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(翻译科学)，以及特定的挑战主题15-AA-101：确定青少年的行为是否以及如何影响发育中的大脑的连接。青春期是与情感和社会行为的非线性变化相关的发育期，许多精神障碍的发病风险迅速上升。尽管哺乳动物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过程中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，这些过程是青春期特有的，或者在青春期受到不同的调控。尽管这种变化对精神障碍具有潜在的重要性，但相对较少的研究直接研究了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的轨迹追踪研究，表明在大鼠中，前额叶皮质(PFC)到基底杏仁核(BA)的输入在类似于青春期后期的时期经历了修剪。对BA的PFC输入的重塑，以及可能在颞叶皮质输入的类似变化，可能在情感和社会行为的适应性成熟中很重要。相反，这些神经发育过程的中断可能导致青春期或青春期神经和精神病理学的出现。这些数据清楚地表明，研究行为对青少年大脑回路的影响必须首先考虑正在进行的发育过程，这些过程可能是感兴趣的神经回路的内在特征。在此，我们假设，类似于发育早期感觉皮质回路的修剪调节，杏仁核前额叶和颞叶皮质输入的修剪可以通过经验进行修改。鉴于大鼠的青春期(P25-P55；见年龄范围正当性建议)与对同龄人增加的反应有关，我们建议测试这一假设，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，在描述了BA的颞叶皮质输入的重塑特征之后，我们将测试在青春期，修剪PFC和BA的颞缘皮质输入是否可以被社会经验所改变。考虑到BA赛道是由显著的欲望或厌恶事件招募的，社交条件将从同伴/游戏丰富到孤立和威胁。从青春期前(P24)开始，大鼠将被安置在下列条件之一：同龄人(青春期大鼠的特点是积极玩耍)、同伴剥夺(与去卵巢的老年雌性动物一起居住)、完全社会剥夺(单独居住)、或具有间歇性社会威胁的单独居住(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时更大。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。这些研究将对青春期皮质-边缘环路的结构和功能成熟有更全面的了解。 公共卫生相关性：在青春期和青春期，许多精神疾病的风险急剧增加。然而，这种易感性增加背后可能存在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。我们的发现将对青春期产生更完整的理解，因为青春期是调节情绪调节和社会认知的大脑回路的独特、敏感的发展时期。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相关的心理和神经病理，包括精神分裂症、焦虑和物质滥用障碍。

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.