Insomnia and disturbed sleep are common symptoms in mood and anxiety disorders, including major depression and posttraumatic stress disorder (PTSD). 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-suppressing effects. The prevailing hypothesis is that CRF- induced insomnia reflects a state of hyperarousal, due to activation of wake-enhancing neuronal systems, including hypocretin (HCRT) neurons in the lateral hypothalamus and noradrenergic neurons in the locus coeruleus. However, we have evidence that central administration of CRF disrupts the activity of critical sleep-regulatory neurons located in the ventrolateral preoptic area (VLPO) and median preoptic nucleus (MnPN). Experiments proposed in this application address the critical question: """"""""Is insomnia associated with CRF hyperactivity due to hyperarousal, a deficiency in sleep-promoting circuits, or a combination of both?"""""""" We propose three aims to answer this question. During the previous funding period we determined that neuronal discharge in the MnPN and VLPO is tightly coupled to changing homeostatic sleep need during sleep deprivation (SD) and recovery sleep (RS).
In Aim 1 we will determine if increased CRF signaling in the preoptic hypothalamus dissociates MnPN and VLPO neuronal activity from homeostatic sleep drive. CRF agonists will be delivered directly into the MnPN and VLPO via a microdialysis probe, while single unit activity is recorded immediately adjacent to the probe. We will determine if CRF suppresses the normal increase in MnPN and VLPO neuronal discharge that occurs during SD and RS. In a second experiment under Aim 1 we will determine if local dialysis perfusion of CRF antagonists prevents the suppression of c-fos expression in VLPO and MnPN neurons that is evoked by intracerebroventricular (ICV) infusion of CRF.
Aim 2 will evaluate the functional importance of activation of HCRT neurons in mediating sleep disturbance following central CRF administration. We will determine if ICV infusion of a dual HCRT receptor antagonist will block CRF-induced suppression of RS following SD. We will also determine if HCRT antagonist prevents the suppression c-fos expression in MnPN and VLPO neurons that occurs in response to CRF. Completion of Aims 1 and 2 should reveal the relative importance of preoptic sleep- regulatory neurons versus HCRT neurons as functional targets of CRF effects on sleep.
Aim 3 will determine if increased CRF signaling exacerbates sleep disturbance in rats exposed to an acute social stressor. We will examine the effects of ICV administration of CRF on the magnitude and duration of the insomnia that male rats exhibit during acute exposure to the soiled bedding of a male conspecific. We will determine if CRF-induced enhancement of insomnia is accompanied by suppression of c-fos expression in the MnPN and VLPO. We will also compare the ability of ICV infusion of CRF antagonist and HCRT antagonist to prevent the CRF enhancement of stress-induced insomnia. Depression and PTSD are prevalent disorders in U.S. combat Veterans. Managing sleep disturbance in these disorders is important because insomnia can exacerbate depressive symptoms and increase anxiety. There is consensus that CRF hyperactivity is a critical feature of the pathophysiology of depression and PTSD. The sleep altering effects of CRF are well-established, but underlying mechanisms are unresolved. Determining if CRF-induced insomnia reflects disruption of sleep-regulatory circuits, or if this insomnia is purely a phenomenon of hyperarousal will inform strategies for the pharmacological management of sleep disturbance in mood and anxiety disorders.

Public Health Relevance

Experiments proposed here are designed to identify critical sites in sleep- and arousal- regulatory brain circuits that are targeted by corticotrophin releasing factor (CRF). This is an understudied problem in sleep neurobiology, where sleep-altering effects of CRF are well established, but mechanisms of action are unresolved. The critical question we ask is: Does CRF impact sleep, at least in part, through effects on GABAergic sleep-promoting neuronal systems in the preoptic hypothalamus, or is CRF-induced insomnia exclusively due excitation of neuronal systems that actively promote arousal? This is an important question, and its answer can inform strategies for developing treatments for sleep disturbance associated with CRF hyperactivity. Disturbed sleep is a common symptom in mood and anxiety disorders. Insomnia and other sleep disturbances have long been viewed as important secondary symptoms in major depression and posttraumatic stress disorder (PTSD) and are now recognized as potential risk factors for the development these disorders. There is evidence of chronic hyperactivity in brain CRF systems in both depression and PTSD. Several studies have linked elevated concentrations of CRF in cerebrospinal fluid (CSF) with depression. At least three studies have documented elevated levels of CRF in the CSF of subjects with PTSD. PTSD and depression are highly prevalent disorders in U.S. combat Veterans. Reports of lifetime prevalence of war zone-related PTSD among men and women who served during the Vietnam War range from 20-31%. This contrasts with the estimated lifetime prevalence of PTSD in the general U.S. population of 7.8%. Co-morbid depression is a common feature in PTSD. In a group of Iraq and Afghanistan Veterans accessing VA Healthcare for the first time between April 2002 and March 2008, 21.8% received a diagnosis of PTSD, and 17.4% received a diagnosis of depression. Rationale for finding improved treatments for sleep disturbance in Veterans with mood and anxiety disorders includes improvement in general quality of life, avoiding exacerbation of depressive symptoms and anxiety secondary to insomnia, and recently described correlations between insomnia severity and decreased hippocampal volume in Veterans with PTSD.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology C (NURC)
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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