How is anxiety-related information relayed across hippocampal-prefrontal circuits

焦虑相关信息如何在海马-前额叶回路中传递

• 批准号: 10380441
• 负责人: Mazen A Kheirbek
• 金额: $ 8.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380441
• 关键词: Acute; Affect; Amygdaloid structure; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological Assay; Brain; Communication; Complex; Data; Distress; Emotional; Environment; Frequencies; Hippocampus (Brain); Image; Interneurons; Knowledge; Lesion; Measures; Medial; Membrane; Modeling; Mus; Neurons; Output; Pathologic; Periodicity; Phase; Play; Population; Prefrontal Cortex; Risk Assessment; Rodent; Role; Signal Transduction; Source; Stream; Testing; Therapeutic; Theta Rhythm; United States; Work; anxiety-related behavior; arm; base; cell type; disability; inhibitory neuron; novel; operation; optogenetics; parent grant; prevent; public health relevance; recruit; relating to nervous system; response; transmission process; voltage

PROJECT SUMMARY / ABSTRACT (PARENT GRANT) The hippocampus (HPC) and prefrontal cortex (PFC) are implicated in anxiety disorders. In rodents, the ventral HPC (vHPC) and medial PFC (mPFC) form a circuit that regulates anxiety-related behavior in the elevated plus maze (EPM). The vHPC and mPFC synchronize in the theta-frequency (4-12 Hz) range during exploration of anxiogenic regions, and disrupting communication between the vHPC and mPFC prevents mice from avoiding the anxiety-provoking open arms of the EPM. Here we propose to reveal the detailed circuit interactions between the vHPC and mPFC that are crucial for anxiety-related behavior. In particular, our preliminary data has shown that populations of vHPC neurons are recruited during exploration of the open arms in the EPM, and inhibiting vHPC neurons disrupts open arm avoidance. However it is not known whether certain classes of mPFC neurons have preferential access to anxiety-related input from the vHPC. To answer this question, we will study vHPC neurons which project to specific classes of neurons in the mPFC, as mice explore the EPM. We will also study mPFC neurons which project to specific targets, e.g., the basolateral amygdala, to determine how they encode anxiety-related information. We hypothesize that classes of mPFC projection neurons which receive anxiety-related input from the vHPC will also encode anxiety-related information. Finally, we will study how prefrontal interneurons respond to theta-frequency input from the vHPC and regulate the anxiety-related responses of mPFC projection neurons. Our preliminary studies have shown that specific inhibitory neurons in the mPFC regulate prefrontal responses to vHPC input and contribute to anxiety-related avoidance. Here, we will test the hypothesis that in the EPM, theta-frequency input from the vHPC recruits these interneurons, thereby enhancing prefrontal responses to anxiety-related input from the vHPC and anxiety-related avoidance. Specifically, we will examine whether prefrontal inhibitory neurons synchronize to theta-frequency input from the vHPC during exploration of the EPM. Finally, we will examine how prefrontal interneurons regulate anxiety-related activity within specific classes of mPFC projection neurons. Together, these studies will elucidate cell-type specific and circuit-level mechanisms underlying the role of hippocampal- prefrontal networks in a commonly studied anxiety behavior. They will also answer general questions about how complex brain circuits operate. E.g., can one source of input differentially transmit emotionally-relevant information to various neuronal subtypes in a downstream target? How do inhibitory interneurons organize their activity in response to a rhythmic input? Do interneurons regulate emotional representations selectively, within specific projection neurons, or nonspecifically, across a network? The answers to these questions will reveal novel targets for disrupting pathological brain states associated with anxiety disorders.

项目摘要/摘要(家长赠款) 海马体(HPC)和前额叶皮质(PFC)与焦虑症有关。在啮齿动物中，腹侧 HPC(VHPC)和内侧PFC(MPFC)形成一个回路，调节高加值患者的焦虑相关行为 迷宫(EPM)。在探测期间，vHPC和mPFC在theta频率(4-12赫兹)范围内同步 焦虑敏感区，干扰vHPC和mPFC之间的通讯阻止小鼠避免 令人焦虑的EPM张开双臂。在这里，我们打算揭示详细的电路相互作用 VHPC和mPFC之间的关系，这对焦虑相关的行为是至关重要的。特别是，我们的初步数据 已经表明，vHPC神经元群体在探索EPM的张开的手臂时被招募， 而抑制vHPC神经元会扰乱开放的手臂回避。然而，目前尚不清楚某些类别的 MPFC神经元优先从vHPC获得与焦虑相关的信息。为了回答这个问题，我们 将研究vHPC神经元，这些神经元投射到mPFC中的特定神经元类别，就像小鼠探索EPM一样。 我们还将研究投射到特定靶点的mPFC神经元，例如基底外侧杏仁核，以 确定他们如何编码与焦虑相关的信息。我们假设mpfc投影的类别 从vHPC接受与焦虑相关的输入的神经元也将编码与焦虑相关的信息。 最后，我们将研究前额叶中间神经元对来自vHPC的theta频率输入的反应和调节 MPFC投射神经元的焦虑相关反应。我们的初步研究表明，特定的 MPFC中的抑制性神经元调节对vHPC输入的前额叶反应，并参与焦虑相关 回避。在这里，我们将检验这一假设，即在EPM中，来自vHPC新兵的theta频率输入 这些中间神经元，从而增强前额叶对来自vHPC的焦虑相关输入的反应 与焦虑相关的回避。具体地说，我们将检查前额叶抑制神经元是否与 在EPM勘探过程中来自vHPC的频率输入。最后，我们将研究前额叶如何 中间神经元在特定类别的mPFC投射神经元中调节与焦虑相关的活动。一起， 这些研究将阐明细胞类型的特异性和电路水平的机制潜在的海马区- 前额叶网络是一种普遍研究的焦虑行为。他们还将回答有关以下方面的一般问题 复杂的大脑回路如何运作。例如，一个输入源能否以不同方式传递与情感相关的信息 下游靶点中不同神经元亚型的信息？抑制性中间神经元是如何组织起来的 它们的活动是对节奏输入的反应吗？中间神经元是否有选择地调节情绪表征， 是在特定的投射神经元内，还是在整个网络上？这些问题的答案将是 揭示扰乱与焦虑症相关的病理大脑状态的新靶点。