# Impact of Corticotropin Releasing Factor on Sleep Regulation

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2020 · —

## Abstract

Insomnia and disturbed sleep are common symptoms in mood and anxiety disorders. Depression and
PTSD are associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. Brain levels of
corticotrophin-releasing factor (CRF), a critical neuropeptide regulator of the HPA axis, are chronically
elevated in these disorders. CRF has well characterized wake-promoting/sleep-disruptive effects.
Previous work from our laboratory and others has identified GABAergic neurons in the preoptic
hypothalamus as critical regulators of sleep onset, sleep maintenance and sleep homeostasis. During
the previous funding period, we demonstrated that acute elevations of CRF has sleep disruptive effects
mediated, in part, by actions on preoptic neurons. We provide preliminary data that the disruption of sleep
homeostasis that accompanies chronic partial sleep restriction can be reversed by administration of CRF
receptor antagonists. We hypothesize that activation of CRF neurons occurring in response to the stress
of chronic sleep restriction 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 in the rostral medulla. We propose four specific aims to address these
hypotheses. Aim 1 will determine if CRF disrupts preoptic and medullary sleep-regulatory neuronal activity
during chronic sleep restriction in rats. Aim 2 will determine the nuclei of origin of CRF neuronal afferents
to GABAergic sleep regulatory neurons in the preoptic hypothalamus and the rostral medulla through
targeted microinjections in the hypothalamus and extended amygdala of AAV-DIO-mcherry in CRF-ires-
CRE knock-in mice. Aim 3 will identify CRF neuronal populations responsible for the negative modulation
of sleep homeostasis by expressing channel rhodopsin-2 and hM3Dq excitatory designer receptor in
hypothalamic and extended amygdala nuclei that contain CRH neurons and determining the effects of
light-induced and chemogenetic excitation of different CRF neuronal populations on sleep homeostasis.
Aim 4 will determine if chemogenetic silencing of CRF neurons restores homeostatic responses to sleep
loss during chronic sleep restriction. Insomnia and insufficient sleep are common in psychiatric disorders
that are associated with and/or exacerbated by physiological or psychological stress. We propose to
examine fundamental mechanisms and circuits that might underlie the negative impact of chronic mild
stressors on the homeostatic regulation of sleep, with the goal of identifying critical regulatory nodes that
can be targeted for therapy. Chronic sleep disturbance can contribute to maladaptive stress and may be
a modifiable risk factor for poor psychiatric and health outcomes in PTSD, depression and other disorders.

## Key facts

- **NIH application ID:** 9815408
- **Project number:** 5I01BX001556-08
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Ronald Szymusiak
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-10-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815408

## Citation

> US National Institutes of Health, RePORTER application 9815408, Impact of Corticotropin Releasing Factor on Sleep Regulation (5I01BX001556-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9815408. Licensed CC0.

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