Specification of sleep-wake control neurons in the basal forebrain

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Chronic stress is a risk factor for the onset of psychiatric and somatic disease. Deployment and combat exposure are routinely cited as stressors for Service members, and stress-related psychiatric conditions are a leading cause of permanent disability and illness within VA Healthcare. On a neurological level, stress disrupts the physiological balance between excitatory and inhibitory neurotransmission. This dysregulation of synaptic network activity is routinely cited as a cause for numerous intractable psychiatric conditions, including depression, schizophrenia, and insomnia. Veterans Affairs has faced a steep rise in the incidence and diagnosis of sleep disorders like insomnia in recent years, representing an increasing healthcare cost for the VA and, critically, an enhanced risk factor for suicide among Veterans. An overarching goal of the parent grant is to advance understanding of the neurobiology of sleep, facilitating development of next-generation therapeutics. It will identify novel populations of GABAergic neurons in the basal forebrain (BF), an integratory brain region that regulates sleep and attention. Of these cell types, our preliminary data indicate chemogenetic activation of BF neuronal PAS domain 1-expressing (NPAS1+) cells strongly promotes wakefulness. Recent preclinical literature has identified a role of BF NPAS1+ cell activation in stress susceptibility and affect (Morais-Silva et al., 2021), potentially mediated by dense projections of stress-activated corticotropin-releasing factor (CRF) neurons from the central amygdala (Hunt et al., 2018). These findings support a hypothesis that stress upregulates the activity of BF NPAS1+ cells, contributing to the onset of insomnia and related psychiatric conditions. This hypothesis will be investigated in 2 aims, exploring the effects of stress on in vitro electrical properties of NPAS1+ neurons (aim 1) and resultant in vivo effects on sleep behavior (aim 2). This research supplement provides an ideal training opportunity for Dr. Timothy Troppoli, the mentee. Dr. Troppoli received a Ph.D. from the University of Maryland’s Molecular Medicine program in September 2021 and has recently joined the Department of Psychiatry at Harvard Medical School (HMS) and VA BHS as a Health Science Specialist. The mentee’s primary research interest concerns stress-induced disruption of synaptic neurotransmission and the onset of depressive disorders and psychiatric disease. Dr. Troppoli has a history of productive, high-impact research in this field, publishing 4 papers (two as first author) investigating the mechanisms and target engagement of novel antidepressant-like compounds. The mentee’s research background and expertise compliment the goals of this research supplement, while the proposed experiments will significantly enhance Dr. Troppoli’s independence and productivity as a neuroscientist at VA BHS using state-of-the-art whole-cell patch-clamp techniques, advanced microscopy, chemogenetics, and sleep/EEG analysis. Training in these approaches will be provided by mentor Dr. Ritchie Brown and co-mentor Dr. James McKenna, members of VA BHS/HMS and experts in the field of sleep research. Dr. Brown has successfully mentored 8 junior researchers, including VA CDA2 recipients. He will train the mentee in electrophysiology and chemogenetics and guide his career development. Dr. McKenna’s background in BF neuroanatomy and preclinical models of stress-induced insomnia will bolster the analytical rigor of this work, aid in interpretation of results and assist in experimental design for future BF work. Successful completion of the proposed aims will characterize stress-induced functional deficits of NPAS1+ cells of the BF, providing the first evidence of their role in stress-induced insomnia and psychiatric disease. The proposed experiments expand the scope of the parent grant, will guide the development of novel therapeutics for Veterans, and provide preliminary data for a future VA Career Development Award with a distinct focus on convergent mechanisms of stress, sleep, and depression.