Neuroinflammation and social behavior across the lifespan

描述（由申请人提供）：衰老是一个多因素的过程，其中包括社会动机和社会识别能力在内的各种神经行为功能以不同的速度下降，但对这些有害变化的神经基础知之甚少。本研究的主要目的是利用大鼠作为模型系统，研究衰老过程中社会行为瓦解的神经机制。我们假设，在衰老过程中，社会行为的逐渐下降是对社会刺激的动机驱动减少和识别受损的症状。我们认为，衰老的两个既定后果——循环雄激素水平的逐渐下降，称为雄性停滞，以及中枢神经系统向促炎症状态的逐渐过渡——在衰老期间社会行为的瓦解中发挥了关键作用。所提出的机制是，循环雄激素的逐渐丧失导致促炎细胞因子如白细胞介素-1的去抑制，从而缩短下丘脑室旁核（PVN）中催产素（OT）的释放和内侧杏仁核（MeA）的释放，这是社会动机/识别过程的关键条件。因此，Specific Aim 1将通过一系列社会行为任务来表征社会行为缺陷的年龄相关性质，同时确定MeA中OT神经元在老年大鼠社会行为退化中的作用。特异性目的2将测试CNS促炎状态对老年大鼠社会行为回路迟钝反应的影响以及抗炎药的治疗效果。具体目标3将确定性腺激素在中枢神经系统向促炎状态转变中的作用及其对社会行为的影响及其各自的作用机制。这项工作的结果将把衰老过程的几个核心特征（雄激素下降、炎症加剧、神经肽调节改变）整合到一个有意义的机制描述中，描述社会行为如何在整个生命周期中受到侵蚀，并提供一些特定的治疗靶点来逆转这一过程。因此，目前的研究对将啮齿动物模型的发现转化为直接改善老龄人口的生活质量具有很大的希望。

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.