Project Summary In addition to its well-known cognitive deficits, Alzheimer’s disease (AD) is often associated with debilitating changes in affective behavior, including anxiety, depression and altered social engagement. Mechanistic connections between the hallmark cytopathologies of AD and neuropsychiatric traits remains poorly defined. Both AD and mood disorders have been associated with neuroinflammation, with CNS elevations of the major pro-inflammatory mediator IL-1β seen in both disorders. We and others have found that serotonin (5-HT) synthesizing neurons are relatively unique as neuronal sites of expression of the receptor for IL-1β, IL-1R1. Serotonergic projections to the hippocampus, a site of significant, inflammatory cytokine-inducing pathology in AD, are believed to contribute to both cognition and mood. We have shown that serotonergic IL-1R1 activation leads to rapid elevations in activity of the antidepressant-sensitive 5-HT transporter (SERT), enhancing clearance of 5-HT and diminishing extracellular 5-HT availability. Others have shown that while AD pathology extends to forebrain-projecting serotonergic raphe nuclei it also leads to and ectopic expression of SERT by astrocytes. These combined effects can diminish the capacity for serotonergic signaling, reduced anti- inflammatory 5-HT stimulation of microglia, further increasing IL-1 levels and promoting negative affective states. In this regard, recent studies have indicated that SERT antagonism by 5-HT-selective reuptake inhibitors (SSRIs), drugs used to treat affective disorders in AD patients, has been reported to reduce A plaque burden as well as cognitive deficits in AD. We propose that IL-1β elevations that arise as a consequence of AD pathology lead to alterations in 5-HT signaling in the hippocampus via serotonergic IL-1R1 activation, changes that can accelerate cytopathologies, disrupt the function and plasticity of 5-HT modulated hippocampal circuitry, and support both affective and cognitive disturbances observed in AD. Here we pursue our hypothesis through a unique, four-way collaborative project involving an expert in SERT and serotonergic dysfunction (Blakely), an expert in the evaluation of hippocampal physiology and the study of AD genetic mouse models (Ashery), an expert in the signaling and functional contributions of IL-1R1s (Quan), and an expert in assessment of the behavior of genetic mouse models (Hahn). We utilize a conditional strategy to eliminate IL-1 signaling specifically in serotonergic raphe neurons in an AD mouse model (5XFAD), attentive to issues of sex- dependence. Through our efforts, we will determine whether the biochemical, cellular, physiological and affective/cognitive disturbances that arise from 5XFAD mutations require IL-1R1 signaling to 5-HT neurons. Data obtained in this effort can then be extended through more sustained funding to further elucidate the timing, mechanisms and broader circuit specificities driving, and responding to,...