Social experience and remodeling of amygdalar circuits in rat adolescence

大鼠青春期的社会经历和杏仁核回路的重塑

• 批准号: 7938814
• 负责人: Holly Marie Moore
• 金额: $ 37.91万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938814
• 关键词: ARHGEF5 gene; Accounting; Address; Adolescence; Adolescent; Adolescent Behavior; Adult; Affect; Affective; Age; Amygdaloid structure; Anxiety; Area; Behavior; Behavioral; Brain; Caspase-1; Cell Nucleus; Characteristics; Cognition; Cognitive; Data; Deposition; Development; Developmental Process; Disease; Dorsal; Emotional; Environment; Event; Female; Gene Expression; Housing; Human; Injection of therapeutic agent; Knowledge; Label; Learning; Maps; Mediating; Memory; Mental disorders; Methods; Modeling; Molecular Profiling; Neurons; Optical Methods; Pattern; Plastics; Play; Prefrontal Cortex; Process; Psychopathology; Puberty; Rattus; Recruitment Activity; Regulation; Relative (related person); Risk; Schizophrenia; Sensory; Social Behavior; Social Conditions; Social Environment; Social Interaction; Social Perception; Social isolation; Stimulus; Structure; Substance abuse problem; Testing; Thalamic structure; Time; Tracer; Translational Research; aged; behavior change; behavior influence; cortico-limbic circuits; deprivation; emerging adult; entorhinal cortex; experience; human MPP1 protein; human TFRC protein; interest; male; nerve supply; neural circuit; neuropathology; novel strategies; peer; postnatal; prepuberty; prevent; public health relevance; research study; social; social cognition; social deprivation; social group; young adult

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.

描述（由申请人提供）：本申请介绍了广泛的挑战领域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展中心的联系。青春期是与情感和社会行为的非线性变化相关的发展时期，以及许多精神疾病的发作风险迅速上升。尽管哺乳动物物种之间的社会和认知特征范围很大，但在从假期期到成年期的过渡期间，许多物种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存良好的神经发育过程，这些过程特有或不同地调节了青春期。尽管这种变化对精神疾病具有潜在的重要性，但相对较少的研究在青春期直接检查了神经回路结构。为了解决这一问题，我们最近完成了一项定量的跟踪研究，表明在大鼠的前额叶皮质（PFC）输入中，基础杏仁核（BA）在类似于青春期的时期内进行修剪。 PFC输入对BA的重塑，以及时间皮质输入的可能发生的类似变化，对于情感和社会行为的自适应成熟可能很重要。相反，这些神经发育过程的破坏可能有助于青春期或年轻成年中神经和心理病理学的出现。这些数据清楚地表明，对青少年脑电路的行为影响的研究必须首先考虑到可能对感兴趣的神经回路固有的正在进行的发育过程。在本文中，我们假设，类似于早期发育中感觉皮质回路修剪的调节，可以通过经验来修改前额叶和颞叶皮质输入的修剪和颞皮质输入。鉴于大鼠中的青春期（P25-P55；请参阅年龄范围的理由建议）与对同龄人的反应性的提高有关，我们建议测试以下假设：在青春期，社交经验调节了皮质 - 杏仁核电的结构重塑。因此，在对BA的时间皮质输入中重塑的表征之后，我们将测试在青春期，PFC修剪和颞叶的皮质输入对BA的修剪是否可以通过社交经验来修改。鉴于BA电路是由显着的食欲或厌恶事件招募的，因此社交状况的范围从同伴/游戏富含威胁到隔离。从Young（“ Pre”）青春期（P24）大鼠开始以下一个条件：同龄人（在青春大鼠中具有剧烈运动），同龄人剥夺（具有老化的Ovariectomized雌性的住房），充分的社会剥夺（单一住房） ），或具有间歇性社会威胁（侵略性男性）的单一住房。我们还将测试这些社会操纵对青春期相对于成年时的青春期经历时对皮质 - 杏仁核电路的影响是否更大。这些社会环境对皮质 - 杏仁核连通性的差异影响将通过定量逆行追踪方法进行评估。这些研究将对青春期中皮质膜电路的结构和功能成熟产生更全面的了解。 公共卫生相关性：在青春期和成年期间，许多精神疾病的风险急剧增加。但是，尚不清楚可能是这种增加的脆弱性的神经发育变化。拟议的研究将开始在我们的知识上弥合这一重要差距。我们的发现将对青春期有了更完整的了解，这是介导情绪调节和社会认知的独特，敏感的发展时期。此外，这些发现将有助于制定新的策略，以预防与许多精神病患者有关的精神病学和神经病理学，包括精神分裂症，焦虑和滥用药物疾病。