Molecular Mechanisms Controlling Brain imaging Brown wins INSIDE 2 of Memory 3 attention 5 advance 6 Swartz Prize Genes & Disease

Neuroscience News

WINTER 2020 Neuroscientists discover a molecular mechanism that allows memories to form When the brain forms a memory of a new chromatin modifications. In these regions, the DIRECTOR’S MESSAGE experience, neurons called engram cells encode chromatin became looser, allowing the DNA the details of the memory and are later reacti- to become more accessible. To the researchers’ vated whenever we recall it. A new study reveals surprise, nearly all of these regions were in Dear Friends, that this process is controlled by large-scale stretches of DNA where no genes are found. There is no question that 2020 was a trying remodeling of cells’ chromatin. These regions contain noncoding sequences year, pretty much no matter who you are. called enhancers, which interact with genes to This remodeling, which allows specific genes Everything is more difficult, and that difficulty help turn them on. The researchers also found is harder to navigate, when we cannot endure involved in storing memories to become more it all together. But as best as we can, we have active, takes place in multiple stages all adapted and persevered. spread out over several days. Changes to the density and arrangement of chro- In this edition’s cover story (page 7), we look matin, a highly compressed structure at a theme in our research that similarly consisting of DNA and proteins called pits determination against difficulty. When histones, can control how active specific scientists are able to associate a gene with genes are within a given cell. disease, either as a cause or a significant risk factor, it rightfully inspires new hope, but a “This paper is the first to really reveal this tremendous amount of hard work lays ahead, very mysterious process of how differ- especially in neuroscience. To translate that ent waves of genes become activated, knowledge into therapies, researchers must and what is the epigenetic mechanism endeavor to understand how alterations in the underlying these different waves of gene affect the development or degeneration of gene expression,” says Li-Huei Tsai, the In this mouse brain cross-section, "engram" cells the brain. This has proven to be no easy task, are stained yellow. director of MIT’s Picower Institute for but several Picower researchers have been Learning and Memory and the senior able to make important progress, including with several recent studies. author of the study. that the chromatin modifications did not have any effect on gene expression. We are not alone. At our Aging Brain Initiative Asaf Marco, an MIT postdoc, is the lead symposium, colleagues from around the world author of the paper, which appeared in The researchers then analyzed engram cells five shared key progress against neurodegenerative Nature Neuroscience. days after memory formation. As memories diseases. You can find a recap on page 10. In the first stage of memory formation, genes were consolidated, or strengthened, over that period, the 3D structure of the chro- In several other stories that follow in our known as immediate early genes are turned on matin surrounding the enhancers changed, in engram cells, but these genes soon return to news section we report on other exciting bringing the enhancers closer to their target new insights into the brain’s extraordinary normal activity levels. Tsai and Marco’s team genes. This still didn’t turn on those genes, complexity. We show how DNA opens up to wanted to explore what happens later in the but it primed them to be expressed when the enable memory recall and how neural circuits process to coordinate the long-term storage memory was recalled. endow us with the ability to ignore distraction of memories. and restrain impulses. We illuminate the role Next, the researchers placed some of the mice They hypothesized that the process could of brainwaves in guiding brain function and back into the chamber where they received the be controlled by epigenomic modifications, describe new ways of imaging the brain. We foot shock, reactivating the memory. In the which are chemical alterations of chroma- even describe a new method for understanding engram cells, the researchers found that the tin that control whether a particular gene how changes in skin conductance reflect primed enhancers interacted frequently with changes in the subconscious nervous system, is accessible or not. To study epigenomic their target genes, leading to a surge in the sometimes providing a measure of hidden changes in individual engram cells over time, expression of those genes. stress or anxiety. the researchers genetically engineered mice to permanently tag engram cells in the hippo- Many of the genes turned on during memory Our hope is that 2021 offers a new and campus with a fluorescent protein when a recall are involved in promoting protein higher degree of peace and prosperity for everyone. Here’s hoping that with continued memory is formed. These mice received a synthesis at the synapses, helping neurons determination and good fortune we can mild foot shock that they learned to associ- strengthen their connections with other experience a Happy New Year in the lab and ate with the cage in which they received the neurons. The researchers also found that the in our lives and do so, once again, together. shock. When this memory formed, the hippo- neurons’ dendrites — branched extensions that campal cells encoding the memory began to receive input from other neurons — developed produce a yellow fluorescent protein marker. more spines, offering further evidence that LI-HUEI TSAI, DIRECTOR The Picower Institute for Learning and Memory Right after a memory was formed, the research- their connections were further strengthened. ers found that many regions of DNA undergo Scientists identify specific brain region and circuits controlling attention

The attentional control that organisms presentation or by hyperactive-impulsive In the second task, before seeing the light need to succeed comes from two abilities: the presentation. Perhaps we can conceive new that flagged the reward portal (this time for focus to ignore distractions and the discipline strategies to tackle different types of ADHD.” three seconds), the mice saw a “cue” flash. to curb impulses. A new study by Sometimes that cue would be on MIT neuroscientists shows that the opposite side, sometimes in the these abilities are independent, middle and sometimes on the correct but that the activity of norepineph- side. Again LC stimulation improved rine-producing neurons in a single correctness and suppressed impulses brain region, the locus coeruleus while inhibition reduced correctness (LC), controls both by targeting and increased impulses. Importantly, two distinct areas of the prefron- stimulated-LC mice showed no differ- tal cortex. ence in reaction time regardless of cue position because they were focused “Our results demonstrate a funda- on the reward goal. But reaction time mental causal role of LC neuronal varied in inhibited-LC mice because activation in the implementation of they were distracted by the cue—when attentional control by the selective it was on the wrong side they found the modulation of neural activity in portal more slowly than normal and its target areas,” wrote the authors when the cue was on the correct side of the study from the research they reacted faster. group of Susumu Tonegawa, Picower Professor of Biology and In task three, the mice faced the Neuroscience at RIKEN-MIT possibility of constant distraction by Laboratory of Neural Circuit irrelevant lights while they waited for Genetics at The Picower Institute the three-second signal of the food for Learning and Memory and reward location. The same results Howard Hughes Medical Institute. ocurred, with one exception. When there were no distractors, with three Prior studies have suggested that Neurons in the locus coeruleus, stained green, are key for long seconds to notice the signal, norepinephrine-producing, or controlling attention and impulsive behavior. noradrenergic, neurons in the inhibited-LC mice did not lapse LC might have this role, but the in performing correctly. They only showed the deficit amid distractors. most convincing evidence has been correla- Unexpectedly the study also raised new ques- tive rather than causal, said study lead author tions about the LC’s role in anxiety, Bari said, To test whether attentional focus and impulse Andrea Bari, a research scientist. In the new because to the team’s surprise, stimulating LC control were independent, the team controlled study in the Proceedings of the National activity also happened to reduce anxiety in the LC activity and norepinephrine release not at Academy of Sciences, the team demonstrated mice. That’s an area for future investigation. the main neuron bodies as before, but now clear causality by using optogenetics to only where their long projections connected precisely control LC noradrenergic neurons Locus focus to specific areas of the prefrontal cortex (PFC). in mice as the rodents engaged in three Going on some of Bari’s prior research and After establishing their method of taking bidi- attentional control tasks. Optogenetics is a other hints, they targeted the dorso-medial PFC rectional optogenetic control of noradrenergic genetic technology that allows scientists to (dmPFC) and the ventro-lateral orbitofrontal LC neurons—meaning that with different control neural activity with flashes of light. cortex (vlOFC). Stimulating LC connections colors of light they could either stimulate or The manipulations immediately and reliably into the dmPFC increased correct perfor- inhibit activity—the researchers tested the impacted the rodents’ performance. mance but did not reduce premature responses. effects of each manipulation. In the first task, Meanwhile, stimulating LC connections in the The results, the authors said, could aid efforts the rodents had to wait for a half-second flash vlOFC did not improve correct performance, to understand and treat psychiatric disorders in that signaled which of two portals held a food but did reduce premature responses. which attentional control or either of its compo- reward. Mice in whom LC neurons were opto- nent abilities is compromised, such as attention genetically stimulated did the task correctly “Our results reveal that the attentional control of deficit and hyperactivity disorder (ADHD). more often and made fewer premature moves behavior is modulated by the synergistic effects “ADHD patients may suffer both distractibility than when not manipulated. Mice whose LC of two dissociable coeruleo-cortical pathways, and impulsivity,” said co-author and research neurons were inhibited did the task correctly with LC projections to dmPFC enhancing scientist Michele Pignatelli “but you can also less often (less attention meant missing that attention and LC projections to vlOFC reduc- have cases mainly characterized by inattentive light flash) and jumped the gun more often. ing impulsivity,” the authors wrote.

PICOWER DISCOVERIES 3 Alzheimer’s risk gene disrupts endocytosis, but another disease-linked gene could help a postdoc in the lab of the late Susan Lindquist and then the lab of Li-Huei Tsai, Picower Professor of Neuroscience. By comparing lab-cultured human astrocytes that were identical except in whether they had the APOE4 or APOE3 variants, the researchers found several signs of disrupted endocytosis, specifically in the early stage of the process when key proteins were notably reduced in the APOE4-carrying cells. They were able to directly observe that the afflicted astrocytes were less capable of bringing in materials from the outside. The team modeled the APOE4 endocytosis deficit in yeast cells and used those to screen Astrocytes are a key type of brain cell. A new study shows how Alzhemer's risk genes affect for proteins that might provide a protective their function. effect. They found that expressiong an analog of a human gene called PICALM improved APOE4 cells’ endocytosis. When the scientists overexpressed PICALM in APOE4 human Scientists at The Picower Institute and substantially increases Alzheimer’s risk. The astrocytes, it repaired early endocytosis new study in Cell Reports finds that in astrocytes, the Whitehead Institute have found evidence function, as measured by the increased intake which are the most common non-neuron cell that the most prominent Alzheimer’s disease of test proteins. risk gene may disrupt a fundamental process in the brain, the variant hampers the process in a key type of brain cell. Moreover, in a of endocytosis, which is a major way that “Both APOE and PICALM are Alzheimer’s risk sign of how important it is to delve into the cells bring materials in from outside. That genes,” Tsai said. “It is really interesting that complex ways that genes intersect in disease, functional deficit could undermine several of the two genes converge on endocytosis. This they found that increasing the expression of the vital roles that astrocytes play in the brain. indicates that faulty endocytosis plays a key role in the etiology of Alzheimer’s.” another Alzheimer’s-associated gene in those The study’s co-lead authors are Grzegorz cells could help alleviate the problem. Sienski of the Whitehead Institute and Scientists have been working for decades to Priyanka Narayan, a researcher at the National understand why the APOE4 gene variant Institutes of Health who co-led the work while As information flows through brain’s hierarchy, higher regions use higher frequency waves

Your brain processes information in a information up and down the hierarchy. would decrease. When the image had to be held in mind, theta and gamma power went down hierarchy of regions along its surface, or cortex, “We wanted to obtain an overarching picture so and alpha and beta power went up in bursts. ranging from “lower” areas that parse incoming that’s what we did,” said Earl Miller, Picower sensations to “higher” executive regions that Professor of Neuroscience and senior author of While this pattern applied across all three formulate plans. MIT neuroscientists seeking the study. “We addressed the question of what regions, a key difference was that each region to explain how this organization emerges does this look like all over the cortex.” employed a distinct peak within each frequency report two broad trends: In each of three band. While the visual cortex beta band, for Picower Institute postdoc Andre Bastos and distinct regions, information encoding or its instance, peaked at 11 Hz, parietal beta peaked Mikael Lundqvist of Stockholm University and inhibition was associated with a similar tug at 15 Hz and prefrontal beta peaked at 19 Hz. MIT are the study’s co-first authors. of war between specific brain wave frequency Meanwhile visual cortex gamma peaked at bands, and the higher a region’s status in the In the visual cortex, the parietal cortex and the 65 Hz, parietal gamma topped at 72 Hz and hierarchy, the higher the peak frequency of its prefrontal cortex they found that when animals prefrontal gamma at 80 Hz. waves in each of those bands. first saw an image or recalled that image in “The increased frequency in the oscillatory The team’s new study in the Journal of a later test, the power of theta and gamma rhythms may help sculpt information flow in Cognitive Neuroscience provides a unifying view frequency bands of brain waves would increase the cortex,” the authors wrote. of how brain waves may control the flow of in bursts and power in alpha and beta bands

4 PICOWER DISCOVERIES Live imaging method brings structural information to mapping of brain function

Scientists distinguish brain regions by what they do, but have lacked a way to overlay infor- mation about how they are built, especially in live animals while they are performing the functions of interest. Now MIT researchers have produced an unprecedented pairing of functional mapping in live mice with distin- guishing structural information for each region. “Our study shows for the first time that struc- tural and functional coupling of visual areas in the mouse brain can be detected at sub-cellular resolution in vivo,” wrote the authors based in Six different regions in the visual cortex of a mouse show distinct anatomy of blood vessels the lab of Mriganka Sur, Newton Professor of and myelin fibers. Neuroscience in The Picower Institute. The technique could give scientists more they do? The critical thing is to precisely map identify functional regions by engineering precise ways to distinguish the borders and or match the functional representation of each neurons to flash when they become electri- contents of regions they wish to study, help- area with its anatomical uniqueness.” cally active (and show changes in calcium) ing them better understand how structural To develop tools to help answer those ques- in response to a particular stimulation. distinctions develop within individuals in tions, postdoc Murat Yildirim led the research Three-photon microscopy can finely resolve different functional regions over time. Sur’s lab, published in Biomedical Optics Express. The individual cells and their smaller substructures for instance, is intensely interested in under- team combined a method of charting func- as deep as a millimeter or more—enough to see standing the development of the visual system, tional areas—retinotopic mapping—with all the way through the cortex. THG, mean- which involves many brain areas. deep structural information measured while, adds the capability to finely resolve both by a technology Yildirim has helped to blood vessels and the fibers of a material called “There is something profound in the way that myelin that wrap the long, tendrilous axons of vision is represented and created in mamma- pioneer—third-harmonic generation (THG) three-photon microscopy. many neurons. This allowed them to discern lian brains,” Sur said. “Where do these areas unique structural attributes for each region. come from, what do they mean and what do In retinotopic mapping, researchers can Statistical model improves analysis of skin conductance Electrodermal activity – the sweat-induced research team sought a model to match the The researchers formulated an inverse Gaussian fluctuations of skin conductance made famous actual physiology of sweat. When stimulated by model of EDA and then put it to the test with 11 in TV dramatizations of lie-detector tests – can the sympathetic nervous system, glands under volunteers who wore skin conductance monitors strongly indicate subconscious, or “sympathetic,” the skin build up a reservoir of sweat and then for an hour as they sat quietly, read or watched nervous system activity, but only if it is analyzed release it when they are full. This kind of process, videos. Even while “at rest” people’s thoughts and optimally. In the Proceedings of the National called “integrate-and-fire,” is also characteristic feelings wander, creating variation in the EDA Academy of Sciences, an MIT-based team of of natural phenomena like the electrical spiking signal. The inverse Gaussian produced a tight fit scientists provides a new, fast and accurate of nerve cells and geyser eruptions, said senior with the readings in all 11. In 9 of the 11 cases, statistical model for analyzing EDA. author Emery N. Brown, Edward Hood Taplin adding one of a few related statistical models Professor at The Picower Institute. tightened the inverse Gaussian’s fit a little further. Existing methods either compute averages of the signal that obscure its instantaneous nature or Sandya Subramanian, a graduate student in the Subramanian said that in practical use, an inefficiently force measurements into a fit with Harvard-MIT Health Sciences and Technology EDA monitoring system based on an inverse signal processing models that have nothing to do program is the study’s lead author. Gaussian model alone could immediately be with what’s going on in the body. useful, but it could also be quickly fine-tuned by Brown and Subramanian recognized that there initial readings from a subject to apply the best To make EDA analysis faster and more accurate is a well-established statistical formula for combination of models to fit the raw data. for interpreting internal cognitive states (like describing integrate-and-fire systems called an anxiety) or physiological states (like sleep), the “inverse Gaussian.”

PICOWER DISCOVERIES 5 New trial to Brown wins SfN’s Swartz Prize test brain wave The Society for Neuroscience announced said. “The prize recognizes my group’s work Oct. 26 that it has awarded the Swartz Prize for to characterize more accurately the properties Theoretical and Computational Neuroscience of neural systems by developing and applying stimulation as to Emery N. Brown, Edward Hood Taplin statistical methods and signal processing Professor of Medical Engineering and Alzheimer’s Computational Neuroscience at MIT. Brown, a member of The Picower Institute and the Institute for Medical Engineering and preventative Science, is a neuroscientist, a statistician and a practicing anesthesiologist at Massachusetts Wth a new $1.8 million grant from the General Hospital and Harvard Medical School. Part the Cloud-Gates Partnership Grant His research has produced principled and Program of the Alzheimer’s Association, efficient new methods for decoding patterns researchers at Massachusetts Institute of of neural and brain network activity and has Technology and Massachusetts General advanced neuroscientific understanding of Hospital are launching a new clinical trial how anesthetics affect the brain, which can to test whether stimulating a key frequency improve patient care. of brain waves with light and sound can “Dr. Brown’s seminal scientific contributions prevent the advance of Alzheimer’s disease to neural signal processing and the theory pathology even before volunteers experience of anesthetic mechanisms, together with his Emery N. Brown speaks at the 2019 symptoms such as memory impairment. service as an educator and a physician, make Society for Neuroscience annual meeting. him highly deserving of the 2020 Swartz Prize,” “Because Alzheimer’s disease leads to SfN President Barry Everitt said in a press neurodegeneration and cognitive decline, algorithms that capture their dynamical release announcing the award. “Dr. Brown has features. It further recognizes our efforts to the best time for intervention may be demonstrated an unusually broad knowledge of before those symptoms even begin,” uncover the neurophysiological mechanisms neuroscience, a deep understanding of theoretical of how anesthetics work and to translate said Li-Huei Tsai, Picower Professor of and computational tools, and an uncanny ability those insights into new practices for managing Neuroscience and director of The Picower to find explanatory simplicity lurking beneath patients receiving anesthesia care. Institute for Learning and Memory at MIT. complicated observational phenomena.” “We are hopeful that our safe, non-invasive “Finally,” he added, “receipt of the Swartz Brown said the recognition made him thankful approach of sensory stimulation of Prize makes me eternally grateful for the for the chances his research, teaching and 40Hz gamma brain rhythms can have a outstanding colleagues, graduate students, medical practice have given him to work with preventative benefit for patients. We are post-docs, undergraduates, research assistants colleagues and students. very grateful to Part the Cloud-Gates and staff with whom I have had the good Partnership Grant Program for their “Receiving the Swartz Prize is a great honor,” he fortune to work.” support in funding rigorous research to test this exciting possibility.” In extensive testing with multiple mouse models of Alzheimer’s, the light and sound Picower researcher earns BBRF stimulation technique, called Gamma ENtrainment Using Sensory Stimuli Young Investigator grant (GENUS), improved cognition and memory, prevented neurodegeneration, Vincent Breton-Provencher, a postdoc in the lab of Newton Professor of and reduced amyloid and tau protein Neuroscience Mriganka Sur, is among a select group of promising researchers buildups. The research showed that to be awarded Young Investigator grants, The Brain & Behavior Research increasing 40Hz brain rhythm power and Foundation announced this fall. synchrony stimulated the brain’s immune cells and its blood vessels to clear out the Breton-Provencher is working to understand the neurobiology of attention toxic proteins. Early results from human to better diagnose ADHD and disruptive behavior, and to develop potential testing at MIT show that GENUS is well treatments. To do so he studies the neurotransmitter noradrenaline (NA) in tolerated and increases 40Hz power and a brain region called the locus coeruleus (LC), specifically looking at circuits synchrony, just like in the mice. connecting the LC to the motor and prefrontal cortices, and their involvement in sustained attention and cognitive flexibility. His experiments will seek to determine how NA activity The new study, conducted in collaboration affects cortical computations in neurons during attention, which could aid in understanding the with neurologist Keith Johnson at MGH, heterogeneity of ADHD dysfunctions. will enroll 50 volunteers aged 55 or older who show signs of amyloid protein plaque "I am very honored to be receiving the Young Investigator Award from BBRF, which will support buildup in PET scans but who remain my research on the role of noradrenaline in learning and attention that I am currently conducting cognitively normal. at MIT,” Breton-Provencher said. “As I am about to start my own lab by the summer of 2021 at the Université Laval in Québec City, the award will also be a tremendous help for this transition period.”

6 PICOWER PEOPLE Genes & Disease Picower scientists are making the dauntingly long but highly motivating climb between associating a gene with disease and developing potential treatments.

DNA’s resemblance to a twisted ladder Because the brain is a uniquely complex Genetic cause provides an apt metaphor. Identifying a system that constantly adapts and changes, specific gene as the cause of disease or as a diseases of the central nervous system Picower Professor Mark Bear has been waging can be especially tricky to understand a battle against Fragile X syndrome, the leading significant risk factor gives researchers clear heritable cause of intellectual disability and mechanistically, especially when their direction toward developing treatments, autism, for nearly 20 years. Fragile X is caused but it also puts them at the bottom pathology plays out over the course of by mutation—specifically CGG nucleotide rung of what history has shown to be a decades, said Myriam Heiman, Associate repeats—in the FMR1 gene that can eliminate long climb. Undeterred, several Picower Professor in the Picower Institute and the production of the protein FMRP. As such it is Institute labs have embraced the challenge Broad Institute of MIT and Harvard. a “simple” disease, Bear says. of turning genetic knowledge into the In the early days of the Human Genome “We actually know the cause,” he says. “We neuroscience needed to produce clinical Project many people hoped that identifying don’t have to guess about it. All that goes advances for developmental, psychiatric and genes would make finding treatments wrong in individuals with Fragile X syndrome neurodegenerative brain disorders. straightforward. Sometimes this is possible. is due to the absence of this FMRP protein.” Their goal is to pinpoint how a genetic In the brain-affecting metabolic disease The work started back in 2002 with a paper aberration undermines the function of PKU, for instance, identifying the genetically in the Proceedings of the National Academy inherited loss of ability to regulate the brain cells and circuits. Learning how things of Sciences (PNAS). In fundamental research biochemical phenylalanine led to a clear go wrong puts within reach new ideas for on mechanisms of synaptic plasticity—the therapeutic strategy of restricting diet preventing or reversing those problems. way neurons change their circuit connections (though a cure remains undiscovered). in response to experience to enable Indeed some strategies developed at the development, learning Picower Institute have advanced potential “But many diseases of the nervous system and memory—Bear’s lab therapies all the way to clinical trials. don’t follow that paradigm,” said Heiman, who this year has published two papers discovered that loss of “Discovery of the gene is just the first step in in Neuron finding novel mechanisms FMRP exaggerates the a mechanism-based understanding and it can and potential therapeutic targets in consequences of activating take decades,” says Mriganka Sur, Newton Huntington’s disease, a fatal and incurable a neurotransmitter receptor Professor of Neuroscience. Sur is a global neurodegenerative disorder. Scientists have called metabotropic leader in studying how mutations in the gene known for more than 25 years that just glutamate receptor 5, or MECP2 hinder the development of neurons one type of mutation—an accumulation mGluR5. Activating and neural circuits and the maturation of repeating CAG trinucleotides in the mGluR5 causes synapses to weaken, a normal of neural connections, called synapses, Huntingtin gene—causes toxic aggregation process called long-term depression, but disrupting intellectual development in of Huntingtin protein, but as Heiman’s new without the brake provided by FMRP, there patients with Rett Syndrome, an autism- research shows, there is still a lot to learn is too much LTD. like disorder. about how that makes neurons vulnerable. CONTINUES ON PAGE 8

PICOWERPICOWER DISCOVERIES DISCOVERIES 7 Neuroscience in 2006, Sur’s lab discovered the deaths of specific neurons in a brain Genes & Disease evidence that a protein called IGF1 is a region called the striatum, Heiman has been CONTINUED FROM PAGE 7 crucial component in how synapses in the using new, unbiased techniques to study the With this mechanistic insight, Bear’s lab visual cortex in newborn mice develop in brains of Huntington’s disease patients and also hatched a strategy of treating Fragile X by response to visual activity. IGF1 is regulated those of mouse models of the disease. Unbiased inhibiting mGluR5. They showed in Neuron by MeCP2 and is indeed notably reduced means she isn’t confining her in 2007 that it was enormously effective in in mouse models of Rett Syndrome. Sur’s studies to prior hypotheses mouse models and eventually brought a lab has shown that the lack of IGF1, in because doing so would be to candidate drug to advanced clinical trials, turn, reduces levels of proteins such assume that the field already but it fell short of meeting the clinical goals PI3K/Akt, and that undermines still other knows everything that’s set by regulators. proteins needed for synapses to strengthen going wrong. But in diseases and mature properly. In a paper in 2014 in of the aging brain, it is very Undaunted, earlier this year Bear’s team PNAS the team showed that treating mice by hard to fully understand published a new study in Science Translational dosing them with IGF1 corrects functional, the drivers of disease Medicine (STM) demonstrating a promising structural, and molecular mechanisms updated approach. Study data indicated that downstream of MeCP2 and improves mouse pathology, Heiman said. Decades of damage one potential problem was that patients behavior. Since then, the idea has been tested and compensation can obscure underlying could build up a tolerance to the mGluR5 in Rett syndrome patients in clinical trials. mechanisms. She likens it to examining an medicine. So Bear’s lab pursued another One trial did not show sufficient efficacy, but unprotected crime scene. target in the mGluR5 pathway: the enzyme another phase III study is still pending. “There have been many mechanisms put GSK3-alpha. Working with scientists at forward in the past, but they haven’t been the Broad Institute, they tested a new drug Sur’s lab has not stopped working on the successful in clinical trials,” Heiman said. to inhibit the enzyme, which is overactive problem. Several lab members continue to in Fragile X mouse models, and found study how the gene regulation and expression In January she published a study in which her lab knocked out all 22,000 genes found in the mouse striatum in a way in which any given cell had only about one gene knocked out. No one had ever accomplished this feat before in a mammal’s brain, but by doing so Heiman’s team was able to learn which genes are necessary for neurons to survive. When her team did the screen in Huntington’s disease model mice, they identified a particular gene family, called Nme, that had never been associated with Huntington’s before, but which was clearly necessary for neurons to survive the disease. The gene, as it turns out, Huntigton's disease neurons in the right panel show high levels of PKR (stained green), indicating may help cells dispose of protein aggregates immune response to mitochondrial RNA, compared to normal controls (left panel). (such as mutant Huntingtin). Heiman’s team showed that when Nme1 is overexpressed in the mouse models of Huntington’s, disease that doing so successfully reversed several cascade that depends on MeCP2 affects symptoms appear to improve. symptoms. The drug showed no concerning neural development, not only in mice but side effects in the mice and the rodents did also in complex 3D models of human brain Then in July, Heiman’s lab produced another not build up tolerance. tissue called cerebral organoids. And in study based on unbiased profiling of gene expression in striatal neurons known to be “We don’t know whether the mGluR5 trials STM last year, Sur collaborated with MIT biologist Rudolf Jaenisch of the Whitehead vulnerable in the disease. In this case, the failed because of treatment resistance, but it’s researchers looked at gene transcription and a viable hypothesis,” Bear says. “What we do Institute to show that increasing expression of another key protein in the cascade, KCC2, translation (as measured by levels of RNAs) know is with the GSK3 alpha inhibitor, we in different types of cells in both human and do not see that in mice.” also provided therapeutic benefits in mouse mouse brains. Across both species, and across models, offering a fresh lead. Sur’s quest to treat Rett syndrome has different stages of the disease, they found that some parallels with Bear’s experience. He, “Nothing has worked in patients yet, but you RNA from mitochondria were misplaced in too, happened upon a know we have to keep trying,” Sur said. “It’s striatal cells, called spiny projection neurons, promising treatment a very hard problem. It goes to the heart that are particularly vulnerable to dying. strategy by performing of how the brain is made, which is a very They found evidence that the brain cells fundamental research on complex process.” were perishing amid an immune response synaptic plasticity (which So, as it turns out, is the process by which to the errant mitochondrial RNA, which is a core research theme at looked to the cells like a viral invader. This The Picower Institute). the brain is unmade in neurodegenerative disorders such as Huntington’s disease. insight offers another new mechanism of MECP2’s protein Huntington’s pathobiology that could be regulates the expression In her work to understand the mechanisms targeted in the future. of hundreds of other genes. In Nature by which the huntingtin mutation leads to CONTINUES ON PAGE 9

8 PICOWER DISCOVERIES CONTINUED FROM PAGE 8 Genetic risk factors On the other side of the Picower Institute’s fourth floor, Picower Professor and Institute director Li-Huei Tsai is hunting for therapies for a different neurodegenerative disease: Alzheimer’s. Her lab takes many approaches, but among them is understanding the mechanistic failures brought about by the disease’s single biggest genetic risk factor, the APOE4 variant of the APOE gene. As with autism spectrum disorders, the vast majority of Alzheimer’s cases cannot be traced to a clear inherited genetic cause (Fragile X and Rett syndromes are exceptions). Tsai lab researchers created a blood-brain barrier model in the lab. With the APOE4 gene variant, Instead, most Alzheimer’s is associated with vessels accumulated a lot of amyloid protein (green). variations in many genes, which are not causal but appear to convey extra risk. For that information to be useful, scientists need however, by showing that overexpression you have going for you?,” Nedivi said. to what effect the variations have. of another Alzheimer’s associated gene, “The constellation of SYNE1 variants in PICALM, corrected the defect. combination with the rest of your genetic Over the last few years, Tsai’s lab has revealed makeup, as well as other factors in your life Not only was the study an important several things that go wrong in brain cells will determine together whether you will advance in understanding how APOE4 may carrying APOE4 vs. the more common develop the disease.” APOE3 version. In 2018, undermine brain function, and maybe how they used stem cells to treat it, but also it highlighted the value of Nedivi’s lab discovered CPG2 while screening derived from patients’ an emerging strategy in studying Alzheimer’s neurons for proteins whose expression skin cells to create disease and assessing it in patients: polygenic depends on synaptic activity. Their 2004 study in Neuron revealed that CPG2 is cultures of key brain cell risk. Scientists are beginning to realize that expressed in an area right next to excitatory types: neurons, microglia they need to know how genetic variants may synapses that helps to traffic receptors for the and astrocytes. In Neuron combine and accumulate to affect disease risk neurotransmitter glutamate to the synapse. the team showed that for patients, Tsai said. As such, it is important for helping synapses APOE4 neurons secreted “It’s a concept people have talked about for a adapt to activity levels by adding or removing more amyloid protein, a hallmark of long time, but I think now people are finally these receptors. In the 2019 study, Nedivi’s Alzheimer’s pathology, than APOE3 neurons. beginning to think seriously about how to research team identified several SYNE1 APOE4 Meanwhile, astrocytes and microgllia work on it,” Tsai said. “Someone’s risk for variants in people with biopolar disorder showed less ability to remove amyloid. developing Alzheimer’s is probably to a large and tested the effect of these variants on In a study earlier this year in Nature part based on their genetics—how many risk CPG2 level or function in rat neurons. They Medicine, Tsai’s lab used similar techniques alleles they carry.” found that the different genetic aberrations to engineer APOE3 and APOE4 versions of The same is likely true in bipolar disorder, undermined CPG2 in various ways— by the blood-brain barrier (BBB), the security said Elly Nedivi, William R. and Linda reducing its expression, or attenuating fence that keeps unwanted pathogens or R. Young Professor of Neuroscience in the its ability to regulate glutamate receptor chemicals from entering the brain. The BBB Picower Institute. In 2019 in Molecular trafficking, particularly in response to changes is almost always disrupted in Alzheimer’s Psychiatry, she showed how single and in synaptic transmission, when it’s most by a strongly correlated condition called combinations of variants in the gene needed. The study was the first to connect Cerebral Amyloid Angiopathy. Tsai’s team SYNE1 appear to undermine the ability to the finding of genetic factors in bipolar to a was able to show that APOE4 made the regulate synaptic strength in bipolar disorder. specific physiological mechanism in the brain. BBB more vulnerable particularly because However, none of these Nedivi’s lab is following up on the findings. of disrupted functioning among specific variants which affect This fall she hired a new postdoctoral vascular cells called pericytes. The scientists expression or function researcher to continue this work, in particular went on to identify the specific mechanistic of CPG2, a key protein to test whether the detrimental affects of pathway that becomes errant and that it can encoded by SYNE1, are bipolar patient mutations in CPG2 can be corrected with specific medications. sufficient to outright cause be counteracted pharmaceutically. “I love A few months later, Tsai’s lab published bipolar disorder on their this project,” Nedivi said. “I think it has yet another set of findings about APOE4’s own. Instead they likely enormous potential for both therapeutics, ill-effect in the brain. They showed that increase a susceptibility as well as diagnostics.” that is influenced by many factors – much astrocytes with APOE4 appeared to struggle After all, as in the other ongoing efforts of with the crucial process of endocytosis, like family history contributes to the chance Picower Institute researchers, it represents a major means by which the cells bring of developing heart disease, but is not the rewarding possibility—even if it’s a steep material into their bodies, which in turn can deterministic on its own. climb—of going from identifying genes, to undermine how they support healthy brain “It’s a risk—its something that’s against developing neuroscientific understanding, to function. This study took a hopeful turn, you, but the question is what else do treating devastating diseases.

PICOWER DISCOVERIES 9 Symposium highlights numerous leads to combat neurodegeneration

Her team has shown that overexpression of a protein that specifically blocks that action preserves synapses and protects brain function. Colonna has shown that in people with partic- ular variants of the gene Trem2, microglia fail to surround and engulf amyloid beta protein as they should but he has also found an antibody that stimulates microglia with these deficien- cies to spring back into action. Several speakers discussed the problem of protein misfolding and aggregation in neurode- generation. Valina Dawson of Johns Hopkins University showed how toxic forms of a protein called alpha synuclein might invade the brain Picower Clinical Fellow Diane Chan, a neurologist in the Tsai lab, discusses human testing of by traveling from the gut through the vagus sensory light and sound stimulation to prevent or treat Alzheimer's disease. nerve. That causes alpha synuclein already there to misfold, explaining how it can lead to Parkinson’s disease damage. Dawson’s lab The neuroscientists who spoke at production of harmful proteins or enhancing has also identified the receptor that lets toxic MIT’s Aging Brain Initiative symposium, needed protein production. His lab helped to alpha synuclein into neurons and has shown “Molecular and Cellular Mechanisms of pioneer the idea for ALS in 2006 and now it’s that blocking that receptor protects cells. Neurodegeneration” Sept. 22 delved deep into being applied to treat spinal muscular atrophy the complexities of devastating brain diseases and is being tested for Huntington’s disease In her studies of Huntington’s, Picower such as Alzheimer’s disease, ALS, Huntington’s and ALS. Institute member Myriam Heiman has sought to understand why specific cells in a region disease and Parkinson’s disease, but in essence Neurologist Diane Chan is leading human they addressed a simple, two-part question: of the brain called the striatum are especially clinical studies in Tsai’s lab of a potential susceptible to an aggregation of huntingtin What goes wrong in the aging brain and how Alzheimer’s therapy. After observing that the can finding that out help us do something protein. To find out, she engaged in an unbi- power of neural rhythms at “gamma” frequency ased genetic screen of the entire mouse genome, about it? Their answers provided many tangible of 40 Hz are lessened in Alzheimer’s, Tsai’s lab signs of progress and reasons for hope. looking for genes that, if knocked out, would led the discovery that exposing mice to light or make neurons carrying the Huntington’s More than 1,300 people from 48 countries sound at that frequency can increase gamma mutation especially vulnerable. In her talk she tuned in online over the course of the day. power and restore synchrony of neural activ- described her recent study that found several “Neurodegeneration is a very multifaceted and ity across brain regions. In mouse models the genes including a novel one, Nme1. Further difficult problem that affects tens of millions technique improves memory and cognition, investigation revealed that Nme1 likely helps of people around the world,” said Li-Huei Tsai, prevents neural death and reduces the accu- promote clearance of huntingtin aggregates. In Picower Professor of Neuroscience, director of mulation of proteins known as key biomarkers disease model mice, she showed that overex- The Picower Institute and founding director of disease progression. In a small sample of pressing Nme1 reduced disease symptoms. of the ABI. “The good news is that many very human volunteers tested so far, the method has proven safe and well tolerated, increases 40 Hz Another troublesome protein is tau. Lennart talented and dedicated researchers are working Mucke of the University of California at San on it.” gamma rhythm power and network connec- tivity and may be contributing to improved Francisco presented evidence that in both Speaker after speaker not only shared new sleep, Chan reported. Testing for improve- Alzheimer’s and even some autism spectrum insights into the nature of diseases that cause ments in memory and cognition have not been disorders, tau can still enable dysfunction in brain cells to die, but also described promising completed yet, however. disease processes, even when tau itself is in a new treatment strategies. Some are advancing healthy form. For instance, he’s found that through clinical trials. Dorothy Schafer of the University of the protein is necessary for neuronal hyper- Massachusetts Medical School and Marco excitability to emerge in Alzheimer’s disease Keynote speaker Don Cleveland of the Colonna of Washington University are both models. His research suggests that lowering University of California at San Diego described looking at brain immune cells called microglia. overall healthy tau levels might have thera- a technology called antisense oligonucleotide In a mouse model of multiple sclerosis, Schafer peutic benefits in some diseases. therapy, which involves synthesizing “designer has pinpointed the molecular process by which DNA drugs” that can intercede to compensate microglia end up engulfing and destroying the For extended coverage of the symposium visit for a genetic mutation, either by reducing the connections between neurons, called synapses. http://bit.ly/ABI-2020

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Neuroscience News Winter 2020

▶ OUR VISION The Picower Institute is a community of scientists dedicated to understanding TOP ROW: Mark F. Bear, Picower Professor of Neuroscience, Department of Brain the mechanisms that drive learning and memory and related functions such and Cognitive Sciences, Investigator, Howard Hughes Medical Institute (HHMI); Emery as cognition, emotion, perception, and consciousness. Institute researchers Brown, Edward Hood Taplin Professor of Computational Neuroscience and Health explore the brain at multiple scales, from genes and molecules, to cells Sciences & Technology, The Picower Institute for Learning and Memory, Department and synapses, to circuits and systems, producing novel insights into how of Brain and Cognitive Sciences, Massachusetts Institute of Technology; Gloria Choi, disruptions in these mechanisms can lead to developmental, psychiatric, or Samuel A. Goldblith Career Development Associate Professor, Department of Brain and neurodegenerative disease. Cognitive Sciences; Kwanghun Chung, Associate Professor, Departments of Chemical Engineering and Brain and Cognitive Sciences, Institute of Medical Engineering and ▶ SUPPORT THE PICOWER INSTITUTE Science core faculty; Steven Flavell, Lister Brothers Career Development Assistant For more information on our research or how to make a gift to the Picower Professor of Neuroscience, The Picower Institute for Learning and Memory, Department Institute for Learning and Memory, please contact: of Brain and Cognitive Sciences, Massachusetts Institute of Technology; Myriam Heiman, Asha Bhakar, PhD, [email protected], Tel: 617-258-0759. Associate Professor of Neuroscience, Department of Brain and Cognitive Sciences, Broad Institute core member; Troy Littleton, Menicon Professor of Biology and Neuroscience, ▶ HOW TO SUBMIT & SUBSCRIBE Departments of Biology and Brain and Cognitive Sciences. Subscriptions to Neuroscience News are available at no charge in print or PDF form. To subscribe or submit story ideas and comments, send your mailing or BOTTOM ROW: Earl Miller, Picower Professor of Neuroscience, Department of Brain email address to: David Orenstein, [email protected], Tel: 617-324-2079. and Cognitive Sciences; Elly Nedivi, William R. (1964) & Linda R. Young Professor of Neuroscience, The Picower Institute for Learning and Memory, Departments of ▶ Brain and Cognitive Sciences and Biology; Mriganka Sur, Paul E. Newton Professor of EDITORIAL CONTRIBUTORS Neuroscience, Director of The Simons Center for the Social Brain; Susumu Tonegawa, David Orenstein and Anne Trafton Picower Professor of Biology and Neuroscience, Departments of Brain and Cognitive Sciences and Biology, Investigator, Howard Hughes Medical Institute, Investigator and ▶ CONTACT THE PICOWER INSTITUTE Director of the RIKEN-MIT Center for Neural Circuit Genetics; Li-Huei Tsai, Picower The Picower Institute for Learning and Memory Professor of Neuroscience, Department of Brain and Cognitive Sciences, Director, Massachusetts Institute of Technology, The Picower Institute for Learning and Memory; Matthew Wilson, Sherman Fairchild 77 Massachusetts Avenue, Building 46, Room 1303, Professor in Neurobiology, Departments of Brain and Cognitive Sciences and Biology, Cambridge, MA 02139-4307, Tel: 617-324-0305 picower.mit.edu Associate Director, The Picower Institute for Learning and Memory.

Choi photo by Justin Knight