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），以及具体的挑战主题15- aa -101：确定青少年行为是否以及如何影响发育中的大脑连接。青春期是一个与情感和社会行为非线性变化相关的发育时期，也是许多精神疾病发病风险迅速上升的时期。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过程中表现出相似的行为变化。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节。尽管这种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检查了青少年时期的神经回路结构。为了解决这个问题，我们最近完成了一项定量的通道追踪研究，表明在大鼠中，前额皮质（PFC）对基底杏仁核（BA）的输入在类似于青春期后期的时期经历了修剪。PFC输入BA的重塑，以及可能类似的颞皮质输入的变化，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会导致青春期或青年期神经和精神病理的出现。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到正在进行的发育过程，这些过程可能是神经回路所固有的。在此，我们假设，与发育早期感觉皮层回路的修剪调节类似，前额叶和颞叶皮层对杏仁核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；见年龄范围的论证建议）与对同伴的反应性增加有关，我们建议验证在青春期，社会经验调节皮质-杏仁核回路的结构重塑的假设。因此，在表征颞叶皮层对脑区输入的重塑之后，我们将测试在青春期，PFC的修剪和颞边缘皮层对脑区输入的修剪是否可以通过社会经验进行修改。鉴于BA回路被突出的食欲或厌恶事件所招募，社会条件将从同伴/游戏丰富到孤立与威胁。从幼年（“前”）青春期（P24）开始，大鼠将被安置在以下一种条件下：与同伴一起（青春期大鼠的特点是激烈的玩耍），同伴剥夺（与切除卵巢的老年雌鼠住在一起），完全社会剥夺（单独住），或单独住有间歇性社会威胁（攻击性雄鼠）。我们还将测试这些社会操纵对皮质-杏仁核回路的影响是否在青春期比在成年期更大。这些社会环境对皮质-杏仁核连通性的不同影响将通过定量逆行追踪方法进行评估。这些研究将使我们对青春期皮质边缘回路的结构和功能成熟有更全面的了解。

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.