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

项目摘要 焦虑症是最常见的精神疾病，困扰着全球2.73亿人。的 焦虑症的症状非常复杂，其原因也知之甚少。此外， 大量患有焦虑症的患者也表现出抑郁样症状， 这使得诊断和治疗更加复杂。在这个项目中，我们建议利用 重复社交失败压力（RSDS）模型，诱导焦虑或混合焦虑/抑郁表型 在不同的小鼠亚组中研究调节这些行为的神经机制。以下 根据RSDS，基于小鼠的社会互动测试行为将小鼠分成两个亚组： 回避显示小鼠（易感）和非回避显示小鼠（恢复性）。虽然易受影响 小鼠表现出几种与抑郁症相关的行为，包括社交回避、快感缺乏和绝望， 这些抑郁性异常在有弹性的小鼠中不存在。然而，RSDS引起严重的焦虑 在敏感和有弹性的小鼠中的行为。因此，在这个项目中，我们将其标记为焦虑/抑郁 （A/D）和焦虑（A）亚组。越来越多的研究表明， 焦虑和抑郁中皮质边缘腹侧被盖区（VTA）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， 腹侧被盖区投射到内侧前皮质的DA能神经元（VTA-mPFC）和腹侧被盖区DA能神经元（VTA-mPFC） 在A/D小鼠（抑郁易感小鼠）中选择性地投射到延髓核（VTA-NAc），但 而不是在A小鼠（抑郁恢复组）中。我们的光遗传学研究进一步证明了 这些回路中的放电适应不良与抑郁相关行为之间的联系。但我们 惊人地发现，VTA神经元投射到杏仁核（VTA-Amg）的放电活动是 在A/D-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 中心假设是VTA-Amg回路可能在介导焦虑样 RSDS后在A/D-和A-小鼠中观察到的行为。为了验证这一点，我们提出了两个具体的 目的：（a）研究A/D型和A型雄性大鼠腹侧被盖区-Amg DA神经元的病理变化， 通过使用离体脑切片制备和来自完整动物的体内光电极记录的雌性小鼠; 和（B）确定腹侧被盖区-Amg DA神经元在介导RSDS诱导的焦虑中的功能作用 通过光遗传学操纵雄性和雌性小鼠的这些回路来进行行为。通过利用这些细胞 类型和电路特定的电生理和光遗传学技术，我们将确定是否有因果关系， VTA-Amg DA回路的神经元活动与焦虑相关行为之间存在相关性。

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.