Nearly all animals exhibit more sleep early in life, suggesting a conserved role for sleep during development. Early developmental sleep is hypothesized to have a role in normal brain patterning, and sleep disturbances during a critical period can have long-lasting neurobehavioral sequelae in humans. Yet, it is unknown whether sleep is required for normal structural maturation of the brain and what mechanisms control excess sleep in developing animals. This proposal utilizes the powerful model system Drosophila melanogaster to determine how early developmental disruptions in sleep impact neural circuit formation and adult behaviors. This project directly engages the Systems and Cognitive Neuroscience Program at NINDS, and specifically addresses goals of the 2011 NIH Sleep Disorders Research Plan, including: 1) elucidating molecular pathophysiological mechanisms and windows of vulnerability to sleep deficiency with respect to impaired neurological development and synaptic function, and 2) identifying the processes by which sleep disturbances during vulnerable periods of development confer risk in the trajectory of normal brain development. Candidate: Matthew Kayser received his MD and PhD in Neuroscience from the University of Pennsylvania, where he also completed Psychiatry residency. He is currently a postdoctoral fellow in the Center for Sleep and Circadian Neurobiology at Penn, pursuing training in a laboratory dedicated to understanding genetic and neurobiological substrates of sleep and circadian rhythms. This proposal builds on his established interest in neural development, will produce novel scientific results, and additionally provides critical training to the candidate. The applicant's long-term goal is to become an R01-funded independent investigator studying how sleep early in life sculpts brain circuits and can contribute to later neurobehavioral abnormalities. Environment: Dr. Kayser's mentor, Dr. Amita Sehgal, provides unparalleled expertise. Dr. Sehgal is world-renowned for her research on sleep and circadian rhythms utilizing Drosophila. She has been continuously funded by HHMI and NIH for over 15 years and offers extensive resources for the work described in this proposal. Dr. Sehgal also has a robust track record of mentorship. The applicant's career development plan entails rigorous training in sleep and Drosophila genetics/neurobiology, coursework in areas crucial to his success, and close guidance from a diverse and dedicated network of scientific advisors. In addition, Dr. Kayser has the full support of the Department of Psychiatry at Penn, to which he is being actively recruited as a tenure-track Assistant Professor. Research: Preliminary results show that sleep ontogeny in Drosophila is controlled by a developmental delay in wake-promoting dopaminergic activity, and we have identified a specific dopaminergic neural circuit controlling sleep in young flies. Sleep loss induced by hyperexcitation of this circuit only during a critical developmental window leads to lasting deficis in adult social behaviors. These behavioral deficits have been traced to a single olfactory glomerulus involved in pheromone-dependent courtship activity. This glomerulus uniquely displays extensive sleep-dependent growth in young flies, suggesting that rapidly growing regions of brain are most susceptible to sleep perturbations early in life. Moreover, we hypothesize that enhanced growth of this glomerulus reflects a higher rate of synapse addition. This proposal will build on preliminary data to 1) determine a mechanism controlling developmental changes in dopaminergic activity, 2) show that critical period sleep deprivation impairs a normal developmental program underlying adult behaviors, and 3) test a role for sleep in synaptogenesis. The proposed scientific inquiry, Dr. Sehgal's mentorship, and the enthusiastic support of the candidate's division and advisory committee will enable Dr. Kayser to launch a successful career as an independent physician-scientist.

Public Health Relevance

Abnormal sleep during development can result in long-lasting neurobehavioral abnormalities and has been linked to adult neuropsychiatric disorders. The goal of this proposal is to identify the mechanisms controlling sleep in early life and determine how sleep during this time serves to promote normal structural maturation of the brain. This work will improve understanding of why we sleep more when young and may lead to new approaches for preventing neuropsychiatric illness.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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He, Janet
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University of Pennsylvania
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United States
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Szuperak, Milan; Churgin, Matthew A; Borja, Austin J et al. (2018) A sleep state in Drosophila larvae required for neural stem cell proliferation. Elife 7:
Dilley, Leela C; Vigderman, Abigail; Williams, Charlette E et al. (2018) Behavioral and genetic features of sleep ontogeny in Drosophila. Sleep 41:
Machado, Daniel R; Afonso, Dinis Js; Kenny, Alexandra R et al. (2017) Identification of octopaminergic neurons that modulate sleep suppression by male sex drive. Elife 6:
Kayser, Matthew S; Biron, David (2016) Sleep and Development in Genetically Tractable Model Organisms. Genetics 203:21-33
Kayser, Matthew S; Mainwaring, Benjamin; Yue, Zhifeng et al. (2015) Sleep deprivation suppresses aggression in Drosophila. Elife 4:e07643
Kayser, Matthew S (2015) Fact or fiction? Examining a role for N-methyl-D-aspartate receptor autoantibodies in psychiatric illness. Biol Psychiatry 77:506-7
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