Promoting stress-resilience prevents AD-associated neuropsychiatric symptoms

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

PROJECT SUMMARY Alzheimer's disease (AD) is commonly associated with social behavioral abnormalities and neuropsychiatric symptoms (NPS). In fact, NPS are increasingly recognized as core features of AD. However, research in AD has been primarily focused on the diagnostic and therapeutic treatment of memory deficits. There is an urgent need to better understand the neurobiology, behavior, and underlying mechanisms of NPS in AD. In response to PAR-23-207, we propose to investigate the influences of individual vulnerability to stress on the expression of NPS syndromes in mouse models of AD and to test the hypothesis that promoting stress resilience could prevent or delay the future emergence of AD-associated NPS. Stress is a major risk factor for neuropsychiatric disorders. In mice, we found that stress-susceptible (SUS) mice exhibit a spectrum of social, motivational, and reward deficits that are similar to the NPS, such as apathy, anxiety, and social withdrawal in human AD. We established that stress-susceptibility is associated with aberrant microglia activation in the prefrontal cortex (PFC) and, in turn, disrupts PFC neurophysiological properties. Moreover, gene expression analysis in the PFC of SUS mice showed several differentially expressed genes resembling those of disease-associated microglia (DAM) found in AD. Critically, stress- resilient mice maintain healthy-like PFC neurophysiological properties and healthy-like microglia activity. Our data shows that by manipulating microglia activity during stress exposure, we prevented stress-induced anhedonia and social withdrawal. Based on these observations, we hypothesize that vulnerability to prior stress exposure, stress-SUS, may prime PFC microglia in the PFC and promote the initiation and progression of AD-associated NPS behavioral and neuronal deficits, and oppositely, the active resilient mechanisms of stress-RES individuals, could prevent or delay AD-associated NPS and neuronal deficits. Using the 5xFAD and the 3xTg mouse models and leveraging two different stress paradigms: chronic social defeat stress and chronic variable stress, we propose to promote stress-resilience and to assess its short-term and long-term impacts on 1) NPS-like behavior development; 2) cortical neuronal activity and molecular underpinnings, and 3) circuit-connectivity associated with NPS-like phenotypes. To account for sex as a biological variable, we will characterize molecular, electrophysiological, and behavioral responses to stress, and AD-type NPS predispositions in female and male mice. We will employ cutting-edge methodology from cognitive and affective neuroscience and integrate multiple levels of analysis to address neurobiological, behavioral, and molecular mechanisms. These studies will uncover the active resilient mechanism(s) in the brain and offer novel targets for the prevention and treatment of NPS in the context of AD.