Neuronal Connectivity in Brain Function and Disease: Novel Mechanisms and Therapeutic Targets

Neuronal Connectivity in Brain Function and Disease: Novel Mechanisms and Therapeutic Targets

Tuesday, March 22, 2016

The New York Academy of Sciences

The brain is a puzzle of remarkable genetic, structural and functional complexity. Ambitious projects aim to map the mammalian brain and define its circuitry on an ultrastructural level. These efforts are complemented by conceptual advances into how development and experience shape the connectivity underlying its most basic functions. Our symposium will address both: the importance of structural synaptic plasticity in shaping neuronal connections and circuitry, and the technical advances enabling the functional analysis of brain ultrastructure and circuitry. We will discuss how mapping the brain circuitry and its relationship to behavior will help us to understand the formation of thoughts and emotions as functional outputs of brain connectivity, as well as the current and future applications of these novel insights for diagnosis and therapy.

*Reception to follow.

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This event will also be broadcast as a webinar; registration is required.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

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Agenda

* Presentation titles and times are subject to change.


Tuesday March 22, 2016

12:00 PM

Welcome and Introduction
Caitlin McOmish, PhD, The New York Academy of Sciences
Thomas Franke, MD, PhD, NYU School of Medicine

12:15 PM

Circuit-Based Analyses for Assessing Hormonal Modulation of Neural Circuits
Bruce McEwen, PhD, The Rockefeller University

12:45 PM

Mapping the Heterogeneous Regulation of Cortical Activity by Striatal Projections
Bernardo Sabatini, MD PhD, Harvard Medical School

1:15 PM

EyeWire: Crowdsourcing Neuroscience with an Online Game
Amy Robinson, EyeWire and Massachusetts Institute of Technology

1:45 PM

Coffee and Poster Session

2:15 PM

Synaptic Remodeling and its Role in Sleep and Memory
Wenbiao Gan, PhD, NYU Langone Medical Center

2:45 PM

Synaptic Dysfunction and Social Behavior in Autism Spectrum Disorders
David Sulzer, PhD, Columbia University Medical Center

3:15 PM

Synaptic Remodeling in Drug Addiction
Eric Nestler, MD, PhD, Icahn School of Medicine at Mount Sinai

3:45 PM

Closing Remarks and Poster Award Winner Presentations
Eric Nestler, MD PhD, Mount Sinai School of Medicine

4:00 PM

Networking Reception and Poster Session

5:00 PM

Close

Organizers

Thomas F. Franke, MD, PhD

NYU School of Medicine

Dr. Franke is an Associate Professor of Psychiatry, and Biochemistry & Molecular Pharmacology at the NYU School of Medicine. He joined the NYUSoM faculty in 2007. Dr. Franke received his MD in 1992 from the University of Lübeck in Germany and his MD, PhD in Medical Virology in 1995 from Justus Liebig University in Germany. Dr. Franke is a pioneer in the field of Akt signal transduction, in which he was the first to demonstrate the regulation of Akt by growth factors downstream of activated PI 3-kinase. His current work investigates Akt's relevance in behavioral neuroscience by exploring the biochemical and structural consequences of Akt activity in higher-order neural functions. Building on his previous research on the contribution of Akt dysfunction to cancer biology, Dr. Franke employs pharmacology and mutant mouse models to examine Akt's involvement in mental disease, including addiction and depression. His research will expand our current understanding of how Akt contributes to normal brain physiology, and create new opportunities for diagnostic and therapeutic approaches to psychiatric and neurodegenerative disorders.

Eric Nestler, MD, PhD

Icahn School of Medicine at Mount Sinai

Dr. Nestler is the Nash Family Professor of Neuroscience at the Icahn School of Medicine at Mount Sinai in New York City, where he serves as Chair of the Department of Neuroscience and Director of the Friedman Brain Institute. He received his BA, PhD, and MD degrees, and psychiatry residency training, from Yale University. He served on the Yale faculty from 1987–2000, where he was the Elizabeth Mears and House Jameson Professor of Psychiatry and Neurobiology, and Director of the Division of Molecular Psychiatry. He moved to Dallas in 2000 where he served as the Lou and Ellen McGinley Distinguished Professor and Chair of the Department of Psychiatry at The University of Texas Southwestern Medical Center until moving to New York in 2008. Dr. Nestler is a member of the Institute of Medicine and a Fellow of the American Academy of Arts and Sciences. He is a past President of the American College of Neuropsychopharmacology and President Elect of the Society for Neuroscience. The goal of Dr. Nestler's research is to better understand the molecular mechanisms of addiction and depression based on work in animal models, and to use this information to develop improved treatments of these disorders.

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy of Sciences

Speakers

Wenbiao Gan, PhD

NYU Langone Medical Center

Dr. Wen-Biao Gan is a professor in the Department of Neuroscience and Physiology and Skirball Institute at New York University School of Medicine. He obtained his PhD in Neurobiology from Columbia University in 1995. Dr. Gan's research focuses on understanding how the brain is able to integrate new information continuously while stably maintaining previously stored memories. Using transcranial two-photon microscopy to study changes in postsynaptic dendritic spines in living mouse cerebral cortex, his laboratory has shown that the majority of dendritic spines in diverse regions of the cortex persist throughout adulthood and can serve as a structural basis for long-term information storage. In addition, learning and novel sensory experience lead to a small degree of new dendritic spine formation via a highly selective process. These new spines likely play an important role in modifying neuronal circuit function and contribute to new information storage. Over the years, his laboratory has contributed to the understanding of how motor learning, fear learning and extinction, stress hormone glucocorticoids, microglia, and sleep affect synaptic plasticity in the living mouse cortex. More recently, his laboratory has developed new behavioral paradigms to image activity of dendrites and dendritic spines in the cortex of awake behaving mice and identified a fundamental role of dendritic calcium spikes in learning-dependent synaptic plasticity.

Bruce McEwen, PhD

Rockefeller University

Bruce S. McEwen obtained his PhD in Cell Biology in 1964 from The Rockefeller University. He is a member of the US National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences. He served as President of the Society for Neuroscience in 1997–98. As a neuroscientist and neuroendocrinologist, McEwen studies environmentally-regulated, variable gene expression in brain, mediated by circulating steroid hormones and endogenous neurotransmitters in relation to brain sexual differentiation and the actions of sex and stress hormones on the adult brain, in particular related to structural and functional plasticity via epigenetic mechanisms. His laboratory discovered adrenal steroid receptors in the hippocampus in 1968 that was the gateway for discovering effects of circulating hormones on cognitive function, mood regulation and other CNS functions. His laboratory combines molecular, anatomical, pharmacological, physiological and behavioral methodologies and relates their findings to human clinical information. His current research focuses on stress effects on amygdala and prefrontal cortex, as well as hippocampus, and his laboratory also investigates sex hormone effects and sex differences in these brain regions involved in cognitive function and mood regulation.

Eric Nestler, MD, PhD

Icahn School of Medicine at Mount Sinai

Dr. Nestler is the Nash Family Professor of Neuroscience at the Icahn School of Medicine at Mount Sinai in New York City, where he serves as Chair of the Department of Neuroscience and Director of the Friedman Brain Institute. He received his BA, PhD, and MD degrees, and psychiatry residency training, from Yale University. He served on the Yale faculty from 1987–2000, where he was the Elizabeth Mears and House Jameson Professor of Psychiatry and Neurobiology, and Director of the Division of Molecular Psychiatry. He moved to Dallas in 2000 where he served as the Lou and Ellen McGinley Distinguished Professor and Chair of the Department of Psychiatry at The University of Texas Southwestern Medical Center until moving to New York in 2008. Dr. Nestler is a member of the Institute of Medicine and a Fellow of the American Academy of Arts and Sciences. He is a past President of the American College of Neuropsychopharmacology and President Elect of the Society for Neuroscience. The goal of Dr. Nestler's research is to better understand the molecular mechanisms of addiction and depression based on work in animal models, and to use this information to develop improved treatments of these disorders.

Amy Robinson

MIT

Amy Robinson is the Executive Director of EyeWire, a game to map the brain that began at MIT. EyeWire crowdsources neuroscience, challenging hundreds of thousands of players around the world to solve 3D puzzles, which actually map out neurons. This allows neuroscientists to chart synaptic connections and model circuitry. Robinson has advised The White House OSTP and the US Senate on crowdsourcing and open innovation. Under her leadership, Eyewire's neuroscience visualizations have appeared at TED and in Times Square NYC. She helped create the world's first neuroscience virtual reality experience. Robinson curates the NIH 3D Print Exchange Neuroscience collection, which features several 3D printable neurons discovered by Eyewire gamers. Fast Company credits Robinson with "making neuroscience into a playground for the hot tech du jour." Robinson has written for Vice, the BBC, Nature, and Forbes. She tweets @amyleerobinson. Amy is a long time TEDster and founded the TEDx Music Project, a collection of the best live music from TEDx events around the world. She was named to the Forbes 30 Under 30 in 2015.

Bernardo Sabatini, MD, PhD

Harvard Medical School

Bernardo Sabatini obtained a PhD from the Department of Neurobiology and his MD degree from the Harvard/Massachusetts Institute of Technology Program in Health Sciences and Technology in 1999. Dr. Sabatini chose to not pursue further medical training, and instead began a postdoctoral fellowship in the laboratory of Dr. Karel Svoboda at Cold Spring Harbor Laboratory in New York. After his postdoctoral research, Dr. Sabatini joined the faculty in the Department of Neurobiology at Harvard Medical School in 2001. In 2008 Dr. Sabatini was named an investigator of the Howard Hughes Medical Institute and in 2010 was named the Takeda Professor of Neurobiology at Harvard Medical School. His laboratory seeks to uncover the mechanisms of synapse and circuit plasticity that permit new behaviors to be learned and refined. They are interested in the developmental changes that occur after birth that make learning possible, as well as in the circuit changes that are triggered by the process of learning. Lastly, they examine how perturbations of these processes contribute to human neuropsychiatric disorders such as Tuberous Sclerosis Complex and Parkinson's disease.

In order to conduct their studies, Dr. Sabatini's laboratory creates new optical and chemical methods to be able to observe and manipulate the biochemical signaling associated with synapse function. In 2014 Dr. Sabatini was elected to the American Academy of Arts and Sciences, and was also the recipient of the 2013–2014 A. Clifford Barger Excellence in Mentoring Award. He serves on a number of scientific advisory boards including the Simons Center for the Global Brain, the Max Planck Florida Institute, and others both domestically and abroad. Dr. Sabatini is currently the Alice and Rodman W. Moorhead III Professor of Neurobiology at HMS. He lives in Newton with his wife, who is a physician at MGH, and their 3 boys.

David Sulzer, PhD

Columbia University Medical Center

Dr. Sulzer is a Professor of Neurology, Psychiatry, and Pharmacology at Columbia University Medical Center and the New York Psychiatric Institute. He received his Ph.D from the Department of Biology at Columbia University.

Dr. Sulzer's lab (www.sulzerlab.org) is involved in research devoted to understanding the synapses of the basal ganglia, particularly in investigating how synapses of the cortex, striatum, and dopamine neurons are selected to underlie learning and decision making; and elucidating the causes of diseases that produce disorders of the basal ganglia, including Parkinson's Huntington's, drug dependence, autism and schizophrenia. Dr. Sulzer has authored over 150 publications in the field of dopamine and basal ganglia synaptic physiology and disease and has introduced multiple new therapeutic directions.

Relevant approaches explored in the lab include the development of the system for postnatal culture of midbrain dopamine neurons; discovery of co-release of glutamate from dopamine neurons; introduction the mechanism of amphetamine action; the first recording of quantal neurotransmitter release in the CNS, using amperometry at dopamine terminals; discovery of multiple means to alter quantal size, including the effects of L-DOPA, amphetamine, vesicle transporter expression, alpha-synuclein expression, and fusion pore flickering; introduction of the biosynthetic pathway of neuromelanin; introducing the role of macroautophagy and chaperone-mediated autophagy in neurodegenerative diseases; providing the first optical analysis of corticostriatal transmission; invention of fluorescent false neurotransmitters to provide the first optical means to observe neurotransmitter release in brain; identification of the role of glutamate in controlling axonal outgrowth and branching from growth cones; introduction of autophagy as a means to control developmental synaptic pruning in autism and epilepsy; identification of antigen presentation in neuron subtypes in neurodegeneration.

Sponsors

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American College of Neuropsychopharmacology

Dana Foundation

Nature

Society for Neuroscience

Winter Conference on Brain Research

The Biochemical Pharmacology Discussion Group is proudly supported by

  • Boehringer Ingelheim
  • Pfizer

Abstracts

Novel Mechanisms of Stress in the Brain: Implications for Therapy
Bruce S. McEwen, PhD, The Rockefeller University

The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and non-genomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain over the lifecourse provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.

Co-release and Interactions of Neurotransmitters in the Basal Ganglia
Bernardo L. Sabatini, MD, PhD, Harvard Medical School, HHMI

The basal ganglia are an evolutionarily conserved set of nuclei responsible for sculpting motor action and promoting the repetition of actions that lead to positive outcomes. Within this system, neuromodulators, such as dopamine, acetylcholine, and opioids, regulate the properties of synapses, cellular excitability and biochemical state. Here we present the mechanisms of presynaptic release and postsynaptic action of these molecules. Our results demonstrate prevalence of co-release and co-transmission of neuromodulators with classic neurotransmitters with a high degree of specificity for postsynaptic targets. We discuss these findings in the context of basal ganglia function.

Eyewire
Amy Robinson, EyeWire and Massachusetts Institute of Technology

Eyewire is a game to map the brain. Launched from MIT in 2012, it crowdsources data analysis by engaging hundreds of thousands of gamers. Players analyze AI-segmented neuroimage data, delivered in the form of a 3D puzzle game. Amy Robinson, Executive Director of Eyewire, will share a perspective on crowdsourcing neuroscience from three angles: scientific ingenuity, community engagement, and design and data visualization (covering science communication). She will share a never-before-seen tool for researchers created by Seung Lab, as well as release new insights gained by Eyewire's global community of puzzle gamers.

Experience-dependent Dendritic Spine Plasticity in the Cortex
Wen-Biao Gan, PhD, Molecular Neurobiology Program, Skirball Institute, New York University School of Medicine

Dendritic spines are the postsynaptic components of most excitatory synapses in the mammalian brain. In vivo time-lapse imaging of dendritic spines in the cerebral cortex indicates that spines are highly plastic during development and become remarkably stable in adulthood. In my lecture, I will discuss how learning experiences regulate the development and plasticity of dendritic spines in the living mouse cortex. I will also discuss the role of sleep in learning-induced remodeling of dendritic spines. Because dendritic spines are the key elements for information acquisition and retention, understanding how spines are formed and maintained in the living brain provides important insights into the structural basis of learning and memory.

A Role for mTOR-dependent Neuronal Autophagy in Dendritic Spine Pruning in Normal Development and Autism
David Sulzer, PhD, Columbia University Medical Center and New York State Psychiatric Institute

Dendritic spines are primary sites where neurons receive and integrate excitatory synaptic inputs. Spine pathology has been identified in neuropathological conditions including autism, schizophrenia, Alzheimer disease, drug abuse and treatment-resistant depression. A key regulator for dendritic spine morphogenesis is the mammalian target of rapamycin (mTOR) kinase.
 
Germline mutations in tumor suppressor genes that negatively regulate mTOR, including tuberous sclerosis complex (TSC) genes Tsc1 and Tsc2, are implicated in the pathogenesis of autism. In TSC1/2 mutant mice, we find that mTOR disinhibition supresses macroautophagy (autophagy thereafter), increases dendritic spines, and produces autistic like social behavioral deficits. Using neuronal autophagy deficient mice, we find that autopahgy regulates postnatal synaptic pruning, a process that decreases net synaptic density on cortical projection neurons by ~50% during childhood. Morphological and behavioral changes are reversed by mTOR inhibitor rapamycin in TSC mutant mice, but not in TSC mice deficient for autophagy. These findings suggest a link between mTOR dependent autophagy pathway and pruning of synaptic connections during postnatal development. This was consistent with examination of postmortem brain of autism patients, in which increased dendritic spine density negatively correlates with impaired mTOR-autophagy signaling.
 
Our studies thus provide the first evidence that mTOR dependent autophagy is implicated in neuropsychiatric disorders that feature synaptic pathology. Further identification of the mechanism by which autophagy signaling cascade regulates spine morphogenesis may elucidate morphological alterations within autistic brain and suggest novel therapeutic targets.
 
Coauthor: Guomei Tang, Departments of Neurology, Psychiatry, Pharmacology, Columbia University Medical Center and New York State Psychiatric Institute

Circuit-Specific Adaptations Associated with Drug Addiction
Eric J. Nestler, MD, PhD, Icahn School of Medicine at Mount Sinai

Dendritic spines are the sites of most excitatory synapses in the central nervous system, and chronic administration of drugs of abuse, such as cocaine, alters the density and morphology of such spines on medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a primary reward region. Work over the past decade has shown that dendritic spine morphology dictates synaptic function such that spines with small heads (e.g., thin spines) bear lower levels of surface AMPA receptors than spines with large heads (e.g., mushroom spines). Acute and protracted withdrawal from cocaine produces opposing alterations in the synaptic structure and function of NAc MSNs such that early withdrawal (e.g., 1-day) is characterized by synaptic weakening as evidenced by de novo thin spine formation, while late withdrawal (e.g., 1-month) is characterized by the increased formation of mushroom spines and hence synaptic strengthening. We found recently that expression of the Rap1 small GTPase is upregulated during early cocaine withdrawal and that Rap1 induction increases thin spine formation in NAc MSNs via activation of local AKT/mTOR signaling. Conversely, Rap1 is downregulated during late cocaine withdrawal which causes mushroom spine formation. Further, we found that the increased (early withdrawal) and decreased (late withdrawal) expression of this pathway in NAc MSNs produces opposing effects on cocaine-mediated behavioral reward. Finally, using optogenetics we dissected the excitatory inputs to the NAc that regulate Rap1 signaling in NAc spines. Collectively, these findings shed light on the mechanisms by which cocaine induces dendritic plasticity in NAc MSNs to control reward behavior.

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