Immune mechanisms underlying sex-specific adolescent periods of vulnerability for social dysfunction in aging

性别特异性青少年时期易受衰老社会功能障碍影响的免疫机制

• 批准号: 10266793
• 负责人: Ashley M Kopec
• 金额: $ 16.3万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266793
• 关键词: Adolescence; Adolescent; Adolescent Development; Aging; Behavioral; Brain region; Control Groups; Data; Development; Elderly; Female; Functional disorder; Health; Immune; Immune signaling; Impaired cognition; Impairment; Individual; Inflammatory; Life; Loneliness; Longevity; Male Adolescents; Measures; Mediating; Memory impairment; Mental Health; Microglia; Molecular; Mus; Neuroimmune; Nucleus Accumbens; Outcome; Pharmacology; Play; Rattus; Reporting; Rewards; Role; Shapes; Signal Transduction; Social Behavior; Social Change; Social Network; Social isolation; Social support; Stimulus; Synaptic Receptors; Testing; Walkers; aged; brain cell; brain tissue; cognitive function; early adolescence; healthy aging; insight; male; middle age; mortality; neuromechanism; novel; postnatal; preservation; ranpirnase; reward circuitry; sex; social; social cognition; social deficits; social engagement; social stress; social vulnerability; spatial memory; stressor; young adult

PROJECT SUMMARY Social networks and support are integral to health and wellness across the lifespan, and social engagement may be particularly important to preserve overall health and cognitive function during aging. However, social behavior and social cognition decline during aging. A better understanding of the neural mechanisms underlying healthy and abnormal social behaviors is fundamental to increasing healthy aging outcomes. Social behaviors are supported by the ‘reward’ circuitry, a network of brain regions that develops during adolescence. We have shown that microglia, the resident immune cells of the brain, play a crucial role in reward circuitry and social behavior development in adolescent rats. Microglia phagocytose and eliminate, or ‘prune’, synaptic receptors in the nucleus accumbens (NAc) reward region between pre-early adolescence in females, and between early-mid adolescence in males. Interfering with microglia-mediated NAc pruning during each sex- specific pruning stage altered social behavior development in both sexes. In this proposal, we will determine how healthy and abnormal immune signaling in the NAc during adolescence sex-specifically shapes social behavior across the lifespan. Specifically, we will determine whether (1) interfering with NAc pruning in adolescent male and female rats increases social behaviors across the lifespan, (2) social stress during adolescence, a pro-inflammatory stimulus that impairs reward circuitry and social behavior development, exacerbates microglial pruning in the NAc, and (3) social stress during adolescence worsens aging-related social behavior dysfunction. Our core hypothesis is that healthy microglia- mediated pruning in the NAc during adolescence supports social behavior throughout the lifespan, and that the sex-specific developmental stages during which NAc pruning occurs will thus constitute sex-specific periods of vulnerability for life long social abnormalities. These studies treat developmental stage and sex as independent variables to advance our understanding of how healthy and abnormal adolescent development in the NAc impacts social behavior and neuro-immune signaling across the lifespan. The successful completion of this proposal will produce novel insights regarding the impact of aberrant sex-specific developmental mechanisms during adolescence that may be important for healthy aging outcomes.

项目总结 社交网络和支持对于整个生命周期的健康和健康以及社交参与都是不可或缺的 对于在衰老过程中保持整体健康和认知功能可能特别重要。然而，社交 随着年龄的增长，行为和社会认知能力会下降。更好地了解潜在的神经机制 健康和不正常的社会行为是增加健康老龄化结果的基础。 社交行为是由“奖赏”电路支持的，这是一个大脑区域网络，在 青春期。我们已经证明，小胶质细胞是大脑的常驻免疫细胞，在奖赏中起着关键作用。 青春期大鼠的环路和社会行为发育。小胶质细胞吞噬和消除，或‘修剪’， 女性伏隔核(NAC)奖赏区域的突触受体 在男性青春期早期和中期之间。在每次性交中干扰小胶质细胞介导的NAC修剪- 特定的修剪阶段改变了两性的社会行为发展。 在这项提案中，我们将确定健康和异常的免疫信号在NAC过程中是如何 青春期性行为--特别是在一生中塑造社会行为。具体来说，我们将确定是否 (1)干扰青春期雄性和雌性大鼠的NAC修剪增加了整个 寿命，(2)青春期的社会压力，一种前炎症刺激，损害奖励回路和 社会行为发展，加剧了NAC中的小胶质细胞修剪，以及(3)在 青春期会加重与衰老相关的社会行为障碍。我们的核心假设是健康的小胶质细胞- 在青春期，在新南威尔士州进行的中介修剪支持了一生中的社会行为，而且 因此，发生NAC修剪的性别特定发育阶段将构成 对终生社会异常的脆弱性。 这些研究将发育阶段和性别作为自变量来促进我们的理解 南卡罗来纳州健康和异常的青少年发育如何影响社会行为和神经免疫 在生命周期内发出信号。这项提案的成功完成将产生关于以下方面的新见解 青春期性别特异性发育机制异常的影响可能对 健康的老龄化结果。