Prefrontal Cortical Microcircuit Mechanisms of Working Memory Deficits in Chronic Stress

 描述(申请人提供)：前额叶皮质(PFC)回路功能障碍已成为抑郁症和其他应激相关神经精神障碍的中心病理发现，并与调节注意力的特征性缺陷有关。 奖励处理和执行控制。所有这些功能都依赖于工作记忆：一种支持信息的短期存储和处理的过程，尽管受到竞争的、与任务无关的信息的干扰。工作记忆部分是由PFC锥体神经元调节的，在记忆痕迹的主动维持过程中，这些神经元表现出持续的活动。这种持续的、内部产生的活动的不同寻常的能力被认为是来自兴奋性锥体细胞和抑制性中间神经元的精确协调活动，但微电路水平的机制仍然不完全清楚。了解这些细胞在工作记忆服务中是如何相互作用的，以及它们在精神和神经发育障碍中是如何被破坏的，这是系统神经科学的根本挑战。在这里，我们将使用光遗传学工具和双光子(2P)钙成像来量化和操纵清醒、行为正常的小鼠的神经活动，并研究锥体细胞如何与两种中间神经元亚型相互作用来支持工作记忆。接下来，我们将检验这一假说，即慢性压力破坏了这些相互作用，改变了PF微电路中兴奋和抑制的平衡，并损害了工作记忆。最后，我们将检验这一假设，即这些效应是由BDNF介导的维持突触内稳的可塑性机制缺陷在分子水平上驱动的。这项工作的结果将促进我们对前额叶微电路如何支持工作记忆的理解，工作记忆是多种精神和神经发育障碍的核心组成部分。它们还可能为未来针对情绪和焦虑症特定神经元亚型的功能障碍设计新的干预措施提供参考。

 DESCRIPTION (provided by applicant): Prefrontal cortical (PFC) circuit dysfunction has emerged as a central pathological finding in depression and other stress-related neuropsychiatric disorders, and has been linked to characteristic deficits in regulating attention, reward processing, and executive control. All of these functions depend on working memory: a process that supports the short-term storage and manipulation of information, despite interference from competing, task-irrelevant information. Working memory is mediated in part by PFC pyramidal neurons, which exhibit sustained activity during active maintenance of a memory trace. This unusual capacity for sustained, internally generated activity is thought to emerge from the precisely coordinated activity of excitatory pyramidal cells and inhibitory interneurons, but the microcircuit-level mechanisms remain incompletely understood. Understanding how these cells interact in the service of working memory-and how they are disrupted in psychiatric and neurodevelopmental disorders-are fundamental challenges for systems neuroscience. Here, we will use optogenetic tools and two-photon (2P) calcium imaging to quantify and manipulate neural activity in awake, behaving mice and investigate how pyramidal cells interact with two interneuron subtypes to support working memory. Next, we will test the hypothesis that chronic stress disrupts these interactions, altering the balance of excitation and inhibition in PF microcircuits and impairing working memory. Finally, we will test the hypothesis that these effects are driven at the molecular level by deficits in BDNF-mediated plasticity mechanisms for maintaining synaptic homeostasis. The results of this work will advance our understanding of how prefrontal microcircuits support working memory, a core component of multiple psychiatric and neurodevelopmental disorders. They may also inform future efforts to design new interventions targeting dysfunction in specific neuronal subtypes in mood and anxiety disorders.