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: 9764736
• 负责人: Mazen A Kheirbek
• 金额: $ 54.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-03 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764736
• 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; prevent; recruit; relating to nervous system; response; transmission process; voltage

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.

海马（HPC）和前额叶皮层（PFC）与焦虑症有关。在啮齿动物中，腹侧 HPC（VHPC）和内侧PFC（MPFC）形成了调节高架焦虑相关行为的电路 迷宫（EPM）。在探索期间，VHPC和MPFC在theta频率（4-12 Hz）范围内同步 焦虑的区域以及破坏VHPC和MPFC之间的沟通可防止小鼠避免 EPM发人深省的张开双臂。在这里，我们建议揭示详细的电路相互作用 在VHPC和MPFC之间对于与焦虑相关的行为至关重要。特别是我们的初步数据 已经表明，在探索EPM中的张开臂时，招募了VHPC神经元的种群， 抑制VHPC神经元会破坏敞开的手臂避免。但是，尚不知道某些类别是否 MPFC神经元优先访问VHPC的焦虑相关输入。要回答这个问题，我们 当小鼠探索EPM时，将研究将VHPC神经元投射到MPFC中特定类别的神经元。 我们还将研究针对特定靶标的MPFC神经元，例如基底外侧杏仁核 确定它们如何编码与焦虑有关的信息。我们假设MPFC投影类 从VHPC接收焦虑相关的神经元也将编码与焦虑有关的信息。 最后，我们将研究前额叶中间神经元如何响应VHPC的theta频率输入并调节 MPFC投射神经元的焦虑相关反应。我们的初步研究表明 MPFC中的抑制性神经元调节对VHPC输入的前额叶反应，并有助于与焦虑有关 避免。在这里，我们将测试以下假设：在EPM中，来自VHPC新兵的theta频率输入 这些中间神经元，从而增强了对VHPC的焦虑相关输入的前额叶反应 与焦虑有关的回避。具体而言，我们将检查前额叶抑制性神经元是否同步 EPM探索过程中VHPC的theta频率输入。最后，我们将研究前额叶 神经元调节特定类别MPFC投射神经元中与焦虑相关的活性。一起， 这些研究将阐明海马 - 常见研究的焦虑行为中的前额叶网络。他们还将回答有关的一般问题 脑电路的复杂程度如何。例如，输入的一个来源可以差异传递情感上的传播 向下游目标中各种神经元亚型的信息信息？抑制性中间神经元如何组织 他们对节奏输入的活性？在选择性地调节情绪表征， 在特定的投影神经元中，或者是非特定于网络的？这些问题的答案将 揭示了破坏与焦虑症相关的病理大脑状态的新颖目标。