DOCSLIB.ORG

Engrailed Is Required in Maturing Serotonin Neurons To

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Engrailed Is Required in Maturing Serotonin Neurons To ENGRAILED IS REQUIRED IN MATURING SEROTONIN NEURONS TO REGULATE THE CYTOARCHITECTURE AND SURVIVAL OF THE DORSAL RAPHE NUCLEUS by STEPHANIE R. FOX Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Evan S. Deneris Department of Neurosciences CASE WESTERN RESERVE UNIVERSITY August 2012 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Stephanie R. Fox . candidate for the Doctor of Philosophy degree*. (signed) Jerry Silver . (chair of the committee) Evan Deneris . Heather Broihier . Stephen Maricich . (date) 5/21/2012 . *We also certify that written approval has been obtained for any proprietary material contained within. Table of contents List of tables ................................................................................................... 4 List of figures .................................................................................................. 5 Abstract ........................................................................................................... 7 Chapter 1 - Introduction to the central serotonin system and engrailed transcription factors ....................................................................................... 9 Central serotonin system .............................................................................. 9 5-HT neuron identity .......................................................................... 11 Molecular control of 5-HT neuron development ............................. 16 Setting up the A-P axis – Mid-hindbrain organizer .................... 17 D-V patterning ........................................................................... 22 Neurogenesis ............................................................................ 23 Terminal differentiation .............................................................. 27 Maturation and maintenance ..................................................... 31 Developmental neuroanatomy .......................................................... 33 Cell body movements and formation of the 5-HT nuclei ............ 34 Formation of ascending and descending projections ................ 35 5-HT transcriptional network and components - relevance to human health .................................................................................................. 38 Maternal care ............................................................................ 40 Mood and emotional behaviors ................................................. 41 Neurodevelopment–implications for autism spectrum disorder . 44 1 Engrailed .................................................................................................. 47 Roles in the CNS ................................................................................ 49 Tissue patterning ....................................................................... 50 Fate selection/ terminal cell type generation ............................. 53 Cell survival ............................................................................... 57 Axon guidance .......................................................................... 58 Engrailed and mental health ............................................................. 61 Aims of thesis ............................................................................................... 64 Chapter 2-Engrailed is required in maturing serotonin neurons to regulate the cytoarchitecture and survival of the dorsal raphe nucleus ................ 75 Summary ............................................................................................ 76 Introduction ........................................................................................ 77 Materials and methods ..................................................................... 79 Results ................................................................................................ 87 En1 and En2 are expressed in postmitotic 5-HT neurons. ........ 87 Conditional targeting of En in maturing 5-HT neurons .............. 89 Engrailed controls maturation of DRN cytoarchitecture ............. 90 Engrailed is required for perinatal maintenance of serotonergic neuron identity........................................................................... 94 En1/2 deficiency causes 5-HT neuron cell death postnatally .... 98 En1/25HTCKO dams display mild deficits in pup rearing ............... 99 Discussion ........................................................................................ 102 2 Chapter 3- Effect of genetic background on serotonergic system development and the Pet-1-/- phenotype ................................................... 131 Summary .......................................................................................... 132 Introduction ...................................................................................... 133 Materials and methods ................................................................... 135 Results .............................................................................................. 139 Comparison of C57BL/6, SJL and wild-type 129/Sv*C57BL/6 139 Interaction between Pet-1 expression and background .......... 140 Reduced pup survival from C57BL/6-Pet-1-/- dams ................. 142 Discussion ........................................................................................ 144 Chapter 4- Discussion ................................................................................ 156 5-HT neurogenesis........................................................................... 158 Cell migration and DRN formation ................................................. 159 Maintenance of 5-HT neuron identity ............................................. 164 Cell survival ...................................................................................... 167 Axon projections ............................................................................. 173 Behavior consequences of conditional En1/2 ablation ................ 175 Final thoughts .................................................................................. 176 References ................................................................................................ 179 3 List of tables Chapter 2 Table. Summary of pup survival .................................................................. 155 4 List of figures Chapter 1 Figure 1. Major components of 5-HT neuron identity .......................... 67 Figure 2. Determinants important for the development of 5-HT neurons ............................................................................................... 69 Figure 3. Neuroanatomical origins of 5-HT neurons ........................... 71 Figure 4. Engrailed is highly conserved amongst species and paralogs .............................................................................................. 73 Chapter 2 Figure 1. Mating strategies for generation of each of the genotypes used in analyses ........................................................................................ 108 Figure 2. Spatiotemporal expression patterns of En1 and En2 in the rostral hindbrain ........................................................................................... 110 Figure 3. En1 expression in 5-HT neurons is maintained postnatally ......................................................................................... 112 Figure 4. Conditional targeting of En1/2 in 5-HT neurons after neurogenesis .................................................................................... 114 Figure 5. Engrailed is required in rostral postmitotic 5-HT neurons to regulate formation of the DRN .......................................................... 116 Figure 6. Engrailed is not required for early maintenance of 5-HT neuron identity .............................................................................................. 119 5 Figure 7. Engrailed is required for maintenance of serotonergic identity in the perinatal period ........................................................................... 121 Figure 8. Engrailed is required in postmitotic 5-HT neurons for maintenance of brain 5-HT levels ..................................................... 123 Figure 9. En1 is the predominant functional engrailed paralog for maintenance of 5-HT neuron identity ................................................ 125 Figure 10. Engrailed is required for survival of postmitotic 5-HT neurons ............................................................................................. 127 Figure 11. Conditional targeting of En1/2 in 5-HT neurons negatively impacts pup outcome measures ....................................................... 129 Chapter 3 Figure 1. Comparison of wild-type C57BL/6, SJL and mixed 129/Sv*C57BL/6 backgrounds .......................................................... 147 Figure 2. Immunohistological comparison of congenic C57BL/6 and SJL and mixed 129/Sv*C57BL/6 Pet-1+/+ and Pet-1-/- mice ...................... 149 Figure 3. HPLC analysis of congenic and mixed background in wild-type and Pet-1 mutant mice ...................................................................... 151 Figure 4. Pup survival and nest building behavior in C57BL/6-Pet-1+/- and Pet-1-/- dams .................................................................................... 153 . 6 Engrailed is Required in Maturing Serotonin Neurons to Regulate the Cytoarchitecture
Load more

Recommended publications
  • Core Transcriptional Regulatory Circuitries in Cancer
    Oncogene (2020) 39:6633–6646 https://doi.org/10.1038/s41388-020-01459-w REVIEW ARTICLE Core transcriptional regulatory circuitries in cancer 1 1,2,3 1 2 1,4,5 Ye Chen ● Liang Xu ● Ruby Yu-Tong Lin ● Markus Müschen ● H. Phillip Koeffler Received: 14 June 2020 / Revised: 30 August 2020 / Accepted: 4 September 2020 / Published online: 17 September 2020 © The Author(s) 2020. This article is published with open access Abstract Transcription factors (TFs) coordinate the on-and-off states of gene expression typically in a combinatorial fashion. Studies from embryonic stem cells and other cell types have revealed that a clique of self-regulated core TFs control cell identity and cell state. These core TFs form interconnected feed-forward transcriptional loops to establish and reinforce the cell-type- specific gene-expression program; the ensemble of core TFs and their regulatory loops constitutes core transcriptional regulatory circuitry (CRC). Here, we summarize recent progress in computational reconstitution and biologic exploration of CRCs across various human malignancies, and consolidate the strategy and methodology for CRC discovery. We also discuss the genetic basis and therapeutic vulnerability of CRC, and highlight new frontiers and future efforts for the study of CRC in cancer. Knowledge of CRC in cancer is fundamental to understanding cancer-specific transcriptional addiction, and should provide important insight to both pathobiology and therapeutics. 1234567890();,: 1234567890();,: Introduction genes. Till now, one critical goal in biology remains to understand the composition and hierarchy of transcriptional Transcriptional regulation is one of the fundamental mole- regulatory network in each specified cell type/lineage.
    [Show full text]
  • Activation of Raphe Nuclei Triggers Rapid and Distinct Effects on Parallel Olfactory Bulb Output Channels
    Activation of raphe nuclei triggers rapid and distinct effects on parallel olfactory bulb output channels The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Kapoor, Vikrant, Allison Provost, Prateek Agarwal, and Venkatesh N. Murthy. 2015. “Activation of raphe nuclei triggers rapid and distinct effects on parallel olfactory bulb output channels.” Nature neuroscience 19 (2): 271-282. doi:10.1038/nn.4219. http:// dx.doi.org/10.1038/nn.4219. Published Version doi:10.1038/nn.4219 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002684 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nat Neurosci Manuscript Author . Author manuscript; Manuscript Author available in PMC 2016 August 01. Published in final edited form as: Nat Neurosci. 2016 February ; 19(2): 271–282. doi:10.1038/nn.4219. Activation of raphe nuclei triggers rapid and distinct effects on parallel olfactory bulb output channels Vikrant Kapoor1,2,†, Allison Provost1,2, Prateek Agarwal1,2, and Venkatesh N. Murthy1,2,† 1Center for Brain Science, Harvard University, Cambridge, MA 02138 2Department of Molecular & Cellular Biology, Harvard University, Cambridge, MA 02138 Abstract The serotonergic raphe nuclei are involved in regulating brain states over time-scales of minutes and hours. We examined more rapid effects of serotonergic activation on two classes of principal neurons in the mouse olfactory bulb, mitral and tufted cells, which send olfactory information to distinct targets.
    [Show full text]
  • Glioblastoma Stem Cells Induce Quiescence in Surrounding Neural Stem Cells Via Notch Signalling
    bioRxiv preprint doi: https://doi.org/10.1101/856062; this version posted November 29, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signalling. Katerina Lawlor1, Maria Angeles Marques-Torrejon2, Gopuraja Dharmalingham3, Yasmine El-Azhar1, Michael D. Schneider1, Steven M. Pollard2§ and Tristan A. Rodríguez1§ 1National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. 2 MRC Centre for Regenerative Medicine & Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK. 3MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Imperial College London, UK §Authors for correspondence: [email protected] and [email protected] Running title: Glioblastoma stem cell competition Keyword: Neural stem cells, quiescence, glioblastoma, Notch, cell competition 1 bioRxiv preprint doi: https://doi.org/10.1101/856062; this version posted November 29, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Abstract 2 There is increasing evidence suggesting that adult neural stem cells (NSCs) are a cell of 3 origin of glioblastoma, the most aggressive form of malignant glioma. The earliest stages of 4 hyperplasia are not easy to explore, but likely involve a cross-talk between normal and 5 transformed NSCs. How normal cells respond to this cross-talk and if they expand or are 6 outcompeted is poorly understood.
    [Show full text]
  • Scaling Our World View: How Monoamines Can Put Context Into Brain Circuitry
    HYPOTHESIS AND THEORY published: 20 December 2018 doi: 10.3389/fncel.2018.00506 Scaling Our World View: How Monoamines Can Put Context Into Brain Circuitry Philipp Stratmann 1,2*, Alin Albu-Schäffer 1,2 and Henrik Jörntell 3 1 Sensor Based Robotic Systems and Intelligent Assistance Systems, Department of Informatics, Technical University of Munich, Garching, Germany, 2 German Aerospace Center (DLR), Institute of Robotics and Mechatronics, Weßling, Germany, 3 Neural Basis of Sensorimotor Control, Department of Experimental Medical Science, Lund University, Lund, Sweden Monoamines are presumed to be diffuse metabotropic neuromodulators of the topographically and temporally precise ionotropic circuitry which dominates CNS functions. Their malfunction is strongly implicated in motor and cognitive disorders, but their function in behavioral and cognitive processing is scarcely understood. In this paper, the principles of such a monoaminergic function are conceptualized for locomotor control. We find that the serotonergic system in the ventral spinal cord scales ionotropic signals and shows topographic order that agrees with differential gain modulation of ionotropic subcircuits. Whereas the subcircuits can collectively signal predictive models of the world based on life-long learning, their differential scaling continuously adjusts these models to changing mechanical contexts based on sensory input on a fast time scale of a few 100 ms. The control theory of biomimetic robots demonstrates that this precision scaling is an effective and resource-efficient
    [Show full text]
  • Context-Dependent Modulation of Auditory Processing by Serotonin
    Hearing Research 279 (2011) 74e84 Contents lists available at ScienceDirect Hearing Research journal homepage: www.elsevier.com/locate/heares Context-dependent modulation of auditory processing by serotonin L.M. Hurley a,*, I.C. Hall b a Indiana University, Jordan Hall/Biology, 1001 E. Third St, Bloomington, IN 47405, USA b Columbia University, 901 Fairchild Center, M.C. 2430, New York, NY 10027, USA article info abstract Article history: Context-dependent plasticity in auditory processing is achieved in part by physiological mechanisms that Received 3 October 2010 link behavioral state to neural responses to sound. The neuromodulator serotonin has many character- Received in revised form istics suitable for such a role. Serotonergic neurons are extrinsic to the auditory system but send 13 December 2010 projections to most auditory regions. These projections release serotonin during particular behavioral Accepted 20 December 2010 contexts. Heightened levels of behavioral arousal and specific extrinsic events, including stressful or Available online 25 December 2010 social events, increase serotonin availability in the auditory system. Although the release of serotonin is likely to be relatively diffuse, highly specific effects of serotonin on auditory neural circuitry are achieved through the localization of serotonergic projections, and through a large array of receptor types that are expressed by specific subsets of auditory neurons. Through this array, serotonin enacts plasticity in auditory processing in multiple ways. Serotonin changes the responses of auditory neurons to input through the alteration of intrinsic and synaptic properties, and alters both short- and long-term forms of plasticity. The infrastructure of the serotonergic system itself is also plastic, responding to age and cochlear trauma.
    [Show full text]
  • Supplemental Materials ZNF281 Enhances Cardiac Reprogramming
    Supplemental Materials ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression Huanyu Zhou, Maria Gabriela Morales, Hisayuki Hashimoto, Matthew E. Dickson, Kunhua Song, Wenduo Ye, Min S. Kim, Hanspeter Niederstrasser, Zhaoning Wang, Beibei Chen, Bruce A. Posner, Rhonda Bassel-Duby and Eric N. Olson Supplemental Table 1; related to Figure 1. Supplemental Table 2; related to Figure 1. Supplemental Table 3; related to the “quantitative mRNA measurement” in Materials and Methods section. Supplemental Table 4; related to the “ChIP-seq, gene ontology and pathway analysis” and “RNA-seq” and gene ontology analysis” in Materials and Methods section. Supplemental Figure S1; related to Figure 1. Supplemental Figure S2; related to Figure 2. Supplemental Figure S3; related to Figure 3. Supplemental Figure S4; related to Figure 4. Supplemental Figure S5; related to Figure 6. Supplemental Table S1. Genes included in human retroviral ORF cDNA library. Gene Gene Gene Gene Gene Gene Gene Gene Symbol Symbol Symbol Symbol Symbol Symbol Symbol Symbol AATF BMP8A CEBPE CTNNB1 ESR2 GDF3 HOXA5 IL17D ADIPOQ BRPF1 CEBPG CUX1 ESRRA GDF6 HOXA6 IL17F ADNP BRPF3 CERS1 CX3CL1 ETS1 GIN1 HOXA7 IL18 AEBP1 BUD31 CERS2 CXCL10 ETS2 GLIS3 HOXB1 IL19 AFF4 C17ORF77 CERS4 CXCL11 ETV3 GMEB1 HOXB13 IL1A AHR C1QTNF4 CFL2 CXCL12 ETV7 GPBP1 HOXB5 IL1B AIMP1 C21ORF66 CHIA CXCL13 FAM3B GPER HOXB6 IL1F3 ALS2CR8 CBFA2T2 CIR1 CXCL14 FAM3D GPI HOXB7 IL1F5 ALX1 CBFA2T3 CITED1 CXCL16 FASLG GREM1 HOXB9 IL1F6 ARGFX CBFB CITED2 CXCL3 FBLN1 GREM2 HOXC4 IL1F7
    [Show full text]
  • UNIVERSITY of CALIFORNIA, IRVINE Combinatorial Regulation By
    UNIVERSITY OF CALIFORNIA, IRVINE Combinatorial regulation by maternal transcription factors during activation of the endoderm gene regulatory network DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences by Kitt D. Paraiso Dissertation Committee: Professor Ken W.Y. Cho, Chair Associate Professor Olivier Cinquin Professor Thomas Schilling 2018 Chapter 4 © 2017 Elsevier Ltd. © 2018 Kitt D. Paraiso DEDICATION To the incredibly intelligent and talented people, who in one way or another, helped complete this thesis. ii TABLE OF CONTENTS Page LIST OF FIGURES vii LIST OF TABLES ix LIST OF ABBREVIATIONS X ACKNOWLEDGEMENTS xi CURRICULUM VITAE xii ABSTRACT OF THE DISSERTATION xiv CHAPTER 1: Maternal transcription factors during early endoderm formation in 1 Xenopus Transcription factors co-regulate in a cell type-specific manner 2 Otx1 is expressed in a variety of cell lineages 4 Maternal otx1 in the endodermal conteXt 5 Establishment of enhancers by maternal transcription factors 9 Uncovering the endodermal gene regulatory network 12 Zygotic genome activation and temporal control of gene eXpression 14 The role of maternal transcription factors in early development 18 References 19 CHAPTER 2: Assembly of maternal transcription factors initiates the emergence 26 of tissue-specific zygotic cis-regulatory regions Introduction 28 Identification of maternal vegetally-localized transcription factors 31 Vegt and OtX1 combinatorially regulate the endodermal 33 transcriptome iii
    [Show full text]
  • Celsr1-3 Cadherins in PCP and Brain Development
    CHAPTER SEVEN Celsr1–3 Cadherins in PCP and Brain Development Camille Boutin, André M. Goffinet1, Fadel Tissir1 Institute of Neuroscience, Developmental Neurobiology, Universite´ Catholique de Louvain, Brussels, Belgium 1Corresponding authors: Equal contribution. e-mail address: [email protected]; andre. [email protected] Contents 1. Celsr1–3 Expression Patterns 164 2. Celsr1: A Major Player in Vertebrate PCP 165 3. Celsr2 and 3 in Ciliogenesis 169 4. Celsr1–3 in Neuronal Migration 171 5. Celsr2 and Celsr3 in Brain Wiring 174 5.1 Motifs of Celsr important for their functions 176 References 179 Abstract Cadherin EGF LAG seven-pass G-type receptors 1, 2, and 3 (Celsr1–3) form a family of three atypical cadherins with multiple functions in epithelia and in the nervous system. During the past decade, evidence has accumulated for important and distinct roles of Celsr1–3 in planar cell polarity (PCP) and brain development and maintenance. Although the role of Celsr in PCP is conserved from flies to mammals, other functions may be more distantly related, with Celsr working only with one or a subset of the classical PCP partners. Here, we review the literature on Celsr in PCP and neural devel- opment, point to several remaining questions, and consider future challenges and possible research trends. Celsr1–3 genes encode atypical cadherins of more than 3000 amino acids ( Fig. 7.1). Their large ectodomain is composed of nine N-terminal cadherin repeats (typical cadherins have five repeats), six epidermal growth factor (EGF)-like domains, two laminin G repeats, one hormone receptor motif (HRM), and a G-protein-coupled receptor proteolytic site (GPS).
    [Show full text]
  • Overview of the Reticular Formation (RF)
    TeachSheet Reticular Formation & Diffuse modulatory system Overview of the Reticular Formation (RF) The term reticular formation refers to the neuronal network within the brainstem, although it continues rostrally into the thalamus and hypothalamus and caudally into the propriospinal network of the spinal cord. A “coordinating system” (like the Limbic system) with “connections” to sensory, somatic motor and visceral motor systems Organization can be subdivided into two neuronal cell “columns” (medial to lateral) as well as on the basis of their neurotransmitter release Neuronal columns (many nuclei and names, but these are some of the major ones): o “Medial tegmental field” (large-celled nuclei) . Origin of the reticulospinal pathway . Role in coordinating posture, eye and head movements. o “Lateral tegmental field” (smaller and fewer cells, shorter local projections) . Extends from the medulla to the pons . Coordinate autonomic and limbic functions (e.g. micturition, swallowing, mastication and vocalization) The functions of the reticular formation include their ability to coordinate motor and sensory brainstem nuclei: o Pattern generator . Eye movements; horizontal (PPRF) and vertical (riMLF) . Rhythmical chewing movements (pons) . Posture and locomotion (midbrain and pons) . Swallowing, vomiting, coughing and sneezing (medulla) . Micturition (pons) o Respiratory control (medulla); expiratory, inspiratory, apneustic and pneumotaxic o Cardiovascular control (medulla); vasomotor pressor/depressor, cardioacceleratory and inhibitory. Afferents arise from baroreceptors (carotid sinus and aortic arch), chemoreceptors (carotid sinus, lateral reticular formation chemosensitive area in the medulla) and stretch receptors (lung and respiratory muscles) . Efferents arise from reticular formation neurons within the pons and medulla o Sensory modulation or “gate” control . The term “gating” refers to “modulation” of synaptic transmission from one set of neurons to the next.
    [Show full text]
  • Genetic Evidence That Celsr3 and Celsr2, Together with Fzd3, Regulate Forebrain Wiring in a Vangl-Independent Manner
    Genetic evidence that Celsr3 and Celsr2, together with Fzd3, regulate forebrain wiring in a Vangl-independent manner Yibo Qua, Yuhua Huanga, Jia Fenga, Gonzalo Alvarez-Boladob, Elizabeth A. Grovec, Yingzi Yangd, Fadel Tissire, Libing Zhoua,f,1,2, and Andre M. Goffinete,1,2 aGuangdong–Hong Kong–Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; bDepartment of Neuroanatomy, Heidelberg University, D-69120 Heidelberg, Germany; cNeuroscience, The University of Chicago, Chicago, IL 60637; dNational Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; eWELBIO - Walloon Excellence in Life Sciences and Biotechnology and Institute of Neuroscience, University of Louvain, B1200 Brussels, Belgium; and fState Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong Edited* by Jeremy Nathans, The Johns Hopkins University, Baltimore, MD, and approved June 18, 2014 (received for review February 3, 2014) Celsr3 and Fzd3, members of “core planar cell polarity” (PCP) AC contains commissural axons from the anterior olfactory nu- genes, were shown previously to control forebrain axon guidance clei and from the temporal cortex, which cross the midline at and wiring by acting in axons and/or guidepost cells. Here, we embryonic day 13.5 (E13.5) to E14.5 (11–14). The IC contains show that Celsr2 acts redundantly with Celsr3, and that their com- three main axonal components. Thalamocortical axons (TCA) bined mutation mimics that of Fzd3. The phenotypes generated emerge from the thalamus—formerly called “dorsal” thalamus upon inactivation of Fzd3 in different forebrain compartments are (15)—at E12.5. They run through the prethalamus (former similar to those in conditional Celsr2-3 mutants, indicating that “ventral” thalamus), turn and cross the diencephalon–telen- Fzd3 and Celsr2-3 act in the same population of cells.
    [Show full text]
  • Sclocco Brainstim2019.Pdf
    Brain Stimulation xxx (xxxx) xxx Contents lists available at ScienceDirect Brain Stimulation journal homepage: http://www.journals.elsevier.com/brain-stimulation The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study * Roberta Sclocco a, b, , Ronald G. Garcia a, c, Norman W. Kettner b, Kylie Isenburg a, Harrison P. Fisher a, Catherine S. Hubbard a, Ilknur Ay a, Jonathan R. Polimeni a, Jill Goldstein a, c, d, Nikos Makris a, c, Nicola Toschi a, e, Riccardo Barbieri f, g, Vitaly Napadow a, b a Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA b Department of Radiology, Logan University, Chesterfield, MO, USA c Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA d Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA e Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy f Department of Electronics, Information and Bioengineering, Politecnico di Milano, Italy g Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA article info abstract Article history: Background: Brainstem-focused mechanisms supporting transcutaneous auricular VNS (taVNS) effects Received 12 September 2018 are not well understood, particularly in humans. We employed ultrahigh field (7T) fMRI and evaluated Received in revised form the influence of respiratory phase for optimal targeting, applying our respiratory-gated auricular vagal 2 January 2019 afferent nerve stimulation (RAVANS) technique. Accepted 6 February 2019 Hypothesis: We proposed that targeting of nucleus tractus solitarii (NTS) and cardiovagal modulation in Available online xxx response to taVNS stimuli would be enhanced when stimulation is delivered during a more receptive state, i.e.
    [Show full text]
  • Deficits in Early Neural Tube Identity Found in CHARGE Syndrome
    INSIGHT elife.elifesciences.org CEREBELLAR MALFORMATION Deficits in early neural tube identity found in CHARGE syndrome Long predicted from studies of model vertebrates, the first human example of abnormal patterning of the early neural tube leading to underdevelopment of the cerebellum has been demonstrated. PARTHIV HALDIPUR AND KATHLEEN J MILLEN work by Yu et al. shows that loss of CHD7 also Related research article Yu T, Meiners LC, disrupts the development of the early neural tube, Danielsen K, Wong MTY, Bowler T, which is the forerunner of the central nervous sys- Reinberg D, Scambler PJ, van Ravenswaaij- tem. This results in underdevelopment (hypoplasia) of the cerebellar vermis. This finding is extremely Arts CMA, Basson MA. 2013. Deregulated exciting as it represents the very first example of FGF and homeotic gene expression this particular class of neural birth defect to be underlies cerebellar vermis hypoplasia in observed in humans. CHARGE syndrome. eLife 2:e01305. One of the first steps in the development of the central nervous system is the establishment of doi: 10.7554/eLife.01305 gene expression domains that segment the neural Image MRI scan of a patient with CHARGE tube into the regions that become the forebrain, syndrome the midbrain, the hindbrain and the spinal cord. Subsequently, signalling centres establish the boundaries between these regions and secrete HARGE syndrome is a genetic condition growth factors which pattern the adjacent nervous that involves multiple malformations in tissue (Kiecker and Lumsden, 2012). The best Cnewly born children. The acronym stands understood signalling centre is the Isthmic for coloboma (a hole in the eye), heart defects, Organizer, which forms at the boundary of the choanal atresia (a blockage of the nasal pas- midbrain and the hindbrain.
    [Show full text]