Norepinephrine tunes prefrontal-thalamic circuitry to modulate avoidance behavior

去甲肾上腺素调节前额丘脑回路调节回避行为 摘要 焦虑症是美国最常见的精神疾病，影响了大约18%的人口。然而， 与焦虑相关的潜在机制仍然难以捉摸。最近的证据已经确定了医学上的 前额叶皮质(MPFC)是焦虑和mPFC介导的执行功能障碍的重要调节因子 焦虑症患者。另一方面，去甲肾上腺素(NE)长期以来被认为与压力和焦虑有关。 形态学研究显示PFC中有较高密度的多巴胺-β-羟基酶(DBH)。 而不是在其他皮质中。然而，mPFC如何对其他大脑区域执行自上而下的控制来调节 焦虑相关的回避行为以及去甲肾上腺素(NE)是否和如何调节这种行为 目前仍不清楚。该项目将测试mPFC-室旁丘脑(mPFC-PVT)这一创新概念 对于焦虑和决策来说，赛道是一个以前被忽视的重要目标。我们的初步研究表明 用DREADD病毒Victor化学遗传学抑制mPFC-PVT通路显著延长时间 在高架正迷宫的开放手臂中度过，表明与焦虑相关的回避行为减少。 因此，我们假设mPFC-pPVT神经元在探索厌恶环境时是活跃的， 这会导致回避行为，并引发依赖焦虑的行为。我们将探索在多大程度上 前额叶去甲肾上腺素信号调节这一效应。我们将调查这两个地区之间的交流 通过使用钙成像，对动物行为的详细DeepLabCut分析(目标1)结合G- 基于蛋白偶联受体激活的去甲肾上腺素传感器(AIM 2)治疗焦虑症 行为。Grab-NE将使我们能够实时监测行为自由的动物的前额叶NE动态。 DeepLabCut™将提供对动物姿势的详细分析，时间为亚毫秒 可以用来确定动物情绪状态变化的分辨率。总而言之，我们解决了这些问题 使用最先进的方法提出概念上的创新问题，允许进行精确的、因果的询问 以投射特异性的方式在体内和体外研究这一回路的作用。

Norepinephrine tunes prefrontal-thalamic circuitry to modulate avoidance behavior Abstract Anxiety disorders are the most common mental illness in the U.S., affecting ~18% of the population. However, the underlying mechanisms associated with anxiety remain elusive. Recent evidence has identified the medial prefrontal cortex (mPFC) as a crucial regulator of anxiety and disruption of mPFC-mediated executive functions in anxiety disorders. On the other hand, norepinephrine (NE) has long been associated with stress and anxiety. A morphological study showed a higher density of dopamine beta-hydroxylase (DBH) varicosities in the PFC than in other cortices. However, how the mPFC executes top-down control over other brain regions to regulate anxiety-related approach-avoidance behavior and whether and how this is modulated by norepinephrine (NE) remain unclear. This project will test the innovative concept that mPFC – paraventricular thalamus (mPFC-PVT) circuit is an important previously overlooked target for anxiety and decision-making. Our pilot study suggests that chemogenetically inhibiting mPFC-PVT pathway with DREADD viral victor significantly increased the time spent in the open arm of the elevated plus-maze, indicating a reduction in anxiety-related avoidance behavior. We thus hypothesize that mPFC-pPVT neurons are active during the exploration of aversive environments, which drives avoidance behavior and elicits anxiety-dependent behaviors. We will explore the extent that prefrontal NE signaling modulates this effect. We will investigate the communication between these two regions by using calcium imaging, a detailed DeepLabCut analysis of animal’s behavior (Aim 1) combined with a G- protein-coupled receptor (GPCR) Activation-Based Norepinephrine (GRAB-NE) sensor (Aim 2) for anxiety-like behavior. The GRAB-NE will allow us to monitor prefrontal NE dynamics in real-time in free-behaving animals. The DeepLabCut™ will provide a detailed analysis of an animal’s posture with a sub-millisecond temporal resolution that could be used to determine an animal’s emotional state change. In summary, we address these conceptually innovative questions using state-of-the-art methods, which allow for precise, causal interrogation into the role of this circuit both in vivo and ex vivo in a projection-specific manner.