Effects of early life stress on synaptic function and DA signaling in the VTA

 描述(申请人提供)：不良的早期生活经历，如长期忽视和虐待儿童，会增加儿童、青春期和成年期出现精神健康障碍的风险，包括药物滥用和精神障碍。了解虐待和忽视儿童对早期大脑发育和神经过程的影响，以及根据过去的经验塑造记忆和指导行为的神经过程，是旨在改善受虐待儿童成功治疗前景的研究的重要目标。腹侧被盖区(VTA)的病理性奖赏依赖学习和随后来自VTA的多巴胺(DA)信号调节失调似乎是成瘾和应激相关障碍发生的核心，这表明在该脑区进行选择性干预在治疗此类障碍方面具有潜在的治疗优势。啮齿动物早期母体剥夺(MD)的单个24小时发作被广泛用作严重早期生活应激的动物模型。使用这一模型的研究已经提供了DA信号的失调与后来发展为应激相关障碍的倾向之间的强烈联系。然而，早期MD是如何影响VTA中的奖赏学习过程的，目前还不清楚。在这个提案中，我们将检验我们的假设，即MD触发表观遗传学机制，选择性地减少支持VTA中GABA能可塑性的关键记忆相关基因的表达，这些表观遗传学变化在一定程度上有助于后来的精神病理学的发展。我们的初步数据还表明，MD通过对支持这种可塑性的关键信号分子的表观遗传修饰，选择性地破坏VTA中的GABA能可塑性。我们将使用组合 利用分子、细胞、免疫组织化学、生化、表观遗传学和行为学等技术，对幼年幼鼠、母体剥夺(MD)和非母体剥夺(Non-MD)幼鼠进行研究，以推动对实验性MD的机械性理解，这可能对儿童虐待和忽视的恢复具有很高的适用性。了解MD对VTA中神经元的影响将扩大我们对儿童虐待和忽视的细胞基础中一个重要但被忽视的部分的了解。因此，我们将确定在VTA内调节突触可塑性、记忆形成和DA信号的新机制，这些机制可以在发育早期的MD或其他严重应激事件发生后立即以细胞类型和电路特异性的方式选择性地靶向。

 DESCRIPTION (provided by applicant): Adverse early life experiences such as prolonged child neglect and abuse increase the risk of developing mental health disorders including substance abuse and psychiatric disorders in childhood, adolescence and adulthood. Understanding the consequences of child abuse and neglect on early brain development and neural processes that shape memories and guide behaviors based on past experiences are important goals of research aiming to improve prospects for successful treatment of abused children. Pathological reward-dependent learning within the ventral tegmental area (VTA) and the subsequent dysregulation of dopamine (DA) signaling from the VTA seems to be central to the onset of addiction and stress-related disorders, suggesting the potential therapeutic benefits of selective intervention in this brain area in treatment of such disorders. A single 24h episode o early maternal deprivation (MD) in rodents is widely used as an animal model of severe early life stress. Studies using this model have provided a strong link between the dysregulation of DA signaling and a later propensity to develop stress-related disorders. However it is still unknown how early MD affects the reward learning processes in the VTA. In this proposal, we will test our hypothesis that MD triggers epigenetic mechanisms that selectively reduce expression of critical memory-associated genes that support GABAergic plasticity in the VTA, and these epigenetic changes in part contribute to the development of later psychopathology. Our preliminary data also indicate that MD selectively disrupts GABAergic plasticity in the VTA through epigenetic modifications of critical signaling molecules underlying this plasticity. We will use a combination of molecular, cellular, immunohistochemical, biochemical, epigenetic, and behavioral techniques in naïve, maternally-deprived (MD), and non-maternally-deprived (non-MD) juvenile rats to drive a mechanistic understanding of experimental MD that may be highly applicable to recovery of child abuse and neglect. Understanding the effects of MD on neurons in the VTA will expand our knowledge of an important but neglected part of the cellular basis of child abuse and neglect. Consequently, we will identify novel mechanisms in the regulation of synaptic plasticity, memory formation and DA signaling within the VTA that can be selectively targeted in a cell-type and circuit-specific manner in the period immediately following an episode of MD or other severe stress during early development.