R01NS124017

Genetic and Neural Mechanisms Underlying Emerging Social Behavior in Zebrafish

Our goal is to understand emerging collective behaviors of groups, such as schooling and shoaling in fish. Our approach is to dissect basic sensorimotor transformations in the zebrafish, which we believe play a fundamental role in explaining emerging social interactions.

We have identified two simple and well-described reflexive behaviors: 1) the optomotor reflex (OMR), where fish swim along with whole field motion stimuli, and 2) object evoked re-orienting responses (OER), where fish turn away or towards moving objects, depending on the object's size and movement. We have shown in preliminary modeling studies that an implementation of these two simple "motor primitives" in virtual agents can explain a significant fraction of the emerging social behaviors in adult fish.

A compelling advantage of focusing our studies on these two simple reflexes is that they are robustly expressed in 7-day-old larvae, which facilitates a detailed and quantitative behavioral analysis of the related visuomotor transformation, as well as a dissection of their underlying neural circuitry.

A critical element in our proposal is the generation of mutant zebrafish that we have shown to display subtle but distinctive social behavioral phenotypes at the adult stage. We found that, even in the larval stage, and prior to onset of robust schooling and shoaling behaviors, these mutants already reveal behavioral phenotypes in the context of the OMR and OER, and that these phenotypical deviations are predictive of the later emerging differences in schooling and shoaling in adults.

One of our central goals is the dissection of the specific changes in neural circuitry in the mutants that are responsible for these altered behavioral phenotypes. Some such changes in neural phenotype may manifest at the level of global brain structures, but many are likely to disrupt micro-circuits - either at the level of cellular identities or synaptic connectivity - that underlie both simple behavior in the embryo and more complex behaviors in the adult.

Notably, we already have generated realistic circuit models that form specific hypotheses about the neural networks underlying the OMR and OER in wild-type animals, and these models are readily adjusted to identify and constrain the specific latent variables that are changed in the mutant animals. Such adjusted models serve as ideal priors and specific hypotheses to be tested in brain-wide functional imaging experiments.

Lastly, the identification of detailed neural phenotypes in mutant animals in terms of anatomical location, neuronal cell fate, and synaptic specificity will facilitate linkage of these anatomical and physiological changes to specific cell fates and molecular pathways. Our parallel ongoing efforts in describing and modeling brain-wide neural circuits in zebrafish (within the framework of the U19 Team-Research Brain Circuits Program) will allow us to narrow down which of all these observable neural phenotypes in the mutants are responsible and causally related to the specific neural changes that underlie the changes in behavior.

President And Fellows Of Harvard College

(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]

Massachusetts United States

State-Wide

BRAIN Initiative: Targeted BRAIN Circuits Projects- TargetedBCP (R01 Clinical Trial Not Allowed) (RFA-NS-18-030)

Amendment Since initial award the End Date has been extended from 08/31/24 to 08/31/26 and the total obligations have increased 72% from $2,300,000 to $3,951,973.