Dissection of the anxiety suppression circuitry

4R00MH106649-03 PI：阿维谢克·阿迪卡里 修改后的项目摘要/摘要部分 这项建议将从导师阶段机构(斯坦福大学)转移到R00机构(加州大学洛杉矶分校)。实验计划没有任何变化。目前的建议是针对R00阶段的。避免潜在威胁是高度适应性的，并减少了风险暴露。然而，过度的焦虑和恐惧会导致焦虑症，这会影响到生活的许多方面，从人际关系到职业领域。虽然每种焦虑症都有不同的症状，但它们都有一个核心特征：高度焦虑的自我适应表达。在这里，我们将研究大脑如何抑制焦虑。先前的研究表明，杏仁核在很大程度上是产生高度焦虑和恐惧的原因，而腹侧内侧前额叶皮质(VmPFC)可能通过抑制杏仁核的输出来减少这些行为。事实上，在人类中，较高的vmPFC激活与较低的杏仁核激活和较低的焦虑程度相关。这些数据表明，vmPFC-杏仁核通路可能会减少焦虑和恐惧，但他们依赖于相关的测量方法，不能直接检验这一假设。我使用光遗传学来直接测试vmPFC-杏仁核投射是否抑制焦虑和恐惧。VmPFCamygdala通路的激活有力地抑制了先天焦虑和后天恐惧，而抑制这一通路则增加了焦虑。有趣的是，这些行为效应是由杏仁核中一个研究较少的区域杏仁内侧核(BMA)介导的，因为BMA的直接激活也可以减少焦虑。现在，我将绘制vmPFC-BMA回路中的神经活动图，并剖析该回路的激活如何降低焦虑。我们首先展示了vmPFC活动如何影响体外的BMA(目标1)，揭示了我们行为发现背后的微电路水平的动力学。接下来，为了绘制vmPFC-BMA投射的活动图，我将在探索控制和焦虑环境(目标2)的过程中监测BMA中vmPFC终末的钙瞬变，揭示该投射在高焦虑和低焦虑动物中的活动差异。在目标3中，我将描述BMA的活动及其在焦虑和恐惧期间的产出预测。这个项目所产生的洞察力将指导未来对焦虑的研究。

4R00MH106649-03 PI: Avishek Adhikari Modified Project Summary/Abstract Section This proposal will be moved from the mentored phase institution (Stanford University) to the R00 institution (University of California, Los Angeles). No changes have been made to the experimental plans. The current proposal is specific to the R00 phase. Avoidance of potential threats is highly adaptive, and decreases exposure to risks. However, excessive anxiety and fear leads to anxiety disorders, which impact many aspects of life, from the interpersonal to professional spheres. Although each anxiety disorder has different symptoms, they all share a core feature: mal-adaptive expression of high levels anxiety. Here, we will study how the brain suppresses anxiety. Prior studies showed the amygdala is largely responsible for generating high anxiety and fear, while the ventral medial prefrontal cortex (vmPFC) decreases these behaviors, possibly by inhibiting amygdala output. Indeed, in humans higher vmPFC activation correlates with lower amygdala activation and decreased anxiety. These data suggest the vmPFC-amygdala pathway may decrease anxiety and fear, but they rely on correlative measures, and can't directly test this hypothesis. I used optogenetics to directly test if the vmPFC-amygdala projection suppresses anxiety and fear. Activation of the vmPFCamygdala pathway robustly inhibits innate anxiety and learned fear, while inhibition of this pathway increases anxiety. Intriguingly, these behavioral effects were mediated by a poorly studied region of the amygdala called the basomedial amygdala (BMA), as direct activation of the BMA also decreases anxiety. Now, I will map neural activity in the vmPFC-BMA circuit and dissect how activation of this circuit decreases anxiety. We first showed how vmPFC activity affects the BMA in vitro (Aim 1), uncovering the microcircuit-level dynamics underlying our behavioral findings. Next, to map the activity of the vmPFC-BMA projection, I will monitor calcium transients in the vmPFC terminals in the BMA during exploration of control and anxiogenic environments (Aim 2), revealing how activity of this projection differs in animals with high and low anxiety. In Aim 3, I will characterize activity of the BMA and of its output projections during anxiety and fear. The insights resulting from this project will guide future studies on anxiety.