Thursday, May 2, 2024
5/2/2024
The broad objective of this study is to identify the neural substrate(s) underlying the homeostatic sleep response (HSR), i.e. enhanced sleepiness following prolonged sleep deprivation (SD). SD is experienced by many due to lifestyle or vocational demands and is accompanied by impaired cognition, increased impulsivity, and an increased likelihood of accidents. Furthermore, disrupted sleep is a common feature of many neuropsychiatric disorders. Thus, understanding the mechanisms underlying the HSR is critical to develop measures to combat the deleterious consequences of SD. Specifically, here we will address the central question: “Are all neural wake-promoting systems equally important in triggering the HSR?” Our overarching hypothesis is that basal forebrain (BF) cholinergic neurons (ChAT+) are modulated by glutamate and play a privileged role in the HSR by causing the release of extracellular adenosine (ADex), which increases sleep by inhibiting wake-promoting BF neurons, and thereby adjusts the state of the system towards its' set point. Towards this goal, Aim 1, will test if BF cholinergic neurons, but not the brainstem pedunculopontine tegmental (PPT) cholinergic neurons, are required for HSR. Aim 2 will test the hypothesis that within BF, only those non- cholinergic wake-promoting neurons projecting to, and exciting, BF ChAT+ neurons will induce HSR. Aim 3 will test if stimulation of wake-promoting BF-vGluT2+ and PPT-vGluT2+ neurons will only induce HSR if BF ChAT+ neurons are intact, i.e. the integrity of BF ChAT+ neurons is necessary to trigger the HSR. Finally, Aim 4 will test the dual role of BF ChAT+ neurons in promoting arousal and sleep homeostasis. We will use our novel mouse `optodialysis' probes (Zant et al., 2016) that combine optical manipulation of selective neuronal populations with in vivo microdialysis for detecting local neurochemical changes and/or application of pharmacological agents. The successful completions of these investigations will further our understanding of the neural substrates necessary for inducing the HSR, and thus will help in developing targeted pharmacological interventions against the deleterious effects of sleep loss.
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