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

项目摘要 社交网络和支持是整个生命周期的健康和健康以及社会参与的组成部分 可能对在衰老过程中保持整体健康和认知功能特别重要。但社会 行为和社会认知在衰老过程中下降。更好地理解潜在的神经机制 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“奖励”回路支持的，这是一个大脑区域网络，在社交过程中发展起来。 青春期我们已经证明，小胶质细胞，大脑的常驻免疫细胞，在奖励中发挥着至关重要的作用， 回路和社会行为的发展。小胶质细胞吞噬和消除，或'修剪'， 在女性青春期前早期， 在男性的青春期早期和中期之间。在每个性别期间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育。 在这项提案中，我们将确定如何健康和异常的免疫信号在NAc期间， 青少年期的性行为会影响一生中的社会行为。具体来说，我们将确定 (1)在青春期雄性和雌性大鼠中干扰NAc修剪增加了整个群体的社会行为。 寿命，（2）青春期的社会压力，一种损害奖励回路的促炎刺激， 社会行为发展，加剧NAc中的小胶质细胞修剪，和（3）社会压力， 青少年与年龄相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- 在青春期NAc介导的修剪支持整个生命周期的社会行为， 因此，NAc修剪发生的性别特异性发育阶段将构成性别特异性时期， 易受终身社会异常的影响。 这些研究将发育阶段和性别作为独立变量来推进我们的理解 NAc中健康和异常的青少年发育如何影响社会行为和神经免疫 在整个生命周期中传递信号。该提案的成功完成将产生新的见解， 青春期异常的性别特异性发育机制的影响，这可能是重要的 健康的老龄化结果。

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.