Synaptic and circuit mechanisms of fear suppression

恐惧抑制的突触和回路机制

• 批准号: 10571102
• 负责人: Leon Reijmers
• 金额: $ 56.23万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-05 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10571102
• 关键词: Agreement; Amygdaloid structure; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Brain; Brain region; Conflict (Psychology); Development; Emotions; Exploratory Behavior; Extinction (Psychology); Face; Freezing; Fright; Goals; Hippocampus (Brain); Human; Medial; Memory; Modeling; Mus; Neurons; Output; Pathway interactions; Patients; Pattern; Perception; Phase; Prefrontal Cortex; Resolution; Retrieval; Route; Safety; Testing; base; conditioned fear; design; experience; experimental study; fear memory; insight; memory retrieval; millisecond; neural circuit; novel; novel therapeutics; rational design; recruit; response

Fear behavior, also known as defensive behavior, promotes survival when it is rapidly deployed in response to perceived danger. The perception of danger is informed by previous experiences in similar situations. When these previous experiences are heterogeneous, with some associated with danger and others with safety, the brain faces the computational challenge of simultaneously retrieving conflicting memories of similar situations, rapidly weighing them against the current situation, and immediately deploying a fear response if deemed necessary. A possible solution for this computational challenge is provided by oscillatory activity, which can rapidly promote and gate information flow through neural circuits. Accordingly, experience-dependent fear behavior correlates with various patterns of oscillatory activity in limbic brain regions. Which of these correlations reflect causal contributions of oscillatory activity, and how these contributions are enacted, remains unclear. The goal of this proposal is to gain a mechanistic understanding of how two different patterns of oscillatory activity promote the retrieval of two competing memories of the same context, one associated with danger and the other with safety. The hypotheses tested under this proposal are based on a working model in which two mutually exclusive oscillatory states control information flow through parallel limbic circuits that connect the basolateral amygdala (BLA), the medial prefrontal cortex (mPFC), and the ventral hippocampus (vHIP). Mice will be subjected to consecutive fear conditioning and extinction trials in the same context. This paradigm leads to spontaneous alternation of freezing and exploratory behavior in this context, reflecting competing fear and extinction memories. The retrieval of the fear memory is promoted by one pattern of oscillatory activity in the BLA, while the retrieval of the extinction memory is promoted by a different pattern of oscillatory activity in the BLA. The first aim will test the hypothesis that the two different BLA oscillations synergistically interact with two different BLA engrams, thereby promoting the retrieval of the two memories. For this, fear engram neurons and extinction engram neurons in the BLA will be recorded or manipulated. The second aim will test the hypothesis that different BLA oscillations recruit different mPFC neurons in an experience-dependent manner. For this, functionally defined mPFC neurons will be recorded or manipulated. The third aim will test the hypothesis that the BLA controls parallel vHIP-mPFC pathways during fear and extinction memory retrieval. Neurons in the vHIP that project to the mPFC will be recorded or manipulated during manipulations of BLA activity, oscillations, or engram neurons. Combined, these aims study synergistic relationships between oscillatory activity and engram neurons, thereby increasing the mechanistic understanding of how limbic circuits can rapidly and appropriately deploy, or suppress, experience-dependent fear behavior. This increased mechanistic understanding will facilitate the rational design of novel therapeutic treatments for excessive fear that use targeted induction of oscillatory activity patterns.

恐惧行为，也被称为防御行为，当它被迅速部署以应对 感知危险对危险的感知来自以前在类似情况下的经验。当 这些先前的经历是异质的，有些与危险有关，有些与安全有关， 面临着同时快速检索相似情况的冲突记忆的计算挑战， 将它们与当前形势进行权衡，并在认为必要时立即部署恐惧反应。一 这种计算挑战的可能解决方案是由振荡活动提供的，它可以迅速促进 并通过神经回路控制信息流。因此，经验依赖性恐惧行为与 大脑边缘区域的振荡活动模式各不相同这些相关性中哪一个反映了 振荡活动的贡献，以及这些贡献是如何制定的，仍然不清楚。这个目标 建议是获得一个机械的理解，如何两种不同的模式的振荡活动，促进 在同一个情境中，两个相互竞争的记忆被提取出来，一个与危险有关，另一个与安全有关。 根据这一建议进行的假设测试是基于一个工作模型，其中两个相互排斥的 振荡状态控制着通过连接基底外侧杏仁核的平行边缘回路的信息流 (BLA)内侧前额叶皮层（mPFC）和腹侧海马（vHIP）。小鼠将接受 在相同的背景下连续的恐惧条件反射和灭绝试验。这种模式导致自发的 在这种情况下，冻结和探索行为的交替，反映了竞争的恐惧和灭绝 回忆BLA中的一种振荡活动模式促进了恐惧记忆的恢复， 消退记忆的恢复是由BLA中不同的振荡活动模式促进的。的 第一个目标将测试两种不同的BLA振荡与两种不同的BLA振荡协同相互作用的假设。 BLA痕迹，从而促进两个记忆的检索。为此，恐惧给神经元留下印记， 将记录或操纵BLA中的印迹神经元。第二个目标将检验假设， 不同的BLA振荡以经验依赖的方式募集不同的mPFC神经元。为此， 将记录或操纵功能上限定的mPFC神经元。第三个目标将检验以下假设： BLA在恐惧和消退记忆提取期间控制平行的vHIP-mPFC通路。神经元 投射到mPFC的vHIP将在BLA活性的操纵期间被记录或操纵， 振荡或记忆印记神经元。结合起来，这些目标研究振荡之间的协同关系， 活动和记忆神经元，从而增加了边缘回路如何 快速和适当地部署，或抑制，经验依赖的恐惧行为。这增加了机械性 理解将有助于合理设计新的治疗方法， 定向诱导振荡活动模式。