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

 描述（由申请人提供）：不良的早期生活经历，如长期的儿童忽视和虐待，会增加儿童、青少年和成年期发生精神健康障碍的风险，包括药物滥用和精神疾病。了解虐待和忽视儿童对早期大脑发育和神经过程的影响，这些神经过程根据过去的经验塑造记忆和指导行为，是旨在改善虐待儿童成功治疗前景的研究的重要目标。腹侧被盖区（VTA）内的病理性奖励依赖性学习以及随后来自VTA的多巴胺（DA）信号调节异常似乎是成瘾和应激相关疾病发作的中心，这表明在治疗此类疾病时选择性干预该脑区具有潜在的治疗益处。啮齿类动物的单次24小时早期母亲剥夺（MD）被广泛用作严重早期生活应激的动物模型。使用该模型的研究提供了DA信号失调与后来发展压力相关疾病的倾向之间的强有力的联系。然而，早期MD如何影响VTA中的奖励学习过程仍然是未知的。在这个提议中，我们将测试我们的假设，即MD触发表观遗传机制，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，这些表观遗传变化部分有助于后来精神病理学的发展。我们的初步数据还表明，MD选择性地破坏GABA能可塑性在腹侧被盖区通过表观遗传修饰的关键信号分子的可塑性。我们将使用一个组合 分子，细胞，免疫组织化学，生物化学，表观遗传学和行为技术在幼稚，母亲剥夺（MD），和非母亲剥夺（non-MD）的幼年大鼠，以推动机制的理解实验MD，可能是高度适用于儿童虐待和忽视的恢复。了解MD对腹侧被盖区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认识。因此，我们将确定新的机制，在调节突触可塑性，记忆形成和DA信号内的腹侧被盖区，可以选择性地针对在一个细胞类型和电路特定的方式在一段时间后立即发作的MD或其他严重的压力在早期发展。

 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.