# Roles of CRF-PACAP systems in sleep in mice (Carlezon)

> **NIH NIH P50** · MCLEAN HOSPITAL · 2021 · $345,200

## Abstract

SUMMARY: PROJECT 3
Sleep is affected in many psychiatric illnesses. Some with people with stress-related disorders (e.g., Post-
Traumatic Stress Disorder [PTSD]) sleep less than normal, whereas others sleep more, or have fragmented
sleep patterns that reflect more frequent bouts of sleep and wakefulness. There is considerable evidence that
stress disrupts sleep, and we have shown that chronic stress in mice causes profound alterations in sleep and
diurnal rhythms. In contrast, the effects of sleep dysregulation on brain systems that mediate stress effects are
not thoroughly understood. Periods of poor or restricted sleep may produce molecular alterations that
subsequently affect sleep. Work in rodents demonstrates important similarities and differences between CRF
(corticotropin-releasing factor) and PACAP (pituitary adenylate cyclase-activating polypeptide) effects on
behavior. Although both peptides increase acoustic startle, a measure of vigilance often used in preclinical and
clinical studies of anxiety and fear, PACAP effects tend to be persistent (lasting >1 week), whereas CRF effects
resolve quickly. These types of findings, together with known genetic alterations in CRF and PACAP systems
in people vulnerable to stress-related illness, provide a rationale for comparing and contrasting the neurobiology
of these peptides. The effects of CRF and PACAP on sleep have not been directly compared, particularly over
extended periods of time. Our premise is that these peptide systems affect—and are affected by—sleep. Our
hypothesis is that there is a reciprocal relationship between these peptides and sleep, such that activation of
CRF and/or PACAP systems will affect sleep and, conversely, sleep restriction will affect CRF and/or PACAP
systems, but that the persistence of these effects will differ. Tests will be conducted in male and female mice
implanted with wireless transmitters that enable continuous collection of EEG, EMG, body temperature, and
activity data for several weeks. Molecular analyses will focus on brain areas implicated in the emotional aspects
of stress, including amygdala (AMG), bed nucleus of the stria terminalis (BNST), and prefrontal cortex (PFC), as
well as areas more traditionally implicated in sleep and biological rhythms. We will also perform circuit mapping
studies to provide insights on neural connections between regions that regulate emotional behavior and those
that regulate sleep. In Aim 1, we will compare the effects of altering CRF and PACAP system function on sleep
and biological (diurnal and circadian) rhythms. We will also examine the effects of PAC1R or CRFR1 ablation
in AMG, following up on pilot data showing that stress increases PAC1R expression in this region. In Aim 2, we
will directly compare the effects of acute and repeated sleep restriction on PACAP and CRF systems using
RNAscope to quantify the magnitude of any changes and identify the cell-types in which changes occur. In Aim
3, we will use trans-synap...

## Key facts

- **NIH application ID:** 10116482
- **Project number:** 5P50MH115874-03
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** William A. Carlezon
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,200
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116482

## Citation

> US National Institutes of Health, RePORTER application 10116482, Roles of CRF-PACAP systems in sleep in mice (Carlezon) (5P50MH115874-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10116482. Licensed CC0.

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