Abstract: Cognitive and memory deficits are debilitating features of Alzheimer's disease (AD) and related dementias (ADRD), with devastating impacts on the quality of life for the unfortunately affected. Of the cognitive domains that show early decline in AD/ADRDs, spatial memory is particularly sensitive to impairment, which leads to long-term disability as well as loss of independence causing not only enormous individual suffering but also significant socioeconomic cost for the afflicted and their families. Recent research has pointed to the locus coeruleus as a region in which early tau pathology first emerges. This can then spread transynaptically to efferent regions and notably to the hippocampus, which receives prominent input from the LC. Thus, LC tau pathology could precede widespread neuropathology in AD and ADRD. Given the prominent role of the LC in maintaining arousal and normal sleep-wake patterns, alongside its strong projections to the hippocampus, it is important to investigate the impact of tau pathology in the LC region on network function in other brain regions important for memory and cognition. Our parent grant is aimed at uncovering the sequential structure in the spiking activity of large populations of hippocampal neurons during sharp-wave ripples and examining the dynamics of these sequences across the course of sleep and waking. There is strong evidence directly linking these activity patterns to memory storage and retrieval alongside important cognitive processes, such as planning and episodic simulation. Yet, while the impact of AD and ADRD on memory loss and dysfunction are well-know and have been linked with increased disturbances during sleep, their effects on network activity patterns across sleep and waking that mediate normal function remain largely unknown. In this supplement, we propose to measure and evaluate the dynamics of hippocampal neuronal activities during behavior and subsequent sleep in rats in a novel rodent model of ADRD-related pathology, where wild-type human tau is over-expressed specifically in the locus coeruleus. The proposed experiments are an extension of those to be performed under the parent grant and involve deployment of the same set of analytical tools to test our hypothesis that tau-aggregation in the LC will reduce the flexible restructuring of hippocampal neuronal spike patterns across sleep and waking. This proposal will also initiate a new collaboration between the Kemere and Diba labs with Dr. Sara Burke, an expert in animal models of AD and ADRD and aging, to characterize an important animal model for these disorders. We expect that these studies will significantly further understanding of how tauopathy-related dementias impacts hippocampal network functions that serve in memory and cognition, and help to identify potential therapeutic targets for future treatment.