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.

Public Health Relevance

Post-traumatic stress disorder (PTSD) and depression are highly prevalent in US combat Veterans. Insomnia and disturbed sleep are common features in these and other mood and anxiety disorders. Chronic hyperactivity in brain corticotropin releasing factor (CRF) systems has been linked to PTSD and depression. Building on findings from the previous funding period, experiments proposed here are designed to identify critical sleep regulatory circuits targeted by CRF and evaluate the hypothesis that elevated CRF signaling during chronic mild-moderate stress causes disruption of fundamental diencephalic and brainstem circuits that regulate sleep homeostasis. The goal is to identify critical nodes in these circuits that can be targeted for therapeutic interventions. Severity of insomnia and sleep disturbance have been linked to symptom severity and recurrence in PTSD and depression. Preservation of sleep homeostasis during chronic stress may be a strategy to promote stress resilience and improve outcomes in mood and anxiety disorders.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology R (NURR)
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VA Greater Los Angels Healthcare System
Los Angeles
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Alam, Md Aftab; Kostin, Andrey; Siegel, Jerome et al. (2018) Characteristics of sleep-active neurons in the medullary parafacial zone in rats. Sleep 41:
Donlea, Jeffrey M; Alam, Md Noor; Szymusiak, Ronald (2017) Neuronal substrates of sleep homeostasis; lessons from flies, rats and mice. Curr Opin Neurobiol 44:228-235