Early life stress impacts molecular and network properties that bias the recruitment of pro-stress BLA circuits

情绪压力是许多精神疾病和痛苦事件的重要风险因素 青春期尤为突出。不良童年经历(ACE)对心理和心理健康造成负面影响 身体健康和驱动适应不良行为，然而这些结果背后的神经机制 还没有得到全面的了解。许多与ACE相关的疾病都涉及到体内活动的改变 参与情绪处理的大脑区域，与异常行为相对应。为了更好地理解 网络是如何变得功能失调并损害情绪处理的，这项提议旨在调查 早期生活应激(ELS)对成人局部场势(LFP)网络状态的影响 和压力相关的情绪处理，并揭示潜在的分子机制和电路。 我们假设ELS导致与招募相对应的不同网络状态 负价通路通过一个涉及BLA PV中间神经元功能障碍的机制。 相反的网络状态支配着不同的行为结果，我们的实验室已经证明了这种差异 行为状态包括选择性地激活独特的下游通路。恐惧和安全是联系在一起的 与不同的LFP网络状态，我们的实验室已经表明，操纵部分种群的活动 GABA能小白蛋白(PV)中间神经元的数量足以缠绕这些相互冲突的状态。我们的初步数据 提示ELS改变了基底外侧区PV中间神经元的发育和功能。 杏仁核(BLA)，它是价格处理和情绪调节的关键。此外，ELS归纳 不同的社会行为和LFP网络状态与掠夺性压力相关。当前的目标是 建议研究ELS对BLA网络和行为状态影响的调节机制。 这个项目将建立在我们新的初步数据的基础上来研究ELS对价处理的影响。 观察LFP网络状态的这些变化如何影响通过蜂窝的BLA进行的信息路由 水平，PV中间神经元和投射特异性主神经元的膜和突触特性将是 使用全细胞膜片钳、逆行追踪和光遗传学进行监测。观察ELS如何影响 在网络级别通过BLA进行信息路由，从独立的BLA投影仪进行钙成像 与正价和负价相关的通路将在支持应激的范例中在体内进行。 这个项目将促进我们对发展压力如何影响情绪传递的理解。 通过大脑传递的信息，有可能推动治疗高血压的新的、有针对性的疗法的开发 治疗经历过ACES的成年人的精神障碍。这个项目是由四个人赞助的 专家，每个人将提供指导，解释结果和设计与其专业相关的实验 以及整个项目，除了提供职业建议外。我们制定了一项量身定制的培训计划，以 帮助实现我的研究目标，并为我的学术研究事业做好理想的准备。

Emotional stress is a substantial risk factor for numerous psychiatric illnesses, and distressing events during adolescence are particularly salient. Adverse childhood experiences (ACEs) negatively impact mental and physical health and drive maladaptive behaviors, however the neural mechanisms underlying these outcomes are not comprehensively understood. Many of the disorders associated with ACEs involve altered activity within brain regions involved in emotional processing, corresponding with aberrant behaviors. To better understand how networks become dysfunctional and impair emotional processing, this proposal aims to investigate the impact of early life stress (ELS) on adult local field potential (LFP) network states relating to valence assignment and stress-associated emotional processing, and to reveal the underlying molecular mechanisms and circuitry. We hypothesize that ELS results in divergent network states corresponding with the recruitment of negative valence pathways through a mechanism involving BLA PV interneuron dysfunction. Opposing network states govern different behavioral outcomes, and our lab has demonstrated that divergent behavioral states involve selective activation of unique downstream pathways. Fear and safety are associated with distinct LFP network states, and our lab has shown that manipulating the activity of a fractional population of GABAergic parvalbumin (PV) interneurons is sufficient to entrain these conflicting states. Our preliminary data suggests that ELS alters the development and function of PV interneurons in this region, the basolateral amygdala (BLA), which is critical for valence processing and emotional regulation. Further, ELS induces divergent social behavior and LFP network states associated with predatory stress. The goal of the current proposal is to investigate the mechanisms mediating the impact of ELS on BLA network and behavioral states. This project will build on our novel preliminary data to investigate the effects of ELS on valence processing. To observe how these changes in LFP network state impact information routing through the BLA at the cellular level, the membrane and synaptic properties of PV interneurons and projection-specific principal neurons will be monitored using whole cell patch clamp, retrograde tracing, and optogenetics. To observe how ELS impacts information routing through the BLA at the network level, calcium imaging of BLA projectors from separate pathways associated with positive and negative valence will be performed in vivo during pro-stress paradigms. This project will advance our understanding of how developmental stress impacts the routing of emotional information through the brain, with the potential to advance the development of novel, targeted therapies for the treatment of psychiatric disorders in adults who have experienced ACEs. This project is sponsored by four experts who will each provide guidance interpreting results and designing experiments relating to their specialties and the project as a whole, in addition to providing career advice. We have developed a tailored training plan to assist with achieving my research goals and to ideally position me for a career in academic research.