Social experience and remodeling of amygdalar circuits in rat adolescence

描述（由申请人提供）：本申请涉及广泛的挑战领域15（转化科学）和特定的挑战主题15-AA-101：确定青少年行为是否以及如何影响发育中大脑的连接。青春期是一个情感和社会行为发生非线性变化的发育时期，许多精神疾病的发病风险迅速上升。尽管哺乳动物物种的社会和认知特征差异很大，但许多物种在从青春期到成年期的过渡期间表现出类似的行为变化。这种明显的行为同源性可能反映了保守的神经发育过程，是特定的，或不同的调节，青春期。尽管这些变化对精神疾病具有潜在的重要性，但相对较少的研究直接研究青春期的神经回路结构。为了解决这个问题，我们最近完成了一项定量跟踪研究，表明在大鼠中，前额叶皮层（PFC）的基底杏仁核（BA）的输入进行修剪期间类似于青春期后期。PFC输入到BA的重塑，以及可能类似的颞叶皮质输入的变化，在情感和社会行为的适应性成熟中可能是重要的。相反，这些神经发育过程的中断可能有助于在青春期或青年期出现神经和精神病理学。这些数据清楚地表明，行为对青少年大脑回路的影响的研究必须首先考虑到正在进行的发育过程，这些过程可能是感兴趣的神经回路所固有的。在此，我们假设，类似的修剪在感觉皮层电路的早期发展的监管，修剪前额叶和颞叶皮层输入杏仁核可以修改的经验。考虑到大鼠青春期（P25-P55;见年龄范围合理性建议）与对同伴的反应性增加有关，我们建议检验这一假设，即在青春期，社会经验调节皮质杏仁核回路的结构重塑。因此，以下表征的重建颞叶皮层输入BA，我们将测试是否在青春期，修剪PFC和颞叶边缘皮层输入BA可以修改的社会经验。鉴于BA回路被显著的食欲或厌恶事件招募，社交条件将从同伴/游戏丰富到威胁隔离。从幼年（“前”）青春期（P24）开始，将大鼠圈养在以下条件之一中：与同伴（其特征是青春期大鼠的剧烈玩耍）、同伴剥夺（与切除卵巢的老年雌性大鼠圈养）、完全社会剥夺（单独圈养）或具有间歇性社会威胁的单独圈养（攻击性雄性）。我们还将测试这些社会操作对皮质杏仁核回路的影响是否在青春期比成年期更大。这些社会环境对皮质-杏仁核连接的不同影响将用定量逆行追踪方法进行评估。这些研究将产生一个更完整的了解结构和功能成熟的皮质边缘电路在青春期。 公共卫生相关性：在青春期和青年期，许多精神疾病的风险急剧增加。然而，可能导致这种脆弱性增加的神经发育变化尚不清楚。拟议的研究将开始弥合我们知识中的这一重要差距。我们的研究结果将使我们更全面地理解青春期是一个独特的、敏感的大脑回路发育时期，它调节情绪调节和社会认知。此外，这些发现将有助于开发新的策略，以预防与许多精神疾病（包括精神分裂症，焦虑症和药物滥用障碍）相关的心理和神经病理学。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area 15 (Translational Science), and the Specific Challenge Topic 15-AA-101: Determining If and How Adolescent Behaviors Affect Connections in the Developing Brain. Adolescence is a developmental period associated with non-linear changes in affective and social behavior, and a rapid rise in the risk of onset for a number of psychiatric disorders. Despite the large range in social and cognitive characteristics across mammalian species, many species show similar behavioral changes during the transition from the peri-pubertal period to adulthood. This apparent behavioral homology may reflect well-conserved neurodevelopmental processes that are specific to, or differently regulated in, adolescence. Despite the potential importance of such changes to psychiatric disorders, relatively few studies have directly examined neural circuit structure during adolescence. To address this, we recently completed a quantitative tract-tracing study, showing that in the rat, prefrontal cortical (PFC) inputs to the basal amygdala (BA) undergo pruning during the period analogous to late adolescence. The remodeling of PFC inputs to the BA, and possibly similar changes in temporal cortical inputs, may be important in the adaptive maturation of affective and social behavior. Conversely, disruptions of these neurodevelopmental processes may contribute to the emergence of neuro- and psychopathology in adolescence or young adulthood. These data make clear that the study of behavioral influences on adolescent brain circuitry must first take into account ongoing developmental processes that may be intrinsic to the neural circuit of interest. Herein, we postulate that, similar to the regulation of pruning in sensory cortical circuits earlier in development, pruning of prefrontal and temporal cortical inputs to the amygdala can be modified by experience. Given that adolescence in the rat (P25-P55; see Proposal for justification of age range) is associated with increased responsiveness to peers, we propose to test the hypothesis that during adolescence, social experience modulates the structural remodeling of cortico-amygdalar circuits. Thus, following characterization of remodeling in temporal cortical inputs to the BA, we will test whether during adolescence, pruning of PFC and temporo-limbic cortical inputs to the BA can be modified by social experience. Given that BA circuits are recruited by salient appetitive or aversive events, the social conditions will range from peer/play-enriched to isolation with threat. Beginning in young ("pre") adolescence (P24) rats will be housed in one the following conditions: with peers (which features vigorous play in adolescent rats), peer deprivation (housing with aged ovariectomized female), full social deprivation (single housing), or single housing with intermittent social threat (aggressive male). We will also test whether the effects of these social manipulations on cortico-amygdalar circuits are greater when experienced in adolescence relative to in adulthood. The differential effects of these social environments on cortico-amygdalar connectivity will be assessed with quantitative retrograde tracing methods. These studies will yield a more complete understanding of the structural and functional maturation of cortico-limbic circuits during adolescence. PUBLIC HEALTH RELEVANCE: During adolescence and young adulthood, the risk for many mental illnesses increases sharply. However, the neurodevelopmental changes that may underlie this increased vulnerability are not understood. The proposed studies will begin to bridge this important gap in our knowledge. Our findings will yield a more complete understanding of adolescence as a unique, sensitive period of development for brain circuits that mediate emotional regulation and social cognition. Moreover, the findings will contribute to the development of novel strategies for preventing the psycho- and neuropathology associated with many psychiatric disorders including schizophrenia, anxiety, and substance abuse disorders.