Chronic sleep disturbance affects 10-20% of the population in the developed world, representing a substantial public health problem. Given the ubiquitous nature of sleep across the animal kingdom, intense investigation is underway into the biological functions of sleep. A primary hypothesis is that sleep facilitates memory consolidation following learning, as sleep restriction or fragmentation impairs memory performance across species. The circuitry coupling sleep and memory remains undefined. Recently, ventral tegmental area (VTA) dopaminergic neurons have been demonstrated to control motivational gating of arousal. These cells are well known players in ?reward and salience? circuitry, and send projections to brain centers critical for memory formation and recall (i.e., hippocampus, amygdala, and prefrontal cortex). How these (or local VTA-GABAergic) neurons contribute to sleep-dependent memory consolidation is unknown. Wake-stabilizing hypocretin (Hcrt) neurons in the lateral hypothalamus send dense projections to the VTA, however, it is unknown how (or if) this circuit contributes to Hcrt-mediated arousal or memory function. This proposal will integrate in vivo optogenetics, calcium imaging, and EEG techniques along with behavioral assays to establish (or refute) a role for these cells in sleep-dependent memory consolidation. fMRI technology will be integrated with optogenetic manipulations and quantitative approaches (dynamic causal modeling) to delineate brain-wide responses to Hcrt stimulation. These findings will establish the Hcrt-to-VTA circuit as a node coupling vigilance states to memory consolidation, with the ultimate goal of providing comprehensive insight into disorders of sleep-wake dynamics and memory dysfunction.

Public Health Relevance

Chronic sleep disruption is common throughout the developed world, contributing to cognitive problems including memory disruption. In addition to providing structured opportunities for my professional development, the experiments described herein will advance our fundamental knowledge of neural circuits coupling arousal and memory. Future studies will build on these findings to provide a comprehensive understanding of disorders of sleep and waking as well as memory impairment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32MH115431-02
Application #
9663812
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Van'T Veer, Ashlee V
Project Start
2018-03-01
Project End
2020-06-30
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Tyree, Susan M; Borniger, Jeremy C; de Lecea, Luis (2018) Hypocretin as a Hub for Arousal and Motivation. Front Neurol 9:413