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，恐慌和创伤后应激障碍（PTSD）等精神病疾病与与恐惧相关的行为提高。这部分归因于增加的获取和表达威胁记忆，这发生在威胁情况下遇到的无害刺激成为防御性情绪反应的有效触发因素。研究表明这种记忆形式参与前比皮层，这是一种类似于病理多动症区域的啮齿动物脑区域人内侧前额叶皮层（MPFC）。序前兴奋性神经元被认为可以介导记忆通过向钥匙下游大脑区域发出信号来表达。但是，电路和突触机制这些细胞的基本记忆特异性募集仍然知之甚少。这个项目的目的是识别与小鼠威胁记忆形成相关的前缘突触变化，以阐明发生这些修饰的神经回路，并定义特定的前临界输出连接调解与威胁有关的行为。基于初步实验，这项工作将集中于稀疏人群表达肽标志物生长抑素并表现出增加兴奋性突触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了与刺激相关的增加学习后的活动，并且它们起作用以抑制含白蛋白白蛋白的中间神经元，从而缓解兴奋性神经元发射的重大刹车。在AIM 1中，我们将使用大脑切片电生理学检查介导生长抑素中间神经元活动升高的突触以及它们与白蛋白中间神经元。在AIM 2中，我们将在自由行为中使用光遗传学和基于钙的成像动物测试生长抑素和白蛋白中间神经元在威胁记忆表达中的作用。最后，在 AIM 3，我们将确定介导生长抑制素行为结果的特定兴奋种群这些神经元提供的内神经元操纵以及建立下游大脑区域突触输入。该项目代表了建立情感学习如何改变复杂的首次尝试抑制性刺激处理以支持MPFC内存功能，并将确定减弱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?

DOI：
10.1016/j.brainresbull.2017.11.016
发表时间：
2018-07
期刊：
Brain research bulletin
影响因子：
3.8
作者：
Lucas EK;Clem RL
通讯作者：
Clem RL

GABAergic basal forebrain projections to the periaqueductal gray promote food consumption, reward and predation.

DOI：
10.1038/s41598-021-02157-7
发表时间：
2021-11-22
期刊：
Scientific reports
影响因子：
4.6
作者：
Roman-Ortiz C;Guevara JA;Clem RL
通讯作者：
Clem RL

Ventral hippocampal interneurons govern extinction and relapse of contextual associations.

腹侧海马中间神经元控制情境关联的消失和复发。

DOI：
10.1101/2023.11.28.568835
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Lacagnina,AnthonyF;Dong,TriN;Iyer,RasikaR;Khan,Saqib;Mohamed,MazenK;Clem,RogerL
通讯作者：
Clem,RogerL