Role of VTA-Amygdala Neural Circuit in Mediating Anxiety-Related Behaviors

项目总结 焦虑症是困扰全球2.73亿人的最常见的精神疾病。这个 焦虑症的症状非常复杂，其原因也鲜为人知。此外，一个 相当数量的焦虑症患者也出现了抑郁样症状， 这使得诊断和治疗变得更加复杂。在这个项目中，我们建议利用 导致焦虑或焦虑/抑郁混合表型的重复社会失败应激(RSD)模型 在不同的小鼠亚组中研究调节这些行为的神经机制。跟随 RSD，小鼠根据它们的社交互动测试行为被分为两个亚组： 显示回避的小鼠(易感)和不显示回避的小鼠(有弹性)。虽然易受影响 老鼠表现出几种与抑郁相关的行为，包括社交回避、快感缺失和绝望， 这些抑郁的异常在有弹性的小鼠身上是不存在的。然而，RSD会引起严重的焦虑 在易感和有弹性的小鼠中的行为。因此，在这个项目中，我们将他们标记为焦虑/抑郁 (A/D)和焦虑(A)亚组。越来越多的研究表明， 焦虑和抑郁中的中皮质边缘腹侧被盖区(VTA)和多巴胺(DA)奖赏回路。 利用神经回路探测技术，我们以前观察到发生了不适应的放电活动 投射到前额内侧皮质的VTA-mPFC神经元和VTA DA神经元 选择性地投射到伏核(VTA-NAC)在A/D小鼠(抑郁症易感小鼠)，但 而A系小鼠(耐抑郁组)则不是这样。我们的光遗传学研究进一步证明了 这些回路中的放电不适应与抑郁相关的行为之间存在联系。然而，我们 惊人地发现，投射到杏仁核的VTA神经元的放电活动是 在A/D小鼠和A小鼠中均显著降低。基于这些意想不到的初步发现，我们的 中心假说是VTA-AMG环路可能在调节焦虑症样反应中起关键作用 在A/D小鼠和A小鼠中观察到了RSD后的行为。为了测试这一点，我们提出了两个具体的 目的：(A)研究A/D和A-雄大鼠VTA-AMG DA环神经元的病理变化。 雌性小鼠，采用体外脑片制备和完整动物体内光电极记录； 以及(B)确定VTA-AMGDA神经元在调节RSD诱导的焦虑中的功能作用 通过光遗传操作这些电路在雄性和雌性小鼠中的行为。通过利用这些细胞 类型和电路特定的电生理和光遗传技术，我们将确定原因 VTA-AMG DA环路神经元活动与焦虑相关行为有关。

PROJECT SUMMARY Anxiety disorders are the most common psychiatric illness afflicting 273 million people worldwide. The symptoms of anxiety disorders are highly complex and the causes are poorly understood. Additionally, a substantial number of patients suffering from anxiety disorders also present with depressive-like symptoms, which make the diagnosis and treatment even more complicated. In this project, we propose to utilize the repeated social defeat stress (RSDS) model that induces anxiety or mixed anxiety/depression phenotypes in separate subgroups of mice to investigate neural mechanisms regulating these behaviors. Following RSDS, mice are separated into two subgroups based on their social interaction test behavior: profound avoidance-displaying mice (susceptible) and non-avoidance-displaying mice (resilient). While susceptible mice display several depression-related behaviors, including social avoidance, anhedonia and despair, these depressive abnormalities are absent in resilient mice. However, RSDS induces severe anxiety behaviors in both susceptible and resilient mice. Thus, in this project, we label them as anxiety/depression (A/D) and anxiety (A) subgroups. An increasing number of studies have implicated the role of mesocorticolimbic ventral tegmental area (VTA) dopamine (DA) reward circuitry in anxiety and depression. Utilizing neural circuit-probing techniques, we previously observed that maladaptive firing activity occurred in the VTA DA neurons projecting to the medial prefront cortex (VTA-mPFC) and VTA DA neurons projecting to the nucleus accumbens (VTA-NAc) selectively in A/D mice (depression-susceptible mice), but not in the A-mice (the depression-resilient group). Our optogenetic studies further demonstrated the causal link between the firing maladaptations in these circuits and depression-related behaviors. However, we strikingly found that the firing activity of VTA neurons projecting to the amygdala (VTA-Amg) was dramatically decreased in both A/D- and A-mice. Based on these unexpected preliminary findings, our central hypothesis is that the VTA-Amg circuit may play a crucial role in mediating the anxiety-like behaviors observed in both A/D- and A-mice following RSDS. To test this, we propose two Specific Aims: (a) to investigate the pathological alterations of VTA-Amg DA circuit neurons in A/D- and A-male and female mice by use of ex vivo brain slice preparation and in vivo optrode recordings from intact animals; and (b) to determine the functional role of VTA-Amg DA neurons in mediating RSDS-induced anxiety behaviors by optogenetically manipulating these circuits in male and female mice. By utilizing these cell type- and circuit-specific electrophysiological and optogenetic techniques, we will determine if a causal relationship exists between the neuronal activity of VTA-Amg DA circuit and anxiety-related behaviors.