Persons with Alzheimer's Disease (AD) experience spatial disorientation that emerges early in the disease process. In both humans and rodent models of AD, dysfunction within the retrosplenial cortex (RSC), a crucial locus for spatial navigation and memory, is observed prior to the onset of cognitive decline. Understanding the mechanisms underlying RSC dysfunction is important to develop strategies aimed at improving spatial navigation and memory in AD. We observe aberrant RSC network activity that includes reduced RSC rhythmic synchrony during spatial navigation in a mouse model of AD, yet the cellular and molecular basis for these defects are unknown. Here, using a newly developed mouse line, we identify a specific population of RSC neurons that express the orexin 1 receptor (RSCOX1R) and are activated by the neuropeptide orexin. In WT mice, direct stimulation of these RSCOX1R neurons enhances RSC synchrony, suggesting these neurons are an important population in which to examine cellular mechanisms of AD-related RSC dysfunction, and to target for therapeutic intervention. Orexin signaling affects numerous physiologic processes, including spatial memory, and abnormalities in orexin signaling are implicated in AD pathology. Studies of specific orexin-regulated memory circuits in AD is lacking, however. In this proposal, we examine whether RSCOX1R neurons are directly altered in the 5xFAD model of AD (Aim 1). We also test the hypothesis that the activation of RSCOX1R neurons or enhancement of orexin-signaling/regulation of RSC neurons can restore the AD-associated deficits in RSC rhythmic activity (Aim 2). The completion of this work will pave the way for larger-scale follow up studies across multiple models of AD, with the potential to identify novel RSC and orexin-based therapies aimed at ameliorating a range of spatial memory and cognitive deficits in persons with AD.