# BLR&D Research Career Scientist Award

> **NIH VA IK6** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2020 · —

## Abstract

PROJECT SUMMARY
Insomnia and disturbed sleep are common symptoms in mood and anxiety disorders. Nocturnal
sleep disruption is a frequent complaint following traumatic brain injury (TBI). Previous work in
my laboratory has identified systems of GABAergic neurons in the preoptic hypothalamus that
have critical sleep regulatory functions. GABAergic neurons in the median preoptic nucleus
(MnPO) and the ventrolateral preoptic area (VLPO) are activated during sleep. Adenosine is a
critical endogenous sleep regulatory factor, important in the expression of homeostatic responses
to sleep loss. We have shown that MnPO/VLPO neurons are activated by A2A adenosine receptor
agonists. We have recently demonstrated that discharge of MnPO/VLPO neurons is dynamically
responsive to changing homeostatic sleep drive during sleep deprivation and recovery sleep. We
have further shown that during development, functional maturation of MnPO/VLPO GABAergic
sleep regulatory systems underlies the development of sleep homeostasis. Our overarching
hypothesis is that disruption of homeostatic responses to sleep loss due to dysfunction of preoptic
hypothalamic sleep regulatory circuits contributes to sleep disturbances in mood and anxiety
disorders and TBI. We will test this hypothesis using animal models of these disorders. We will
also expand our understanding of the fundamental interactions between hypothalamic and
brainstem arousal state-regulatory circuits in normal and disordered sleep. Brain levels of
corticotrophin-releasing factor (CRF), a critical neuropeptide regulator of the HPA axis, are
chronically elevated in anxiety disorders and posttraumatic stress disorder (PTSD). CRF has well
characterized wake-promoting/sleep-disruptive effects. We hypothesize that activation of CRF
neurons occurring in response to acute and chronic stress disrupts sleep homeostasis. We
further hypothesize that CRF effects on sleep homeostasis are mediated through suppression of
the activity of sleep-regulatory GABAergic neurons in the preoptic hypothalamus and rostral
medulla. We will use transgenic CRF-cre mice and adenoviral vectors to optogenetically and
chemogenetically manipulate CRF-signaling in the brain, and determine the effects on sleep
homeostasis, functional activity of preoptic and medullary sleep regulatory neuronal populations
and the sleep disruptive effects of acute and chronic stressors. Sleep-wake disturbances
following TBI include daytime sleepiness, nocturnal sleep fragmentation, insomnia and alterations
in the sleep EEG. Previous work has shown that in mouse models of TBI, excessive sleepiness
is associated with reduced activation of orexin neurons. In collaboration with colleagues at the
Portland VA who have expertise in TBI, we have generated preliminary findings that sleep-related
activation of MnPO neurons is dramatically reduced after cortical fluid percussion injury in mice.
We will pursue these preliminary findings and examine the functional status of GABAergic...

## Key facts

- **NIH application ID:** 9899085
- **Project number:** 5IK6BX004208-03
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Ronald Szymusiak
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899085

## Citation

> US National Institutes of Health, RePORTER application 9899085, BLR&D Research Career Scientist Award (5IK6BX004208-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899085. Licensed CC0.

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