Stress-related neuropsychiatric illnesses including major depressive disorder (MDD) are increasingly prevalent and impose a great social and economic burden. Conventional monoamine antidepressants can be slow to achieve efficacy and remission rates are low, highlighting the need for novel, rapid therapeutic treatments. While sleep disturbance is associated with MDD, interestingly, one night of sleep deprivation (SD) produces a dramatic albeit temporary reduction in symptoms. Understanding the neurobiological mechanisms underlying the effects of this counterintuitive strategy can help enhance and prolong its treatment potential. Sleep and wake states are marked by changes in cortical homeostatic synaptic plasticity including within the medial prefrontal cortex (mPFC) a region critically involved in mood and cognitive functions associated with MDD. Anhedonia, or diminished pleasure from previously rewarding activities is a core feature of MDD and mPFC neurons are known to encode effort valuation, or cost-benefit analyses for motivated reward seeking. The neural projection from the dorsal mPFC (dmPFC) to the core region of the nucleus accumbens (NAcc) is especially critical for effortful reward seeking and accumbens-projecting neurons are tuned to encode reward- predictive cues, suggesting that this circuit may be particularly relevant for chronic-stress induced anhedonia- related behavior. The effects of SD on effort valuation and the role of this circuit have not been specifically investigated. SD is known to promote glutamatergic signaling and prolonged wakefulness increases cortical excitability, which may in turn lead to enhanced inducibility of synaptic plasticity. Group 1 metabotropic glutamate receptors including mGluR5 are promising candidates to study antidepressant actions of SD as mGluR5 signaling is decreased the frontal cortex in MDD and increased following one night of SD. Functional mGluR5 is also necessary for maintaining sleep/wake homeostasis and behavioral adaptability to sleep deprivation. For this proposal, I will use cutting-edge in vivo approaches including two-photon (2P) calcium imaging of dmPFC-NAcc neurons during a novel head-fixed effort valuation task (Aim 1), in vivo measurement and manipulation of spine dynamics (Aim 2), and cell-specific photoswitchable control of mGluRs (Aim 3) to test the hypothesis that SD reverses stress-induced deficits in effort valuation by increasing mGluR5 signaling in dmPFC-NAcc projection neurons, which in turn enhances their excitability, restores lost spines, and rescues stress effects on reward-predictive cue encoding. The completion of these aims will provide valuable insight into neurobiological mechanisms of sleep deprivation as a rapid antidepressant strategy. My findings could also inform therapeutic targets to attenuate cognitive deficits associated with MDD and optimize the efficacy of SD.

Public Health Relevance

Major Depressive Disorder (MDD) remains one of the leading causes of disability and reduced quality of life worldwide, however sleep deprivation (SD) is an effective, fast-acting albeit transient therapeutic strategy. Understanding the neurobiological mechanisms underlying antidepressant effects of SD could help inform targets to enhance and extend its treatment potential. I will use a systems-level approach to uncover how SD alters reward behavior and remodels neural activity, dendritic spine formation and glutamatergic signaling in the medial prefrontal cortex (mPFC) in animals exposed to chronic social defeat stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32MH117973-02
Application #
9888208
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Van'T Veer, Ashlee V
Project Start
2019-02-20
Project End
2022-02-19
Budget Start
2020-02-20
Budget End
2021-02-19
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065