BLR&D Research Career Scientist Award

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PROJECT SUMMARY Insomnia and disturbed sleep are common symptoms in mood and anxiety disorders. Nocturnal sleep disruption is a frequent complaint following traumatic brain injury (TBI). Previous work in my laboratory has identified systems of GABAergic neurons in the preoptic hypothalamus that have critical sleep regulatory functions. GABAergic neurons in the median preoptic nucleus (MnPO) and the ventrolateral preoptic area (VLPO) are activated during sleep. Adenosine is a critical endogenous sleep regulatory factor, important in the expression of homeostatic responses to sleep loss. We have shown that MnPO/VLPO neurons are activated by A2A adenosine receptor agonists. We have recently demonstrated that discharge of MnPO/VLPO neurons is dynamically responsive to changing homeostatic sleep drive during sleep deprivation and recovery sleep. We have further shown that during development, functional maturation of MnPO/VLPO GABAergic sleep regulatory systems underlies the development of sleep homeostasis. Our overarching hypothesis is that disruption of homeostatic responses to sleep loss due to dysfunction of preoptic hypothalamic sleep regulatory circuits contributes to sleep disturbances in mood and anxiety disorders and TBI. We will test this hypothesis using animal models of these disorders. We will also expand our understanding of the fundamental interactions between hypothalamic and brainstem arousal state-regulatory circuits in normal and disordered sleep. Brain levels of corticotrophin-releasing factor (CRF), a critical neuropeptide regulator of the HPA axis, are chronically elevated in anxiety disorders and posttraumatic stress disorder (PTSD). CRF has well characterized wake-promoting/sleep-disruptive effects. We hypothesize that activation of CRF neurons occurring in response to acute and chronic stress 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 rostral medulla. We will use transgenic CRF-cre mice and adenoviral vectors to optogenetically and chemogenetically manipulate CRF-signaling in the brain, and determine the effects on sleep homeostasis, functional activity of preoptic and medullary sleep regulatory neuronal populations and the sleep disruptive effects of acute and chronic stressors. Sleep-wake disturbances following TBI include daytime sleepiness, nocturnal sleep fragmentation, insomnia and alterations in the sleep EEG. Previous work has shown that in mouse models of TBI, excessive sleepiness is associated with reduced activation of orexin neurons. In collaboration with colleagues at the Portland VA who have expertise in TBI, we have generated preliminary findings that sleep-related activation of MnPO neurons is dramatically reduced after cortical fluid percussion injury in mice. We will pursue these preliminary findings and examine the functional status of GABAergic sleep- regulatory neurons in the preoptic area and of orexin neurons in the lateral hypothalamus following TBI, and correlate the functional activity in these neuronal systems with the sleep-wake phenotype at different times after brain trauma. In work supported by NIH/NINDS, we will examine interactions between GABAergic circuits in the preoptic hypothalamus and brainstem that regulate the switching among waking, nonREM and REM sleep. The findings derived from these studies will be a foundation for understanding the involvement of these circuits in sleep disruption accompanying psychiatric and neurological disorders.