Project Summary / Abstract Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease that can severely curtail life quality and expectancy. Depression and sleep disorders manifest decades before disease onset and may serve as an important early biomarker. Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) exhibit neurofibrillary changes in the early stages of AD, which may contribute to some of these early non-cognitive symptoms. The goal of this application is to determine whether tau accumulation in 5-HT DRN neurons induces depressive-like behaviors and disordered sleep, leading to chronic sleep disruption. These sleep deficits, in turn, may promote hyperexcitability of 5-HT neurons and lead to neurodegeneration. The increased activity in 5-HT neurons due to sleep deprivation also facilitates the spread of tau pathology to the entorhinal cortex (EC), another region that is impacted early in the course of AD. Loss of 5-HT inputs from the DRN to the EC will disinhibit neurons that project to the hippocampus, precipitating tau spread and the onset of cognitive and memory problems. In Aim 1, we will use in vivo fiber photometry to measure neural activity in 5-HT neurons during tests of depressive-like behavior in mouse models of tauopathy to see if the normal function of these neurons is negatively impacted. We will also monitor 5-HT activity during sleep to see if that is altered by tau pathology. In Aim 2, we will examine the effect of sleep deprivation on 5-HT neuronal excitability and the progression of tau pathology in the brain using electrophysiology and 3D imaging. The role of increased neural activity in 5-HT neurons on the spread of tau pathology will also be examined using chemogenetic manipulations of neural activity. In Aim 3, we will determine whether tau-induced loss of 5-HT inputs to the EC alters 5-HT signaling in principal neurons that project to the hippocampus. We will also establish a role for 5-HT/5-HT2A receptor signaling in the spread of tau pathology to the hippocampus and the onset of cognitive deficits. In total, the proposed research will provide essential information concerning the impact of tau pathology on early behavioral symptoms of AD and the later development of cognitive and memory deficits.