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

VTA-杏仁核神经回路在调节焦虑相关行为中的作用

• 批准号: 10370319
• 负责人: Carole S Morel
• 金额: $ 42.33万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370319
• 关键词: Adaptive Behaviors; Affect; American; Amygdaloid structure; Anhedonia; Anxiety; Anxiety Disorders; Aversive Stimulus; Behavior; Behavioral Symptoms; Brain; Brain Diseases; Brain region; Calcium; Cells; Complex; Data; Depressed mood; Dopamine; Drug Targeting; Electrophysiology (science); Emotions; Environment; Equilibrium; Exhibits; Female; Fiber; Fright; Hyperactivity; Investigation; Label; Link; Maintenance; Major Depressive Disorder; Medial; Mediating; Mental Depression; Mental disorders; Modeling; Molecular; Mus; Neurons; Nucleus Accumbens; Pathologic; Pathological anxiety; Pathway interactions; Patients; Persons; Phenotype; Photometry; Physiological; Play; Population; Prefrontal Cortex; Property; Rewards; Rodent Model; Role; Slice; Stress; Subgroup; Symptoms; Techniques; Testing; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Viral; anxiety symptoms; anxiety-like behavior; anxiety-related behavior; anxious; base; cell type; depressive symptoms; dopaminergic neuron; experience; imaging approach; in vivo; in vivo calcium imaging; insight; male; mental function; neural circuit; neuromechanism; neurophysiology; neuropsychiatry; new therapeutic target; novel; optogenetics; relating to nervous system; social; social defeat

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 complicates the investigation of the underlying mechanisms. In this project, we propose to take advantage of the repeated social defeat stress (RSDS) model that induces anxiety (A) or mixed anxiety/depression (A/D) phenotypes in separate subgroups of mice, in an effort to dissect the neurophysiological substrate regulating anxiety behaviors. Using this model, we unexpectedly identified that specific neural circuit pathological activity is exclusively correlated with anxiety behaviors. Briefly, while RSDS induces severe anxiety behaviors in all subjects exposed, a subset of mice is segregated based on their depressive phenotypes: profound anhedonia and avoidance-displaying mice (susceptible) from mice not displaying these depressive symptoms (resilient). Thus, in this project, we label them as anxiety (A) and anxiety/depression (A/D) subgroups. Numerous studies have implicated the role of ventral tegmental area (VTA) dopamine (DA) subcircuits in anxiety and depression. We previously observed that maladaptive firing activity occurred in the VTA DA neurons projecting to the medial prefrontal cortex (mPFC) and VTA DA neurons projecting to the nucleus accumbens (NAc) in A/D mice (depression-susceptible mice), but not in A mice (depression-resilient group). We further demonstrated the causal link between the firing maladaptations in those circuits and depression-related behaviors. Surprisingly, with the support of our R21, using ex vivo electrophysiological studies we show that the firing activity of VTA neurons projecting to the amygdala (VTA- AMG) is dramatically decreased in both A/D and A mice, and this VTA-AMG circuit activity correlates with the expression of anxiety phenotype but not depressive-related phenotypes. Based on these preliminary findings, our central hypothesis is that the VTA-AMG circuit plays a crucial role in the anxiety-like behaviors observed in both A/D and A mice following RSDS. To test this, we propose three Specific Aims: (I) to investigate the pathological cellular and molecular alterations of VTA-AMG DA circuit neurons in A/D and A male and female mice by use of in vivo optrode recordings and ex vivo brain slice recordings; (II) To define how RSDS alters the activity of VTA-AMG DA neurons during the emergence and expression of anxiety using in vivo calcium fiber photometry recordings, and finally (III) 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, in vivo calcium imaging and optogenetic techniques, we will determine if a causal relationship exists between the neuronal activity of VTA-AMG DA circuit and anxiety-related behaviors.

项目概要 焦虑症是最常见的精神疾病，困扰着全世界 2.73 亿人。这 焦虑症的症状非常复杂，而其原因却知之甚少。另外，一个 大量患有焦虑症的患者也出现抑郁样症状， 这使得对潜在机制的研究变得复杂。在这个项目中，我们建议采取 重复社交失败压力（RSDS）模型的优点是诱发焦虑（A）或混合 不同亚组小鼠的焦虑/抑郁（A/D）表型，试图剖析 调节焦虑行为的神经生理学底物。使用这个模型，我们意外地发现 特定的神经回路病理活动与焦虑行为完全相关。简而言之，虽然 RSDS 在所有暴露的受试者中引起严重的焦虑行为，根据小鼠的情况将一部分小鼠进行隔离 抑郁表型：表现出严重的快感缺乏和回避的小鼠（易感）与非小鼠 表现出这些抑郁症状（有弹性）。因此，在这个项目中，我们将它们标记为焦虑（A）和 焦虑/抑郁（A/D）亚组。许多研究表明腹侧被盖区的作用 (VTA) 多巴胺 (DA) 子电路在焦虑和抑郁中的作用。我们之前观察到适应不良的放电 活动发生在投射到内侧前额皮质 (mPFC) 和 VTA DA 的 VTA DA 神经元中 A/D 小鼠（抑郁易感小鼠）中的神经元投射到伏隔核 (NAc)，但 A 中则不然 小鼠（抑郁恢复组）。我们进一步证明了放电适应不良之间的因果关系 这些回路和抑郁相关的行为。令人惊讶的是，在我们的R21的支持下，使用离体 电生理学研究表明，投射到杏仁核的 VTA 神经元的放电活动（VTA- A/D 和 A 小鼠中 AMG）均显着降低，并且这种 VTA-AMG 回路活动与 表达焦虑表型，但不表达抑郁相关表型。根据这些初步调查结果， 我们的中心假设是 VTA-AMG 回路在类焦虑行为中起着至关重要的作用 在 RSDS 后的 A/D 和 A 小鼠中观察到。为了测试这一点，我们提出了三个具体目标：(I) 研究 A/D 和 A 中 VTA-AMG DA 回路神经元的病理细胞和分子改变 使用体内光极记录和离体脑切片记录对雄性和雌性小鼠进行研究； （二）定义 RSDS 如何在焦虑的出现和表达过程中改变 VTA-AMG DA 神经元的活性 体内钙纤维光度测定记录，最后（III）确定VTA-AMG DA的功能作用 神经元通过光遗传学操纵男性中的这些回路来介导 RSDS 诱导的焦虑行为 和雌性老鼠。通过利用这些细胞类型和电路特异性的电生理学、体内钙成像 和光遗传学技术，我们将确定神经元活动之间是否存在因果关系 VTA-AMG DA 回路和焦虑相关行为。