Norepinephrine tunes prefrontal-thalamic circuitry to modulate avoidance behavior

去甲肾上腺素调节前额丘脑回路以调节回避行为

• 批准号: 10451927
• 负责人: Wen-Jun Gao
• 金额: $ 22.37万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-07 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451927
• 关键词: Address; Adrenergic Agents; Affect; Amygdaloid structure; Animal Behavior; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Arousal; Attention; Behavior; Behavioral; Behavioral Assay; Brain region; CAV2 gene; Calcium; Cell Nucleus; Clinical; Communication; Data Analyses; Decision Making; Detection; Dopamine-beta-monooxygenase; Dorsal; Emotional; Enterobacteria phage P1 Cre recombinase; Environment; Equilibrium; Exhibits; Female; Fiber; Fright; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Hippocampus (Brain); Image; Imaging Device; Insula of Reil; Major Depressive Disorder; Medial; Mediating; Mental disorders; Methods; Monitor; Moods; Morphology; Motivation; Mus; Neurons; Neurotransmitters; Norepinephrine; Pathway interactions; Photometry; Pilot Projects; Play; Population; Post-Traumatic Stress Disorders; Posture; Prefrontal Cortex; Process; Receptor Activation; Reporting; Rewards; Risk-Taking; Rodent; Role; Schizophrenia; Signal Transduction; Stress; Testing; Thalamic structure; Time; Varicosity; Viral; Virus; Wakefulness; addiction; anxiety-like behavior; approach avoidance behavior; arm; avoidance behavior; base; brain dysfunction; common symptom; density; designer receptors exclusively activated by designer drugs; disabling symptom; executive function; flexibility; improved; in vivo; innovation; locus ceruleus structure; male; millisecond; neural circuit; neuromechanism; noradrenergic; optogenetics; particle; relating to nervous system; response; sensor; spatiotemporal; temporal measurement

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.

去甲肾上腺素调节前额丘脑回路以调节回避行为 抽象的 焦虑症是美国最常见的精神疾病，影响约 18% 的人口。然而， 与焦虑相关的潜在机制仍然难以捉摸。最近的证据表明，内侧 前额皮质 (mPFC) 作为焦虑和 mPFC 介导的执行功能破坏的重要调节因子 在焦虑症中。另一方面，去甲肾上腺素（NE）长期以来一直与压力和焦虑有关。 形态学研究显示前额皮质中多巴胺 β-羟化酶 (DBH) 静脉曲张密度较高 比其他皮质。然而，mPFC如何对其他大脑区域进行自上而下的控制来调节 焦虑相关的接近回避行为以及这种行为是否以及如何受到去甲肾上腺素 (NE) 的调节 仍不清楚。该项目将测试 mPFC – 室旁丘脑 (mPFC-PVT) 的创新概念 电路是以前被忽视的焦虑和决策的重要目标。我们的试点研究表明 使用 DREADD 病毒胜利者化学遗传学抑制 mPFC-PVT 通路显着增加了时间 花在高架十字迷宫的开放臂上，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期间是活跃的， 这会驱动回避行为并引发焦虑依赖性行为。我们将探讨在何种程度上 前额叶 NE 信号传导调节这种效应。我们将调查这两个地区之间的通讯 通过使用钙成像，对动物行为进行详细的 DeepLabCut 分析（目标 1），并结合 G- 基于蛋白偶联受体 (GPCR) 激活的去甲肾上腺素 (GRAB-NE) 传感器（目标 2）用于治疗焦虑症 行为。 GRAB-NE 将使我们能够实时监测自由行为动物的前额叶 NE 动态。 DeepLabCut™ 将在亚毫秒时间范围内对动物姿势进行详细分析 可用于确定动物情绪状态变化的分辨率。总而言之，我们解决这些 使用最先进的方法提出概念上创新的问题，从而进行精确的因果询问 以投射特定的方式了解该电路在体内和离体的作用。