权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Prefrontal circuit mechanisms of threat conditioning

威胁条件反射的前额回路机制

基本信息

批准号：
10332742
负责人：
Roger L Clem
金额：
$ 42.12万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10332742
关键词：
Address Amygdaloid structure Animals Area Attenuated Auditory Axon Behavior Behavioral Brain Brain region Calcium Cells Chemosensitization Complex Conditioned Stimulus Cre driver Data Desire for food Disease Disinhibition Dorsal Electrophysiology (science)Emotional Exhibits Extinction (Psychology)Freezing Fright Genetic Genetic Recombination Goals Human Hyperactivity Image Interneurons Investigation Label Learning Medial Mediating Memory Modeling Modification Mood Disorders Mus Neuronal Plasticity Neurons Nucleus Accumbens Output Panic Panic Disorder Parvalbumins Pathologic Peptides Phobias Population Post-Traumatic Stress Disorders Prefrontal Cortex Process Recruitment Activity Reporting Research Rodent Role Signal Transduction Slice Somatostatin Source Stimulus Synapses Synaptic Transmission Synaptic plasticity System Techniques Testing Thalamic structure Time Viral Work base behavioral outcome behavioral response classical conditioning conditioned fear conditioning emotion dysregulation emotional reaction excitatory neuron experience experimental study improved in vivo microendoscope midbrain central gray substance neglect neocortical neural circuit optogenetics recruit stimulus processing transmission process

项目摘要

Psychiatric conditions such as phobia, panic and post-traumatic stress disorder (PTSD) are associated with heightened fear-related behavior. This has been attributed in part to increased acquisition and expression of threat memory, which occurs when an innocuous stimulus encountered under threatening circumstances becomes a potent trigger for defensive emotional reactions. Research indicates that this form of memory engages the prelimbic cortex, a rodent brain region that is analogous to an area of pathological hyperactivity in the human medial prefrontal cortex (mPFC). Prelimbic excitatory neurons are thought to mediate memory expression by signaling to key downstream brain regions. However, the circuit and synaptic mechanisms underlying memory-specific recruitment of these cells remain poorly understood. The purpose of this project is to identify prelimbic synaptic changes associated with threat memory formation in mice, to elucidate the role of neural circuits where these modifications occur, and to define specific prelimbic output connections that mediate threat-related behaviors. Based on preliminary experiments, this work will focus sparse populations of inhibitory interneurons that express the peptide marker somatostatin and exhibit increased excitatory synaptic activity after threat learning. Our central hypothesis is that these cells undergo an increase in stimulus-related activity after learning and that they function to suppress parvalbumin-containing interneurons and thereby relieve a major brake on excitatory neuronal firing. In Aim 1, we will use brain slice electrophysiology to examine synapses mediating elevated activity of somatostatin interneurons as well as their interaction with parvalbumin interneurons. In Aim 2, we will use optogenetics and calcium-based imaging in freely behaving animals to test the role of somatostatin and parvalbumin interneurons in threat memory expression. Finally, in Aim 3, we will identify specific excitatory populations mediating behavioral outcomes of somatostatin interneuron manipulations as well as establish downstream brain regions to which these neurons provide synaptic input. This project represents the first attempt to establish how emotional learning alters complex inhibitory stimulus processing to support mPFC memory functions, and will identify potential targets for attenuating pathological activity and associated behaviors.

恐惧症、惊恐症和创伤后应激障碍 (PTSD) 等精神疾病与与恐惧相关的行为加剧。这部分归因于增加的获取和表达威胁记忆，当在威胁情况下遇到无害刺激时就会发生成为防御性情绪反应的有效触发因素。研究表明，这种形式的记忆参与前边缘皮层，这是一个啮齿类动物的大脑区域，类似于病理性过度活跃的区域人类内侧前额皮质（mPFC）。前边缘兴奋性神经元被认为可以调节记忆通过向关键下游大脑区域发出信号来表达。然而，电路和突触机制这些细胞的潜在记忆特异性募集仍然知之甚少。该项目的目的是识别与小鼠威胁记忆形成相关的前突触变化，阐明发生这些修改的神经回路，并定义特定的前边缘输出连接调解与威胁相关的行为。基于初步实验，这项工作将重点关注稀疏种群表达肽标记生长抑素并表现出兴奋性突触增加的抑制性中间神经元威胁学习后的活动。我们的中心假设是这些细胞经历与刺激相关的增加学习后的活动，并且它们的功能是抑制含有小清蛋白的中间神经元，从而缓解兴奋性神经元放电的主要抑制。在目标 1 中，我们将使用脑切片电生理学来检查介导生长抑素中间神经元活性升高的突触及其与小清蛋白中间神经元。在目标 2 中，我们将使用光遗传学和基于钙的成像来自由行为动物测试生长抑素和小白蛋白中间神经元在威胁记忆表达中的作用。最后，在目标 3，我们将确定介导生长抑素行为结果的特定兴奋人群中间神经元操作以及建立这些神经元提供的下游大脑区域突触输入。该项目是首次尝试确定情绪学习如何改变复杂的情绪抑制刺激处理以支持 mPFC 记忆功能，并将识别潜在目标减轻病理活动和相关行为。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GABAergic microcircuitry of fear memory encoding.

DOI：
10.1016/j.nlm.2021.107504
发表时间：
2021-10
期刊：
Neurobiology of learning and memory
影响因子：
2.7
作者：
Cummings KA;Lacagnina AF;Clem RL
通讯作者：
Clem RL

Control of fear by discrete prefrontal GABAergic populations encoding valence-specific information.

DOI：
10.1016/j.neuron.2022.07.004
发表时间：
2022-09-21
期刊：
NEURON
影响因子：
16.2
作者：
Cummings, Kirstie A.;Bayshtok, Sabina;Dong, Tri N.;Kenny, Paul J.;Clem, Roger L.
通讯作者：
Clem, Roger L.

GABAergic interneurons: The orchestra or the conductor in fear learning and memory?