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.

项目摘要 社交网络和支持是整个生命周期和社交参与的健康和健康不可或缺的一部分 在衰老过程中保留整体健康和认知功能可能尤其重要。但是，社交 衰老期间的行为和社会认知下降。更好地理解神经机制 健康和异常的社会行为是增加健康衰老结果的基础。 社会行为得到“奖励”电路的支持，这是一个大脑区域网络，在 青少年。我们已经表明，小胶质细胞（大脑的居民免疫小球）在奖励中起着至关重要的作用 青少年大鼠的电路和社会行为发展。小胶质细胞吞噬和消除或“修剪”， 伏隔核中的突触受体（NAC）奖励女性青少年之间的奖励区域， 以及男性早期青春期之间的青少年之间。在每个性别中干扰小胶质细胞介导的NAC修剪 - 特定的修剪阶段改变了男女的社会行为发展。 在此提案中，我们将确定NAC中NAC中的健康和异常的免疫信号 青少年性别特定于整个生命周期的社会行为。具体来说，我们将确定是否 （1）干扰青少年男性和女性大鼠的NAC修剪会增加整个整个社会行为 寿命，（2）青少年期间的社会压力，一种促炎性刺激，会损害奖励电路和 社会行为发展，加剧NAC中的小胶质修剪，（3）在 青少年会恶化与衰老有关的社会行为功能障碍。我们的核心假设是健康的小胶质细胞 青少年期间NAC的介导的修剪支持整个生命周期的社会行为，并且 在此期间发生NAC修剪的性别特定的发育阶段将构成特定的性别时期 生活脆弱的社会异常。 这些研究将发展阶段和性别视为独立变量，以提高我们的理解 NAC中的青少年发展如何影响社会行为和神经免疫力 整个寿命的信号传导。该提案的成功完成将产生有关有关的新见解 青少年期间异常性别特异性发展机制的影响可能对 健康的衰老结果。