Adolescent Social Isolation, Social Behavior, and Prefrontal Cortex

描述（由申请人提供）：青少年暴力和攻击的后果构成了一个重大的公共卫生问题，在青春期有攻击行为史的个体中，后期精神病理学（如药物滥用、情绪障碍和虐待性父母）的风险增加。然而，很多仍然未知的神经基板参与侵略和它的发展。本文提出的工作将使用隔离饲养，青少年社会逆境的动物模型，探讨内侧前额叶皮层（mPFC）在雄性和雌性大鼠攻击中的作用，重点是谷氨酸和多巴胺（DA）神经传递作为隔离饲养的结果发生的社会行为失调的潜在机制。谷氨酸和DA相互双向调节，对可塑性和适当的mPFC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 mPFC的发展发生在青春期和成年早期。尽管隔离养育对社会行为的某些影响已经被证明是可逆的，只要将隔离的人重新安置在一个群体中，这不太可能是社会化如何发生的有效模型 临床证据表明，许多具有攻击性的青少年会变成具有攻击性的成年人。因此，我们将评估单独或重复的社会经验后，无论是隔离或群体饲养的青春期大鼠的影响。拟议的工作询问是否立即早期基因蛋白产物（c-fos和Arc）和可塑性相关蛋白PSD-95的激活，所有这些都是敏感的或参与谷氨酸和DA信号，在隔离饲养后改变，以响应随后与新的同性大鼠的社会互动，以及这些蛋白质的变化是否与隔离饲养后观察到的攻击性增加有关。DA和谷氨酸信号传导的突触后相互作用的改变和PSD-95在这些相互作用中的作用将通过使用免疫荧光和共聚焦显微镜评估DA D1和谷氨酸NMDA受体与PSD-95的共定位来探索。实验将探讨突触前的变化所产生的隔离饲养和随后的社会经验的神经递质谷氨酸和DA在体内微透析。此外，将使用NMDA受体（D-环丝氨酸）和DA D1受体（SKF 38393）激动剂的mPFC微量注射来确定这些神经递质系统是否在mPFC中起作用，以介导在隔离饲养大鼠中观察到的攻击性增加。这将有三个具体目标。具体目标1是确定社会互动诱导的mPFC功能激活和可塑性的变化后，隔离饲养的男性和女性大鼠。具体目的是确定mPFC谷氨酸和NMDA受体在雄性和雌性大鼠隔离饲养后的攻击行为中的作用。具体目标3是确定mPFC DA和DA D1受体在雄性和雌性大鼠隔离饲养后攻击行为中的作用。

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.