PROJECT SUMMARY This application is submitted in response to NOT-AG-20-034 to request a supplement to 2R01HL059658-16A1 “Neural Gene Expression in Sleep Deprivation and Regulation”. Sleep disruption is a hallmark of Alzheimer's Disease (AD), often preceding the onset of the severe memory and cognitive deficits associated with the clinical phase of AD by decades. The presence of sleep disruption during both the preclinical and clinical phases of AD highlights the importance of sleep in AD pathogenesis and development, and suggests that sleep disruption may play a causal role in AD pathology. We have identified a rare population of cells in the cerebral cortex that, unlike other cortical neurons, is activated during sleep rather than wake. The hypothesis that underlies the parent R01 is that these cortical GABAergic Type 1 nNOS neurons are critical orchestrators of cortical EEG slow wave activity (SWA), an indicator of sleep homeostasis. These cells may correspond to a subtype of GABAergic cortical somatostatin neurons that have recently been shown to be selectively vulnerable in AD pathogenesis. In this supplement request, we will test the hypothesis that loss or dysfunction of cortical Type 1 nNOS neurons contributes to disturbances in sleep and sleep homeostasis in two mouse models of AD: the FAD-mutant hAPP J20 strain and the PS19 model of tauopathy. We will first characterize the baseline sleep/wake patterns and function of the sleep homeostat in these two models by determining the cortical EEG response to short-term sleep deprivation (SD). Next, we will evaluate the integrity of cortical Type 1 nNOS neuron function in these AD models in vivo by assessing cortical Type 1 nNOS neuronal density and c-FOS expression in these cells in response to SD and during recovery sleep after SD. These in vivo studies will be complemented by cellular electrophysiological studies in vitro to determine the membrane characteristics of cortical Type 1 nNOS neurons from transgenic FAD-mutant hAPP J20 and P301S tauopathy mouse models, as well as the responses of these cells to application of neurotransmitters known to be involved in sleep/wake control. Together, these Aims will enable us to determine whether cortical Type 1 nNOS neurons are intact or dysfunctional in these two mouse AD models with different underlying pathology. These studies will also provide the requisite background information for a subsequent R01 proposal to utilize modern systems neuroscience approaches to selectively manipulate cortical Type 1 nNOS neurons in transgenic mouse AD models and determine the consequences on sleep and AD pathology.