Synaptic and circuit mechanisms of fear suppression

项目总结 暴露疗法是最广泛使用的治疗创伤后应激障碍引起的过度恐惧的方法。 还有恐惧症。在暴露治疗期间，患者反复面对恐惧诱导的情况或 在安全环境中对创伤事件的记忆，随着时间的推移，这会减少大多数患者的恐惧。 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(也称为恐惧消退)是如何起作用的。一个大脑 被称为基底外侧杏仁核(BLA)的区域会引起人类和其他哺乳动物更多的恐惧。我们 研究发现，在恐惧消退的过程中，小鼠的血乳酸会发生变化，这可能有助于抑制恐惧。 具体地说，恐惧消退使BLA恐惧神经元沉默，同时改变了定位的抑制性突触 围绕着这些恐惧神经元。来测试这些智齿周抑制性突触的变化是否会导致恐惧 抑制，我们沉默了小白蛋白阳性(PV+)中间神经元，使这些周围性抑制 突触。这增加了BLA恐惧神经元的激活和恐惧的表达。此外，它还 改变了大脑BLA外称为内侧前额叶皮质的脑区神经元的激活 (Mpfc)。最后，沉默BLA内的PV+中间神经元改变了局域场的频率分布 BLA和mPFC的电位(LFP)振荡，表明神经元的激活发生了广泛的变化 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，在这个模型中， 灭绝通过增加PV+椎体周围突触抑制BLA恐惧神经元的能力来减少恐惧， 从而为抑制恐惧的电路提供了相对于促进恐惧的电路的竞争优势。三个目标 这一建议将检验这一模型是否正确。目标1是确定PV+口周的贡献 在BLA中突触重塑以灭绝诱导的恐惧抑制。为达致这个目标，我们会监察 在恐惧抑制停止工作的条件下，PV+颧骨周围突触的强度 在恐惧消退期间操纵脑源性神经营养因子信号，这被预测为 干扰灭绝诱导的突触周围重塑。目标2是本地化和操控 在消退诱导的恐惧抑制期间，大脑皮层中的功能相反的LFP振荡。为了实现这一目标， 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 调节BLA PV+中间神经元对消退诱导的恐惧抑制的贡献的神经回路。 这将通过分析和操纵到mPFC的两个细分的BLA投影路径来实现。 这一建议的完成可以确定BLA PV+中间神经元在调节 在恐惧消退之后，一个促进恐惧的回路和一个抑制恐惧的回路，这将有助于解释这一理论 为过度恐惧的患者设计新的更有效的治疗方法。

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.