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: 10415032
• 负责人: Mazen A Kheirbek
• 金额: $ 51.39万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415032
• 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.

海马体（HPC）和前额叶皮层（PFC）与焦虑症有关。在啮齿类动物中， HPC（vHPC）和内侧PFC（mPFC）形成一个回路，调节焦虑相关的行为，在升高的正 迷宫（maze）。在探测期间，vHPC和mPFC在θ频率（4-12 Hz）范围内同步， 焦虑区域，并破坏vHPC和mPFC之间的通信，防止小鼠避免 美国人张开的令人焦虑的双臂。在这里，我们建议揭示详细的电路相互作用 vHPC和mPFC之间的联系，这对焦虑相关行为至关重要。特别是，我们的初步数据 已经表明vHPC神经元的群体在探索小脑中的开放臂期间被招募， 并且抑制vHPC神经元破坏开臂回避。然而，目前尚不清楚某些类别的 mPFC神经元优先获得来自vHPC的焦虑相关输入。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中的特定类别的神经元，正如小鼠探索的那样。 我们还将研究投射到特定目标的mPFC神经元，例如，基底外侧杏仁核， 确定他们如何编码焦虑相关信息。我们假设mPFC投射的类别 从vHPC接收焦虑相关输入的神经元也将编码焦虑相关信息。 最后，我们将研究前额叶中间神经元如何对来自vHPC的θ频率输入做出反应并调节 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前额叶对vHPC输入的反应，并有助于焦虑相关的 回避在此，我们将检验以下假设：在VHP中，来自vHPC新兵的θ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， 焦虑相关的回避具体来说，我们将研究前额叶抑制神经元是否同步， θ频率输入的vHPC在探索的过程中，最后，我们将研究前额叶 中间神经元调节特定类别的mPFC投射神经元内的焦虑相关活动。在一起， 这些研究将阐明海马神经元作用的细胞类型特异性和回路水平机制， 前额叶网络在焦虑行为中的作用他们还将回答有关以下方面的一般问题： 复杂的大脑回路是如何运作的例如，在一个示例中，一个输入源是否可以不同地传输情感相关的 下游靶点中的各种神经元亚型的信息？抑制性中间神经元如何组织 他们对有节奏的输入的反应中间神经元是否选择性地调节情绪表征， 在特定的投射神经元内，或者非特定地，通过网络？这些问题的答案将 揭示了破坏与焦虑症相关的病理性大脑状态的新靶点。