Adolescent Social Isolation, Social Behavior, and Prefrontal Cortex

描述（由申请人提供）：青少年暴力和攻击行为的后果构成了一个重大的公共卫生问题，并且在青少年时期有攻击行为史的个体中，后期精神病理（如药物滥用、情绪障碍和虐待父母）的风险增加。然而，关于攻击及其发展的神经基质仍有许多未知之处。本研究将利用青少年社会逆境的动物模型——隔离饲养，探索内侧前额叶皮层（mPFC）在雌雄大鼠攻击行为中的作用，重点研究谷氨酸和多巴胺（DA）神经传递作为隔离饲养导致的社会行为失调的潜在机制。谷氨酸和DA相互双向调节，对mPFC的可塑性和正常功能至关重要。mPFC对执行功能至关重要，包括适当的社会行为，以及许多

DESCRIPTION (provided by applicant): The consequences of youth violence and aggression pose a significant public health problem, and the risk of later psychopathologies such as drug abuse, mood disorders, and abusive parenting is increased in individuals with a history of aggressive behavior during adolescence. However, much remains unknown about the neural substrates involved in aggression and its development. The work proposed here will use isolation rearing, an animal model of adolescent social adversity, to explore the role of the medial prefrontal cortex (mPFC) in aggression in male and female rats, focusing on glutamate and dopamine (DA) neurotransmission as potential mechanisms for the dysregulation of social behavior that occurs as a consequence of isolation rearing. Glutamate and DA modulate each other bidirectionally and are crucial for plasticity and proper mPFC function. The mPFC is critically important for executive function, including appropriate social behavior, and much of the development of the mPFC occurs during adolescence and into early adulthood. Although some of the effects of isolation rearing on social behavior have been shown to be reversible simply by rehousing isolates with a group, this is not likely to be a valid model of how socialization occurs in humans, as clinical evidence indicates that many aggressive adolescents become aggressive adults. Therefore we will assess the effects of single or repeated social experience after either isolation or group rearing of adolescent rats. The proposed work asks whether the activation of immediate early gene protein products (c-fos and Arc) and the plasticity-related protein PSD-95, all of which are sensitive to or involved in glutamate and DA signaling, are altered after isolatio rearing in response to subsequent social interaction with a novel same-sex rat, and whether changes in these proteins are related to the increase in aggression observed after isolation rearing. Alterations in postsynaptic interactions of DA and glutamate signaling and the role of PSD-95 in these interactions will be explored by assessing colocalization of DA D1 and glutamate NMDA receptors with PSD-95 using immunoflurorescence and confocal microscopy. Experiments will explore presynaptic changes produced by isolation rearing and subsequent social experience in the neurotransmitters glutamate and DA using in vivo microdialysis. In addition, mPFC microinjections of NMDA receptor (D-cycloserine) and DA D1 receptor (SKF 38393) agonists will be used to determine whether these neurotransmitter systems act in the mPFC to mediate the increased aggression observed in isolation reared rats. This will be done with 3 Specific Aims. Specific Aim 1 is to determine social-interaction induced changes in mPFC functional activation and plasticity after isolation rearing in male and female rats. Specific Aim is to determine the role of mPFC glutamate and NMDA receptors in aggressive behavior after isolation rearing in male and female rats. Specific Aim 3 is to determine the role of mPFC DA and DA D1 receptors in aggressive behavior after isolation rearing in male and female rats.