Synaptic and circuit mechanisms of fear suppression

恐惧抑制的突触和回路机制

基本信息

  • 批准号:
    10196952
  • 负责人:
  • 金额:
    $ 41.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-08-05 至 2022-05-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Exposure therapy is the most widely used treatment for excessive fear caused by post-traumatic stress disorder and phobias. During exposure therapy the patient repeatedly confronts the fear-inducing situation or the memory of a traumatic event in a safe environment, which over time results in decreased fear in most patients. However, exposure therapy in its current form rarely leads to a permanent suppression of fear. A better understanding of how exposure therapy, also known as fear extinction, works is therefore needed. A brain region called the basolateral amygdala (BLA) can cause increased fear in both humans and other mammals. We found that the BLA of mice undergoes changes during fear extinction that might help to suppress fear. Specifically, fear extinction silenced BLA fear neurons, while changing the inhibitory synapses that are located around these fear neurons. To test if these changes in perisomatic inhibitory synapses contribute to fear suppression, we silenced the parvalbumin-positive (PV+) interneurons that make these perisomatic inhibitory synapses. This increased the activation of BLA fear neurons and the expression of fear. Furthermore, it changed the activation of neurons in a brain region outside of the BLA called the medial prefrontal cortex (mPFC). Finally, silencing PV+ interneurons in the BLA altered the frequency distribution of local field potential (LFP) oscillations in both the BLA and mPFC, indicating broad changes in the activation of neuronal circuits that connect these two brain regions. Based on these results, we formulated a model in which extinction decreases fear by increasing the ability of PV+ perisomatic synapses to inhibit BLA fear neurons, thereby giving fear-suppressing circuits a competitive advantage over fear-promoting circuits. The three aims of this proposal will test if this model is correct. Aim 1 is to determine the contribution of PV+ perisomatic synapse remodeling in the BLA to extinction-induced fear suppression. To achieve this, we will monitor the strength of PV+ perisomatic synapses under conditions when fear suppression stops working, and by manipulating brain-derived neurotrophic factor signaling during fear extinction, which is predicted to interfere with extinction-induced perisomatic synapse remodeling. Aim 2 is to localize and manipulate functionally opposed LFP oscillations in the BLA during extinction-induced fear suppression. To achieve this, we will manipulate the activation state of three types of BLA neurons (PV+ interneurons, fear neurons, extinction neurons), while measuring both LFP oscillations and fear behavior. Aim 3 is to identify downstream neural circuits that mediate the contribution of BLA PV+ interneurons to extinction-induced fear suppression. This will be achieved by analyzing and manipulating BLA projection pathways to two subdivisions of the mPFC. Completion of this proposal can identify a critical role for BLA PV+ interneurons in tuning the balance between a fear-promoting circuit and a fear-suppressing circuit following fear extinction, which would aid the rationale design of new and more effective treatments for patients suffering from excessive fear.
项目摘要 暴露疗法是治疗创伤后应激障碍引起的过度恐惧最广泛使用的疗法 和恐惧症在暴露疗法期间,患者反复面对引起恐惧的情况或 在安全的环境中记忆创伤事件,随着时间的推移,大多数患者的恐惧感会减少。 然而,目前形式的暴露疗法很少能永久抑制恐惧。更好的 因此,需要了解暴露疗法,也称为恐惧消除,是如何工作的。脑 一个叫做基底外侧杏仁核(BLA)的区域会导致人类和其他哺乳动物的恐惧增加。我们 发现老鼠的BLA在恐惧消退过程中发生变化,这可能有助于抑制恐惧。 具体来说,恐惧消退使BLA恐惧神经元沉默,同时改变了位于BLA的抑制性突触。 围绕着这些恐惧神经元。为了测试这些体周抑制性突触的变化是否有助于恐惧 抑制,我们沉默了小清蛋白阳性(PV+)的中间神经元,使这些体周抑制 突触这增加了BLA恐惧神经元的激活和恐惧的表达。而且 改变了BLA之外的大脑区域(称为内侧前额叶皮层)的神经元激活 (mPFC)。最后,沉默BLA中的PV+中间神经元改变了局部场的频率分布 BLA和mPFC中的电位(LFP)振荡,表明神经元激活的广泛变化 连接这两个大脑区域的回路基于这些结果,我们建立了一个模型, 消退通过增加PV+体周突触抑制BLA恐惧神经元的能力来减少恐惧, 从而给予恐惧抑制电路相对于恐惧促进电路的竞争优势。三个目标 这份报告将检验这个模型是否正确。目的1是确定PV+细胞外基质的贡献, BLA中的突触重塑对预防引起的恐惧抑制的影响。为此,我们会监察 当恐惧抑制停止工作时,PV+体周突触的强度, 在恐惧消退过程中操纵脑源性神经营养因子信号,据预测, 干扰抑制诱导的体周突触重塑。目标2是定位和操作 功能上相反的LFP振荡在BLA在预防引起的恐惧抑制。为了实现这一点, 我们将操纵三种类型的BLA神经元(PV+中间神经元,恐惧神经元, 灭绝神经元),同时测量LFP振荡和恐惧行为。目标3是确定下游 介导BLA PV+中间神经元对恐惧诱导的恐惧抑制的贡献的神经回路。 这将通过分析和操纵BLA投射途径至mPFC的两个分区来实现。 完成这一提议可以确定BLA PV+中间神经元在调节以下平衡中的关键作用: 在恐惧消退之后,一个恐惧促进回路和一个恐惧抑制回路,这将有助于理论基础 为患有过度恐惧症的患者设计新的和更有效的治疗方法。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Functional Characterization of the Basal Amygdala-Dorsal BNST Pathway during Contextual Fear Conditioning.
情境恐惧调节过程中基底杏仁核-背侧 BNST 通路的功能特征。
  • DOI:
    10.1523/eneuro.0163-20.2020
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    SasakiRussell,Jennifer;Trouche,Stéphanie;Reijmers,LeonG
  • 通讯作者:
    Reijmers,LeonG
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Leon Reijmers其他文献

Leon Reijmers的其他文献

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{{ truncateString('Leon Reijmers', 18)}}的其他基金

Role of cholecystokinin-expressing interneurons in the oscillatory control of experience-dependent fear behavior
表达胆囊收缩素的中间神经元在经验依赖性恐惧行为的振荡控制中的作用
  • 批准号:
    10348491
  • 财政年份:
    2022
  • 资助金额:
    $ 41.25万
  • 项目类别:
Role of cholecystokinin-expressing interneurons in the oscillatory control of experience-dependent fear behavior
表达胆囊收缩素的中间神经元在经验依赖性恐惧行为的振荡控制中的作用
  • 批准号:
    10629152
  • 财政年份:
    2022
  • 资助金额:
    $ 41.25万
  • 项目类别:
Synaptic and circuit mechanisms of fear suppression
恐惧抑制的突触和回路机制
  • 批准号:
    10571102
  • 财政年份:
    2017
  • 资助金额:
    $ 41.25万
  • 项目类别:
Synaptic and circuit mechanisms of fear suppression
恐惧抑制的突触和回路机制
  • 批准号:
    9380135
  • 财政年份:
    2017
  • 资助金额:
    $ 41.25万
  • 项目类别:
Memory-Related Protein Synthesis in Alzheimer's Disease Mouse Models
阿尔茨海默病小鼠模型中记忆相关的蛋白质合成
  • 批准号:
    9143038
  • 财政年份:
    2015
  • 资助金额:
    $ 41.25万
  • 项目类别:
Memory-Related Protein Synthesis in Alzheimer's Disease Mouse Models
阿尔茨海默病小鼠模型中记忆相关的蛋白质合成
  • 批准号:
    8975046
  • 财政年份:
    2015
  • 资助金额:
    $ 41.25万
  • 项目类别:
Tools for genome-wide profiling of mRNA translated in in-vivo dendrites
对体内树突中翻译的 mRNA 进行全基因组分析的工具
  • 批准号:
    8541890
  • 财政年份:
    2012
  • 资助金额:
    $ 41.25万
  • 项目类别:
Tools for genome-wide profiling of mRNA translated in in-vivo dendrites
对体内树突中翻译的 mRNA 进行全基因组分析的工具
  • 批准号:
    8459664
  • 财政年份:
    2012
  • 资助金额:
    $ 41.25万
  • 项目类别:
Molecular Analysis of Functional Neural Circuits
功能神经回路的分子分析
  • 批准号:
    7847362
  • 财政年份:
    2009
  • 资助金额:
    $ 41.25万
  • 项目类别:
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