U19NS132720

Mechanisms of Neural Circuit Dynamics in Working Memory and Decision-Making - Project Summary/Abstract:

Overall, the overarching goal of this U19 program is to determine how neural computations across brain regions produce two core cognitive processes, working memory and decision-making, and thus to derive fundamental principles of brain function. This renewal application proposes to pursue powerful new themes that emerged from our previous work and to broaden our scope substantially.

To do so, the eight PIs plan a tightly integrated set of experimental and computational studies of mice doing the accumulating towers task—in which they must remember how many towers flash on each side as they run down a maze in virtual reality—and related tasks.

The first theme arises from the finding that neurons across the brain encode task variables and are necessary for task performance. Almost all of these areas exhibit sequential activity, in which neurons are active at different times in the task and, together, tile the trial duration. Project 1 will identify the task features that drive sequential activity, use cooling to identify neural circuits that generate sequential activity, and elucidate its anatomical basis by combining transmission electron microscopy and computational modeling.

A second theme is that manifold inference methods, applied to large-scale hippocampal recordings in our task, reveal the geometry of a joint neural representation for an external variable (position) and an internal, cognitive variable (accumulated evidence). Project 2 will extend our work on the geometry of neural representations to other brain regions. We will examine how geometries and representations in these regions interact with each other, and we will develop models to explain how the observed neural manifolds arise.

A third theme, fueled by our development of statistical methods to infer internal brain states, is that animals’ brains occupy qualitatively different states from trial to trial during the same task block. Our data suggests that behavior in each state requires different neural structures and circuits—in the same animal and the same trial block. Project 3 will use multi-region recordings and perturbations to investigate whether states are local to subcircuits versus global across the brain, extend our behavioral inference methods to neural data, and examine to what extent our inferred states are linked to internal states of arousal, thirst, and hunger.

Elucidating how multiple circuits performing local computations combine into a brain in action is the goal of Projects 4 and 5. Project 4 will probe functional interactions in multi-region recordings, including very large-scale simultaneous electrophysiological recordings with next-generation silicon probes; and through targeted experiments will test two hypotheses of how subcortical regions interact with neocortex. Project 5 will generate a set of mechanistic models that instantiate specific hypothesized roles of different brain regions. These local models will be combined into a single multi-regional model, informed by data from all projects, that will enable us to dissect the roles of individual regions and their interactions in performance of the many variants of our decision-making task.

The Trustees Of Princeton University

(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.

93.279 - Drug Abuse and Addiction Research Programs

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

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Princeton, New Jersey 085406000 United States

Single Zip Code

BRAIN Initiative: Team-Research BRAIN Circuit Programs - TeamBCP (U19 Clinical Trial Not Allowed) (RFA-NS-22-040)

Amendment Since initial award the total obligations have increased 208% from $4,250,000 to $13,099,996.