Neuroinflammation and social behavior across the lifespan

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DESCRIPTION (provided by applicant): Aging is a multifactorial process, in which a variety of neurobehavioral functions including social motivation and social recognition abilities decline at different rates, yet very little is known about the neural basis of these deleterious changes. The overarching goal of this proposal is to evaluate the neural mechanism(s) underlying the disintegration of social behavior during the natural course of aging, using rats as a model system. We hypothesize that the gradual decline in social behavior during senescence is symptomatic of both reduced motivational drive toward, and impaired recognition of, social stimuli. We argue that two established consequences of aging - a progressive decline in circulating androgen levels, termed andropause, and a gradual transition of the CNS toward a heightened state of pro-inflammation - play a key role in the disintegration of social behavior during senescence. The proposed mechanism is that gradual loss of circulating androgens leads to disinhibition of pro-inflammatory cytokines such as interleukin-1, which short-circuits th release of oxytocin (OT) expression in the paraventricular nucleus (PVN) of the hypothalamus and release in the medial amygdala (MeA), a key requisite for social motivation/recognition processes. Thus, Specific Aim 1 will characterize the age-related nature of social behavior deficits using a series of social behavior tasks, while at the same time determining the role of OT neurons in the MeA on the degradation of social behavior in aged rats. Specific Aim 2 will test the impact of the CNS pro-inflammatory state on the blunted response of social behavior circuitry and the therapeutic effect of administration of anti-inflammatory agents in aged rats. Specific Aim 3 will determine the role of gonadal hormones on the transition of the CNS toward a pro-inflammatory state and its impact on social behavior and their respective mechanisms of action. The outcome of the proposed work will integrate several core features of the aging process (declining androgens, heightened inflammation, altered neuropeptide regulation) into a meaningful mechanistic portrait of how social behavior erodes across the lifespan, and offer several specific therapeutic targets for reversing this process. As a result, the present studies hold great promise for translating findings from rodent models into direct improvements in the quality of life for aging populations.