R35NS122181

Cross-Species Analyses of the Molecular and Circuit Basis of Sleep - Summary

Sleep is an enigmatic behavior that is conserved across the animal kingdom. The mechanisms underlying the regulation of sleep remain poorly understood, and the function of sleep is even more elusive. Yet, dysregulation of sleep is a major cause of human morbidity, and understanding why we sleep is a fundamental question in neuroscience research.

We propose that gaining a deep understanding of sleep requires studying this process across molecular, circuit, neurophysiological, and behavioral levels. To accomplish this, our group has been using a multidisciplinary, cross-species approach (Drosophila and mice) to study sleep. The recent work of our group has coalesced around two main themes: how circadian time organizes sleep and arousal, and how dedicated neural circuits encode homeostatic drive.

Our investigations into these processes have led to new insights into 1) the conserved molecular mechanisms mediating the circadian regulation of sleep and arousal; 2) how different types of neural codes impact plasticity and behavior; and 3) how sleep drive is generated, released, and persists in time.

In this research program project, we will build upon our prior studies of the circadian and homeostatic regulation of sleep and develop new approaches to investigate the neurophysiology and function of sleep. First, we will address whether the temporal coding mechanisms found in Drosophila clock neurons are also conserved in the mammalian suprachiasmatic nucleus.

Compared to our understanding of the circadian clock, much less is known about the homeostatic regulation of sleep. Nevertheless, we predict that the nature of neural circuits underlying sleep homeostasis will be conserved, and we will seek to identify a sleep homeostatic integrator circuit in mice.

Our studies of the cellular mechanisms mediating sleep homeostasis have led us to examine the role of astrocytes in sleep behavior. We plan to determine whether sleep-regulating molecular pathways in these cells are conserved and will perform systematic investigations into the role of astrocytes in regulating neuronal physiology and behavior.

To fully exploit the power of the Drosophila model for studying sleep, we will develop a new multimodal imaging method for characterizing and quantifying sleep. Our research has largely focused on how sleep is regulated, but in the future, we will also address the function of sleep in neural plasticity using a simple, defined circuit and new electrophysiological methods.

Finally, we are extending our studies into human disorders, including studying the genetic basis of familial sleepwalking. Our goal is to not only delineate conserved mechanisms underlying sleep and its function but also to uncover fundamental neurobiological principles governing these processes.

The Johns Hopkins 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.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

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

Baltimore, Maryland 212051832 United States

Single Zip Code

Research Program Award (R35 Clinical Trial Optional) (RFA-NS-20-030)

Amendment Since initial award the total obligations have increased 409% from $1,121,619 to $5,714,123.