Molecular and Cellular Correlates of Plasticity in Hippocampal-Prefrontal Circuitry

海马体-前额叶回路与许多神经精神疾病有关。这条赛道非常关键 涉及认知和情绪调节的多个方面，特别容易受到压力的影响，这 是许多此类疾病的关键诱发因素。慢性应激可对神经元产生有害影响 海马区的结构和生理功能，并损害海马区的依赖行为，包括 情境恐惧记忆的加工。在认知过程中，海马体和前额叶皮质进行交流 和情绪任务，通过改变两个区域之间振荡活动的连贯性。然而， 推动这些变化的细胞和分子事件，以及它们是如何 受到压力的影响，并没有得到很好的理解。了解暴露在压力下导致的机制 对于恐惧过程中海马体-前额叶相互作用的中断，调控是一个高度优先的问题，因为 与恐惧相关的行为在许多神经精神障碍中都很突出。我们的初步数据支持 应激影响海马-前额叶通路可塑性的假说，导致脑组织紊乱 这两个区域之间的连通性和增强的恐惧相关行为。许多风险因素 神经精神障碍，包括应激，影响在发育和发育中发挥重要作用的基因 突触的可塑性。因此，神经元之间长距离投射的突触连接中断 海马体和前额叶皮质可能导致海马体-前额叶同步性受损。 然而，缺乏旨在了解这些投射中的分子信号通路的研究 细胞。这一提议的中心假设是，确定的细胞和分子信号转导程序 海马-前额叶投射神经元控制其结构和功能，而这些信号通路 调节神经活动的模式和两个结构之间的连接。这个项目的总体目标是 应用于1)了解应激如何驱动海马额前叶的分子和细胞信号 投射细胞控制它们的生理功能；以及2)决定海马额前叶的可塑性 投射神经元影响这个回路的功能连接，以控制与恐惧相关的行为。我们使用一种 技术复杂的神经形态分析与内窥镜成像和活体相结合 电生理学了解应激如何影响海马-前额叶投射的细胞可塑性 神经元。然后我们确定这些细胞可塑性的相关性如何影响海马体-前额叶的同步性。 在与恐惧相关的行为中。除了细胞关联，我们将分子图谱技术与 逆行病毒方法研究海马-前额叶可塑性的分子贡献 神经元。这项研究将揭示关于分子和细胞信号程序的基本信息 海马-前额叶投射神经元对功能连接做出贡献，信息将是 对未来针对这条道路的战略至关重要。

The hippocampal-prefrontal circuit is implicated in many neuropsychiatric illnesses. This circuit is critically involved in multiple aspects of cognition and emotional regulation, and is particularly vulnerable to stress, which is a key precipitating factor for many of these disorders. Chronic stress can have deleterious effects on neuronal structure and physiological function in the hippocampus, and impair hippocampal-dependent behavior, including processing of contextual fear memories. The hippocampus and prefrontal cortex communicate during cognitive and emotional tasks by altering the coherence of oscillatory activity between the two regions. However, the cellular and molecular events that drive these changes in hippocampal-prefrontal synchrony, and how they are influenced by stress, are not well understood. Understanding the mechanisms by which exposure to stress leads to disruptions in hippocampal-prefrontal interactions during fear regulation is a high priority given that altered fear-related behavior is prominent in many neuropsychiatric disorders. Our preliminary data support the hypothesis that exposure to stress impacts plasticity in the hippocampal-prefrontal pathway, leading to disrupted connectivity between the two regions and enhanced fear-related behavior. Many of the risk factors for neuropsychiatric disorders, including stress, affect genes that play important roles in the development and plasticity of synapses. Hence, disruptions in synaptic connections of the long-range projections between the hippocampus and prefrontal cortex could contribute to impairments in hippocampal-prefrontal synchrony. However, there is a dearth of research aimed at understanding molecular signaling pathways in these projection cells. The central hypothesis of this proposal is that defined programs of cellular and molecular signaling in hippocampal-prefrontal projection neurons control their structure and function, and that these signaling pathways regulate patterns of neural activity and connectivity between the two structures. The overall goals of this application are to 1) understand how stress drives molecular and cellular signaling in hippocampal-prefrontal projection cells to control their physiological function; and 2) determine how plasticity in hippocampal-prefrontal projections neurons impacts functional connectivity in this circuit to control fear-related behavior. We use a technically sophisticated combination of neuronal morphology analysis with endoscopic imaging and in vivo electrophysiology to understand how stress impacts cellular plasticity in hippocampal-prefrontal projection neurons. We then determine how these cellular correlates of plasticity impact hippocampal-prefrontal synchrony during fear-related behavior. In addition to cellular correlates, we combine molecular profiling techniques with retrograde viral approaches to investigate molecular contributions to plasticity in hippocampal-prefrontal neurons. The research will reveal fundamental information about molecular and cellular signaling programs in hippocampal-prefrontal projection neurons that contribute to functional connectivity, information that will be critical for future strategies targeting this pathway.