Neuroinflammation and social behavior across the lifespan

整个生命周期的神经炎症和社会行为

• 批准号: 8847617
• 负责人: Terrence Deak
• 金额: $ 44.57万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847617
• 关键词: Adolescent; Adult; Aging; Aging-Related Process; Amygdaloid structure; Androgens; Andropause; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Behavioral; Biological Models; Buffers; Data; Disinhibition; Elderly; Familiarity; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Health Benefit; Health Status; Hormone replacement therapy; Hypothalamic structure; Immune; Impairment; Inflammation; Inflammatory; Interleukin-1; Investigation; Laboratory Rat; Longevity; Measures; Medial; Mediating; Modeling; Motivation; Nature; Nervous System Trauma; Neural Pathways; Neurons; Neuropeptides; Outcome; Oxytocin; Oxytocin Receptor; Pathway interactions; Pattern; Play; Population; Portraits; Procedures; Process; Quality of life; Rattus; Recovery; Regulation; Relative (related person); Rodent; Rodent Model; Role; Series; Social Behavior; Social Interaction; Staging; Stimulus; Stroke; System; Testing; Therapeutic Effect; Time; Translating; Work; adverse outcome; age related; aged; base; behavior test; cytokine; innovation; male; neural circuit; neurobehavioral; neuroinflammation; neuromechanism; paraventricular nucleus; receptor expression; relating to nervous system; resilience; response; senescence; social; social deprivation; stem; stress reactivity; therapeutic target; young adult

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.

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，但人们对这些有害变化的神经基础知之甚少。该提案的总体目标是使用大鼠作为模型系统，评估自然衰老过程中社会行为瓦解的神经机制。我们假设，衰老过程中社会行为的逐渐下降是对社会刺激的动机减少和对社会刺激的识别能力受损的症状。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（称为男性更年期）和中枢神经系统逐渐向促炎症状态的高度转变——在衰老过程中社会行为的瓦解中发挥着关键作用。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（例如白细胞介素-1）的去抑制，从而缩短了下丘脑室旁核（PVN）中催产素（OT）表达的释放和丘脑中释放的催产素（OT）的释放。内侧杏仁核 (MeA)，是社会动机/识别过程的关键要素。因此，特定目标 1 将使用一系列社会行为任务来表征社会行为缺陷的与年龄相关的性质，同时确定 MeA 中的 OT 神经元对老年大鼠社会行为退化的作用。具体目标 2 将测试中枢神经系统促炎症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物的治疗效果。具体目标 3 将确定性腺激素在中枢神经系统向促炎症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。这项工作的成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，描述社会行为在整个生命周期中如何侵蚀，并提供几个逆转这一过程的具体治疗目标。因此，目前的研究有望将啮齿动物模型的研究结果转化为直接改善老龄化人口的生活质量。