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: 8630316
• 负责人: Terrence Deak
• 金额: $ 48.9万
• 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/8630316
• 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 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; Stress; 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; public health relevance; receptor expression; relating to nervous system; resilience; response; senescence; social; social deprivation; stem; therapeutic target; young adult

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.

项目概要/摘要： 衰老是一个多因素的过程，在这个过程中，包括社交功能在内的各种神经行为功能都受到影响， 动机和社会认知能力以不同的速度下降，但很少有人知道 这些有害变化的神经基础。本提案的总体目标是评估 在自然衰老过程中社会行为解体的神经机制， 使用老鼠作为模型系统。我们假设，在此期间， 衰老是对事物的动力驱动力降低和对事物的认识受损的症状， 社会刺激我们认为，两个既定的后果老化-一个渐进的下降， 循环雄激素水平，称为andropause，和中枢神经系统逐渐过渡到 促炎症状态的升高-在社会行为的瓦解中发挥关键作用， 衰老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，其缩短了促炎细胞因子的释放。 催产素（OT）在下丘脑室旁核（PVN）的表达和释放， 内侧杏仁核（MeA）是社会动机/识别过程的关键必要条件。因此，具体目标 1将使用一系列社会行为来表征社会行为缺陷的年龄相关性质 任务，同时确定OT神经元在MeA中对社会性退化的作用。 老年大鼠的行为具体目标2将测试CNS促炎状态对 社会行为回路的迟钝反应和施用 抗炎药在老年大鼠。具体目标3将确定性腺激素对生殖系统的作用。 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。拟议工作的成果将纳入若干核心内容， 衰老过程的特征（雄激素下降，炎症加剧，神经肽改变 监管）转化为一个有意义的社会行为如何在整个生命周期中侵蚀的机械画像， 为逆转这一过程提供了几个特定的治疗靶点。因此，目前的研究 将啮齿动物模型的发现转化为直接改善 为老龄化人口提供生活保障。