi attended the talk with an overflow crowd. The seminar was followed by a reception with the speakers.

The lectures were preceded by a scientific poster session featuring over 40 separate presentations from researchers representing the various disciplines studied in ZNI laboratories. The range of work speaks to the depth and breadth of the types of research conducted at ZNI. The poster session always affords time for spontaneous yet valuable discussions among the students and researchers at ZNI and USC as well as other members of the broader scientific community.

ZNI is proud to continue the tradition of presenting the annual Zach Hall lecture which has attracted some of the biggest names in science to USC. Photo credit: Steve Cohn Steve credit: Photo

Top left: Dr. Eric Kandel delivers his lecture. Bottom left: Dr. Denise Kandel explains a point. Right: Drs. Berislav Zlokovic, Eric Kandel, Denise Kandel, and Zach Hall stand before the perpetual plaque commemorating the keynote address by the Kandels. ZNI Events 93 Mary Hayley and Selim Zilkha Chair in Alzheimer’s Disease Research

Saying it was “an incredible honor” and one of the great moments in his professional career, Berislav V Zlokovic MD PhD was installed as the inaugural holder of the Mary Hayley and Selim Zilkha Chair in Alzheimer’s Disease Research at a ceremony held 4 May 2017 at the Zilkha Neurogenetic Institute (ZNI). Dr Zlokovic’s research focuses on the links between the health of blood vessels in the brain and degenerative brain diseases. His accomplishments have earned him worldwide acclaim. As

Photo credit: Steve Cohn Steve credit: Photo director of the ZNI, Dr Zlokovic acknowledged the great work of the faculty. Calling his colleagues “talented scientists” he remarked how despite the odds, the researchers at ZNI are securing more grants each year, publishing in the best journals, and importantly, training the next generation of scientists. Dr Zlokovic also thanked President CL Max Nikias, Provost Michael Quick for their support of the institute. He reserved his warmest thanks for Mary Hayley and Selim Zilkha, thanking them for their seemingly endless drive and energy that inspires the researchers at ZNI to do the very best science while building a world-class research institute. Photo credit: Steve Cohn Steve credit: Photo

Dr. Berislav Zlokovic celebrates being appointed the inaugural chair with his wife Zora Mihailovich, Mary Hayley, and Selim Zilkha.

94 ZNI Events 4th Annual Zilkha Symposium on Alzheimer Disease & Related Disorders

The 4th Annual Zilkha Alzheimer Symposium, “From Investigation to Integration: New Basic, Translational & Clinical Efforts in Alzheimer’s Disease & Related Disorders ” was held on 5 May 2017, with national and international leaders in the field convening at USC to share their work:

Christer Betsholtz MD PhD, Professor of Immunology, Genetics & Pathology, Uppsala University, Sweden; Kaj Blennow MD PhD, Professor of Clinical Neurochemistry, University of Gothenburg, Sweden; David Holtzman MD, Professor & Chair of Neurology, Washington University School of Medicine in St. Louis; Costantino Iadecola MD, Director, Feil Family Brain & Mind Research Institute and Professor of Neurology, Weill Cornell Medical College, NY; Virginia Lee PhD, Professor in Alzheimer’s Research, University of Pennsylvania Perelman School of Medicine; Ronald Petersen MD PhD, Director, Mayo Alzheimer’s Disease Research Center and Professor of Neurology, Mayo Clinic College of Medicine, MN; Len Petrucelli PhD, Professor & Chair of Neuroscience, Mayo Clinic Florida; Rudolph Tanzi PhD, Director, Genetics and Aging Research Unit, Massachusetts General Hospital and Professor of Neurology, Harvard University; John Trojanowski MD PhD, Director, NIA Alzheimer’s Disease Center, the NINDS Morris K. Udall Parkinson’s Disease Center, and the Institute on Aging and Professor of Geriatric Medicine and Gerontology, University of Pennsylvania Perelman School of Medicine; Paul Aisen MD, Director, USC Alzheimer’s Therapeutic Research Institute; Professor of Neurology, USC; Berislav Zlokovic MD PhD, Director, Zilkha Neurogenetic Institute and Professor & Chair, Physiology & Biophysics, USC

Discussant leaders included Roger Nitsch MD, Director, Institute of Regenerative Medicine and Professor, University of Zurich; Margaret Ross MD PhD, Professor in Neurology, Weill Cornell Medical College, NY; Sangram Sisodia PhD, Director, Center for Molecular Neurobiology and Professor of Neurobiology, University of Chicago; Robert Vassar PhD, Professor of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University; and Cheryl Wellington PhD, Professor of Pathology and Laboratory Medicine, Djavad Mowfaghian Centre for Brain Health, University of British Columbia.

Session chairs were Maria Carrillo PhD, VP, Medical & Scientific Relations, Alzheimers Association; and Arthur Toga PhD, Director, USC Mark and Mary Stevens Neuroimaging and Informatics Institute and Provost Professor of Opthalmology, USC

Co-organizers for the symposia with Dr Zlokovic were Drs David Holtzman MD (Wash U) and Rudi Tanzi, PhD (Harvard). Opening remarks were given by Dr. Zlokovic and Photo credit: Steve Cohn Steve credit: Photo Mr. Selim Zilkha. The day-long event was underwritten by a generous gift from Eva and Marc Stern.

Planning is now underway for the 5th Annual Zilkha Alzheimer Symposium, “Searching for Solutions: Explorations of Genetic, Vascular and Neuronal Influences and Clinical Therapies,” scheduled for 27 April 2018.

ZNI Events 95 Joint ADRD ZNI Pilot Program

The ADRC and ZNI continued in FY17 to combine resources and efforts to support promising research projects by providing seed funding through the USC Alzheimer Disease Research Center (ADRC) and Zilkha Neurogenetic Institute (ZNI) Pilot Project Program.

The ADRC-ZNI Pilot Project Program invites clinical and basic science investigators to submit letters of intent for 12-month pilot projects. The ADRC focuses on mild cognitive changes related to Alzheimer’s, cerebrovascular disease, and their interactions in diverse communities. With the support of the ZNI, there are new opportunities to explore basic, clinical and psychosocial approaches to the pathogenesis, prevention, and treatment of early cognitive impairment in humans and animal models. The program is especially interested in new approaches to intervention and translational research from preclinical to early phase trials. Projects that use data available through the National Alzheimer’s Coordinating Center or the USC ADRC are strongly encouraged.

The ADRC-ZNI Pilot Project Program grants are designed to support junior faculty level investigators, but are also awarded to senior investigators with experience in areas other than AD research, PIs who want to expand the scope of their work to include the AD research field or who want to explore a new hypothesis, method, or approach that is not an extension of ongoing AD research. Postdoctoral fellows with a faculty sponsor are also eligible. Successful applicants receive direct costs up to $30,000 for one-year pilot projects with the hope that the results will lead to further external funding.

For FY17, four ADRC-ZNI Pilot Awards were given to • Zhen Zhao PhD “Identification of active transcriptional regulatory elements for Alzheimer’s vascular risk genes”

• Hong Wei Dong PhD, Houri Hintiryan PhD and Nicholas Foster PhD “Building an open access functional connectome of glucose homeostasis”

• Justin Ichida PhD “Impaired Microglial Endocytosis of Amyloid Beta Caused by a Mutation in the Enhancer Region of PICALM”

• Jae Jung PhD, Jianning Ge PhD and Zhen Zhao PhD “Discovery of TXNIP-GLUT1 interaction as a therapeutic target for Alzheimer therapy”

The program is expected to continue in FY18, with more awards supporting an additional array of studies. This new collaboration between the ADRC and ZNI enables the support of additional pilot projects, using an integrated solicitation and review process.

96 ZNI Events Los Angeles/Irvine Brain Bee

After hosting the event last year, ZNI once again co-sponsored with UCLA, UCI and LACC the 2017 Los Angeles/Irvine Brain Bee on 21 January 2017. Nearly 100 students ages 14-19 and their families gathered under sunny skies on the Westwood campus as 15 volunteers from USC contributed their time and talents to the day-long experience. Dr John Ringman, Professor of Clinical Neurology, participated both on the professional panel and also represented USC as a Jeopardy judge. Amy Nelson PhD, a postdoctoral scholar in the laboratory of Dr Berislav Zlokovic, recruited, organized and led the USC volunteers to assure the day was a success.

Created by the Society for Neuroscience and held across the US and the world, brain bees are similar to spelling bees, but instead of spelling words, participants answer questions about brain facts and anatomy in a fun and interactive way. There are hands-on activities, posters and demonstrations to engage and educate the community about the brain in a fun and interactive way, and to encourage students to explore higher education and perhaps a career in neuroscience.

After three rounds of Jeopardy, Midori Thomas from University High School was named the first prize winner. Midori and her family received a Bethesda, MD, where she participated in the National Brain Bee, representing Los Angeles. Photo credit: Melanie Sweeney credit: Photo

Left: Contestants in the 2017 Brain Bee represented high schools throughout the southland. Bottom: Students wear protective gear to examine a sheep brain Top right: The three finalists.

ZNI Events 97 Music to Remember

Music to Remember, a program now five years old, sends trained vocalists to sing Christmas carols and other holiday songs at long-term care and assisted living facilities throughout Los Angeles County. ZNI partners with Alzheimer’s Greater Los Angeles (which also produces Memory Mornings programs) and LA Opera as well as the Alzheimer Disease Research Center at the Keck School of Medicine of USC to present this collaborative effort.

Holiday music is part of just about everyone’s earliest memories, and that may be the key to establishing new connections with people suffering from Alzheimer’s. One often remembers things learned when very young, especially if these memories have been reinforced over the years. Holiday music–and for a certain generation, patriotic songs–are auditory experiences that have become ingrained in most of us, due to consistent repetition.

During FY17, a group of LA Opera vocalists sang at more than a dozen hospitals, long-term care or assisted living facilities over five days in December. In addition to singing to people suffering from Alzheimer’s disease and dementia, through separate programs LA Opera shares holiday joy with veterans and children in hospitals. Dressed in coats, capped with Santa hats and carrying bells, LA Opera singers strolled through the following locations during the past year: • Long Beach Veterans Admin (Community Living Center) • Memory Mornings at Alzheimer’s Association • Immaculate Heart Community Residence • Villa Gardens Retirement Community (Summer House) • West LA Veterans (Community Living Center)

The seasonal concerts are part of a general movement toward total patient care. In the course of just 45 minutes of performances by the young singers, one may witness a calm going over someone who is otherwise very disconnected or who may usually be quite agitated. Someone who was only looking down may start to

look up with a renewed focus. The music often Chu Emily credit: Photo causes foot tapping and sometimes, tears.

ZNI Director of Operations, David Warren, enjoys a moment with singers from the LA Opera.

98 ZNI Events ZNI Administration and Operating Budget Behind most successful operations is a strong administrative backbone and ZNI is no exception. Led by David Warren, senior director of operations, finance and administration, the ZNI has a team of talented individuals committed to providing the best in service so that our many researchers may in turn dedicate their attention to the important research conducted here.

Staff include facilities manager Rusty King; human resources manager Barbara Lockley; senior grants administrator Gabriela Torres, contracts and grants coordinators Muoi Thang and Melissa Frank; purchasing budget/business analyst Leslie Ortiz; hr budget/business technician Marlen Turcios; events and program manager Emily Chu; executive assistant Monica Castro; and two lab aides providing glassware and autoclave services, Benilda Ramos and Manuela Osorio.

These individuals provide the day-to-day support that keeps ZNI moving forward.

ZNI serves as a hub for the neuroscience community across campuses, offering a weekly seminar series, hosting neuroscience graduate courses, journal clubs, special lectures, as well as grand rounds for the departments of Neurology, Neurosurgery and Otolaryngology. Everyone at ZNI is focused on creating an environment that results in only the very best science. FY17 Operating Budget

Income Forward Expenses Balance From FY 16

Program Funds (Endowment) $2,605,211 $837,563 $2,092,233 $1,350,541

Departmental Funds (KSOM-Provided) Administrative $617,890 N/A $617,890 - Facilities $185,842 N/A $185,842 - Common Equipment Fund $35,562 N/A $35,479 $83 Chair's Discretionary $150,000 N/A - $150,000

Deans Development Funds $599,428 N/A $599,428 -

Philanthropy Unrestricted Gifts $457,898 $200,214 $115,314 $542,798 Restricted Gifts $1,027,650 - $154,148 $873,503

Endowed Chair (Principal) $500,000 $1,536,438 - $2,036,438

ZNI Administration 99 ZNI Development

The Zilkha Neurogenetic Institute is excited to be a critical part of a larger USC Alzheimer’s Initiative encompassing a highly specialized group of researchers, innovators and clinicians striving to achieve the breakthrough therapies and cures for Alzheimer’s disease. The university experts involved in this endeavor are collaborating to expand their already groundbreaking research exponentially, working to accelerate the implementation of innovative discoveries and promising treatments into clinical trials and therapies to slow or cure the disease.

A cornerstone of the initial naming gift by the WM Keck Foundation, the Zilkha Neurogenetic Institute is uniquely poised to contribute significantly to this cause, by providing researchers with an ideal home for their studies. By accessing our state-of-the-art technology and specially designed laboratories, junior and senior investigators are already producing outstanding results. By building on our existing infrastructure, further philanthropic contributions will allow our researchers to advance the scientific knowledge in their respective fields to new heights.

Specifically ZNI is seeking to • establish endowed chairs for acclaimed senior professors at the Institute • endow and support the operations of our various research programs, centers and cores • build an equipment fund to replace aging items with the latest technologies • invest in the future by recruiting junior and established researchers to join our team • support pilot projects of novel ideas, securing data to apply for broader external funding • provide unique opportunities for graduate students, postdoctoral and clinical fellows

ZNI is home to over 300 researchers, all of whom are working to create a difference. Research programs and centers at ZNI include the Center for Special thanks to our donors for their gifts and pledges: Neurodegeneration and Regeneration; Multiphoton • Anonymous Center; Protein Structure Center; Center for • Wallis Annenberg Genomic Psychiatry; Hearing & Vision Circuit • Gayle & Bryan Batey Center; Biosafety Level-3 Laboratory; the Functional • Helene & Louis Galen Family Biological Imaging Core; a Biomarkers Core; and the Foundation • Zach Hall & Julie Giacobassi Center for Sensory Behaviors and Neural Circuits. • Selena Gomez • Mary Hayley & Selim Zilkha If you wish to partner with ZNI and support our • Gary Kaplan efforts to arrest and reverse Alzheimers and other • WM Keck Foundation related conditions of dementia, please contact the • Dr. Michael A. Martens • Eva & Marc Stern Zilkha Neurogenetic Institute at the Keck School of Medicine of USC via [email protected] or (323) 442-2144.

100 ZNI Development

Zilkha Neurogenetic Institute 1501 San Pablo Street Los Angeles, CA 90033 Phone: (323) 442-2144 Fax: (323) 442-2145 Email: [email protected] www.usc.edu/zni © 2017 Keck Medicine of USC