Molecular and Cellular Correlates of Plasticity in Hippocampal-Prefrontal Circuitry

海马-前额叶回路可塑性的分子和细胞相关性

• 批准号: 10321217
• 负责人: Keri Martinowich
• 金额: $ 64.09万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321217
• 关键词: Affect; Animal Model; Attenuated; Behavior; Behavior Control; Brain Diseases; Brain-Derived Neurotrophic Factor; Cells; Chronic stress; Cognition; Cognitive; Coupling; Data; Development; Disease; Electrophysiology (science); Emotional; Endoscopy; Event; Exposure to; Fright; Functional disorder; Future; Gene Expression; Genes; Goals; Hippocampus (Brain); Impairment; Knowledge; Label; Link; Mediating; Mental Depression; Mental disorders; Mission; Molecular; Molecular Profiling; Morphology; Neurodevelopmental Disorder; Neurons; Pathway interactions; Patients; Pattern; Phase; Physiological; Play; Population; Post-Traumatic Stress Disorders; Precipitating Factors; Prefrontal Cortex; Process; Regulation; Research; Research Design; Retrieval; Risk Factors; Role; Schizophrenia; Signal Pathway; Signal Transduction; Slice; Stress; Structure; Synapses; Techniques; Translations; United States National Institutes of Health; Viral; emotion regulation; enhancing factor; executive function; experimental study; fear memory; in vivo; in vivo imaging; innovation; neural patterning; neuropsychiatric disorder; neuropsychiatry; novel; overexpression; programs; relating to nervous system; response

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.

前额叶-前额叶回路与许多神经精神疾病有关。这条线路非常关键， 参与认知和情绪调节的多个方面，特别容易受到压力的影响， 是许多这些疾病的关键诱因。慢性压力会对神经元产生有害影响， 海马结构和生理功能，并损害海马依赖性行为，包括 情境性恐惧记忆的处理海马体和前额叶皮层在认知过程中进行交流 和情绪任务通过改变两个区域之间的振荡活动的一致性。但 细胞和分子事件，驱动这些变化，在大脑前额叶同步，以及他们是如何 受到压力的影响，并没有得到很好的理解。了解暴露于压力导致 在恐惧调节过程中，大脑前额叶-前额叶相互作用的中断是一个高度优先考虑的问题， 与恐惧相关的行为在许多神经精神障碍中是突出的。我们的初步数据支持 假设暴露于压力会影响大脑前额叶-前额叶通路的可塑性， 这两个区域之间的连接和增强与恐惧相关的行为。许多风险因素 神经精神障碍，包括压力，影响在发育和免疫过程中发挥重要作用的基因。 突触的可塑性因此，在突触连接的远程投射之间的中断， 海马和前额叶皮质可能参与了海马-前额叶同步性的损伤。 然而，缺乏旨在了解这些投射中的分子信号通路的研究。 细胞这一建议的中心假设是，细胞和分子信号的定义程序， 前额叶投射神经元控制着它们的结构和功能， 调节神经活动模式和两个结构之间的连接。本项目的总体目标 应用程序是1）了解压力如何驱动大脑前额叶皮层的分子和细胞信号传导 投射细胞控制其生理功能; 2）确定海马-前额叶的可塑性如何 投射神经元影响该回路中的功能连接，以控制与恐惧相关的行为。我们使用一个 神经元形态学分析与内窥镜成像和体内 电生理学，以了解压力如何影响大脑前额叶投射中的细胞可塑性 神经元然后，我们确定这些可塑性的细胞相关性如何影响大脑前额叶-海马的同步性 与恐惧有关的行为。除了细胞相关性，我们将联合收割机分子分析技术与 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有关分子和细胞信号程序的基本信息， 前额叶-前额叶投射神经元，有助于功能连接，信息， 这对今后针对这一途径的战略至关重要。