Neuroinflammation and social behavior across the lifespan

项目摘要/摘要： 衰老是一个多因素的过程，在这个过程中，包括社交在内的各种神经行为功能 动机和社会认知能力以不同的速度下降，但人们对 这些有害变化的神经基础。这项提案的首要目标是评估 自然衰老过程中社会行为瓦解的神经机制(S)， 以大鼠为模型系统。我们假设在此期间社会行为的逐渐减少 衰老既是动机驱动力减弱的症状，也是认知能力下降的症状。 社会刺激。我们认为，老龄化的两个既定后果--老年人数量的逐渐下降 循环中的雄激素水平，称为雄停顿，以及中枢神经系统向 高度的促炎状态-在社会行为的瓦解中起着关键作用 衰老。所提出的机制是循环中雄激素的逐渐丧失导致 去抑制促炎细胞因子，如白介素1，它短路释放 催产素在下丘脑室旁核的表达及在下丘脑室旁核的释放 杏仁内侧核(MEA)，这是社会动机/认知过程的关键。因此，特定的目标 1将使用一系列社会行为来表征与年龄相关的社会行为缺陷的性质 任务，同时确定催产素神经元在MEA对社会退化的作用 老龄大鼠的行为学研究。特异性目标2将测试中枢神经系统促炎状态对 社会行为回路的钝化反应与用药的疗效 老年大鼠的抗炎药。具体目标3将确定性腺激素在 中枢神经系统向促炎状态的转变及其对社会行为的影响 各自的作用机制。拟议工作成果将综合几个核心内容 衰老过程的特征(雄激素减少、炎症加剧、神经肽改变 监管)变成了一幅有意义的机械肖像，描绘了社会行为在整个生命周期中是如何被侵蚀的，以及 为逆转这一过程提供几个具体的治疗靶点。因此，目前的研究 将啮齿动物模型的发现转化为质量的直接改进有着巨大的希望 老龄化人口的生活。

Project Summary/Abstract: 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 the 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.