Project Summary How does the neuropathology in mouse models of Alzheimer’s disease (AD) influence the function of neural circuitry? Preliminary data demonstrates distinctions in neuropathology severity in different brain regions of AD mouse models. Three of these brain regions, the hypothalamus, hippocampus, and cerebellum, have well characterized neural circuits that function in food intake. We have observed that the hippocampus and hypothalamus contain a high density of Ab plaques and microglia markers in AD mouse models. While these markers worsen with age, we observe virtually no Ab plaques or microglia in the cerebellum. Thus, because our prior work has identified the structure, function and neural activity dynamics of feeding circuits in these three regions, we have a rich experimental framework to assess the impact of these markers of neurodegeneration in three distinct brain regions. We propose to examine the neural activity dynamics and function of circuits in these regions during feeding behavior in different ages of AD mice in order to better understand a) how AD pathology influences neural circuits and b) to identify the aspects of neural circuit function that are protected in the cerebellum. This proposal will test these hypotheses through two aims. Aim 1 examines the neural activity dynamics of hypothalamic, hippocampal and cerebellar feeding circuits in AD mice. Using deep-brain imaging of genetically encoded calcium indicators, we aim to assess whether the absence of neuropathology in the cerebellum of our AD mouse models preserves the neural activity pattern of cerebellar neurons and not hypothalamic/hippocampal neurons during AD progression. We will determine the activity dynamics of hypothalamic, hippocampal and cerebellar feeding circuits in response to feeding or gastric infusion of nutrients in humanized APP-knockin (APP-KI) mice at 3, 6 and 9 months. Aim 2 assesses the ability of hippocampal, hypothalamic and cerebellar circuit function in feeding control of AD mice. We will use optogenetic and chemogenetic approaches to activate and inhibit feeding circuits in APP-KI mice. The ability of these circuits to influence food intake and metabolic parameters in AD mice will be taken at 3, 6, and 9 months and will be compared with non-AD controls. Through the examination of the activity and function of feeding circuits in the context of AD pathogenesis, these aims build off our originally funded R01 to explore how well-defined behavioral outputs and neural function are changed by the neuropathology that underlies AD. These experiments may lead to further support for our hypothesis that the cerebellum represents a neuroprotected region in AD and aging.