R35NS127232

Development, Maintenance, and Human-Specific Evolution of Cortical Circuits - Abstract

Over the past two decades, my laboratory has focused on the identification of novel molecular and cellular mechanisms underlying the development, maintenance (Project 1), and human-specific evolution (Project 2) of cortical circuits.

In Project 1, we propose to study the role of novel molecular effectors regulating the function of the two most abundant organelles in neurons: the endoplasmic reticulum and mitochondria. We discovered that these two organelles are morphologically and functionally very different in axons and dendrites. Even more recently, we identified a novel tethering protein, PDZD8, mediating specialized contacts between these two organelles. ER-mitochondria contacts (ERMCS) are emerging as unique biochemical and physiological signaling platforms in most cells, and we discovered that in dendrites of pyramidal neurons, ERMCS play critical roles in regulating synaptically-evoked Ca2+ dynamics (Hirabayashi et al., Science 2017). We are now proposing to use an array of new techniques to determine the role of PDZD8-dependent ER-mitochondria coupling on dendritic integration, synaptic plasticity, and their impact on the emergence of feature selectivity in CA1 PNS.

Since 2010, we have also initiated a new paradigm to provide insights into one of the most challenging questions in neuroscience: 'What makes the human brain unique?'. In particular, our work tackled whether or not the uniqueness of the human cortical circuits has molecular and physiological determinants at the synaptic level. In Project 2, we propose to continue the new paradigm we implemented, starting to tackle this question by studying the role of human-specific gene duplications (HSGDs) as potential genetic modifiers of circuit development and function. The first example of such an HSGD acting as a human-specific modifier of synaptic development and cortical circuit architecture came from our study on SRGAP2A and its human-specific paralog SRGAP2C. Humanization of SRGAP2C expression in mouse cortical pyramidal neurons phenocopies a partial loss of function of SRGAP2A and leads to the emergence of phenotypic traits characterizing human cortical circuits, protracted period of excitatory and inhibitory synaptic maturation, and increased density of both types of synapses. Our most recent results demonstrate that SRGAP2C increases specifically the formation of cortico-cortical synapses onto layer 2/3 PNS, increased reliability of sensory coding, and improved behavioral performance in tasks involving sensory discrimination (Schmidt et al., bioRxiv (2020); Nature in press). We propose to explore other aspects of SRGAP2A functions and how humanization of SRGAP2C modulates them, including their role in microglial cells where both are expressed and in synaptic plasticity within adult cortical circuits. We will also extend this paradigm to other human-specific gene duplications as potential modifiers of cortical circuit development, limiting our scope to 4 other genes expressed in maturing and adult postmitotic neurons in the mouse and human cortex.

Our projects will tackle with unprecedented relevance the relationship between genes, circuit architecture, circuit function, and behavior in the framework of human cortical circuit evolution.

The Trustees Of Columbia University In The City Of New York

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

New York, New York 10027 United States

Single Zip Code

Research Program Award (R35 Clinical Trial Optional) (RFA-NS-21-020)

Amendment Since initial award the total obligations have increased 303% from $1,215,000 to $4,895,488.