# Neuronal and homeostatic regulation of sleep and wake by corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2022 · $46,752

## Abstract

PROJECT SUMMARY
Sleep is an evolutionarily conserved behavior that is widely observed across the animal kingdom. It is
characterized by transitions between different vigilance states: wake, rapid eye movement (REM) sleep, and
non-REM (NREM) sleep. These transitions are controlled by interactions between different neuronal populations
and are under the influence of homeostatic and circadian mechanisms. As sleep has many beneficial and
restorative effects, good quality sleep is important for mental and physical health. It has been well-established
that stress and sleep have a bidirectional relationship. Stress is known to be a major cause of disrupted sleep.
Chronic sleep disruption can lead to an increased risk of developing psychiatric disorders. The paraventricular
nucleus of the hypothalamus (PVN) contains corticotropin-releasing hormone (CRHPVN) neurons that have been
shown to be activated by stress. Central and systemic administration of CRH has been found to induce
wakefulness. Additional studies have found that central blockade of the CRH receptor 1 (CRHR1) reduces the
wake-promoting effects of CRH injection, suggesting this receptor plays a key role in CRH-mediated arousal.
However, the neural mechanisms by which CRH neurons regulate wakefulness are not very well understood.
Tracing studies have revealed that CRHPVN neurons project to the preoptic area of the hypothalamus (POA), a
well-known sleep center containing neurons that are crucial for sleep regulation. In situ hybridization studies
have shown that CRHR1 is expressed in the POA. While CRH has been implicated as a regulator of wakefulness,
the role that CRHPVN neurons and their projections to the POA (CRHPVN→POA) play in the sleep-wake cycle and
sleep homeostasis has not been fully investigated. The central hypothesis of this proposal is that CRHPVN
neurons control wakefulness and impair the homeostatic response to sleep pressure following chronic stress.
To address this hypothesis, this proposal will use a genetic mouse model, CRH-Cre, to specifically label CRH
neurons, in vivo calcium imaging, optogenetic manipulations, CRISPR-Cas9 gene editing techniques, and a
chronic social defeat stress paradigm to manipulate these neurons and their projections. Aim 1 will determine
the role of CRHPVN→POA projections in regulating sleep and wakefulness. Aim 2 will investigate the role of CRHPVN
neurons and CRHPVN→POA projections in sleep homeostasis following chronic stress. Understanding how CRHPVN
neurons promote wakefulness and regulate sleep homeostasis in response to chronic stress will further elucidate
how the circuits controlling stress are interconnected with those regulating sleep and wakefulness.

## Key facts

- **NIH application ID:** 10464942
- **Project number:** 1F31HL160451-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** ALYSSA N WIEST
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464942

## Citation

> US National Institutes of Health, RePORTER application 10464942, Neuronal and homeostatic regulation of sleep and wake by corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (1F31HL160451-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10464942. Licensed CC0.

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