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: 10586051
• 负责人: Wen-Jun Gao
• 金额: $ 18.59万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586051
• 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; Genetic; Hippocampus; 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; Video Recording; Viral; Virus; Wakefulness; addiction; anxiety-like behavior; approach avoidance behavior; arm; avoidance behavior; 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; neural circuit; neuromechanism; noradrenergic; optogenetics; particle; 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叶-丘脑回路以调节回避行为 摘要 焦虑症是美国最常见的精神疾病，影响了约18%的人口。然而，在这方面， 与焦虑相关的潜在机制仍然难以捉摸。最近的证据表明， 前额叶皮层（mPFC）作为焦虑和mPFC介导的执行功能中断的关键调节器 焦虑症另一方面，去甲肾上腺素（NE）长期以来与压力和焦虑有关。 形态学研究表明，PFC中多巴胺β-羟化酶（DBH）的密度较高 比其他皮层更大。然而，mPFC如何对其他大脑区域执行自上而下的控制， 焦虑相关的接近-回避行为以及是否以及如何受去甲肾上腺素（NE）调节 仍然不清楚。该项目将测试mPFC -室旁丘脑（mPFC-PVT） 电路是一个重要的以前被忽视的目标焦虑和决策。我们的初步研究表明 用DREADD病毒维克托化学遗传学抑制mPFC-PVT途径显著增加了 花在高架十字迷宫的开放臂，表明焦虑相关的回避行为减少。 因此，我们假设mPFC-pPVT神经元在探索令人厌恶的环境时是活跃的， 这会导致回避行为并引发焦虑依赖行为。我们将探讨 前额叶NE信号调节这种作用。我们将调查这两个区域之间的交流 通过使用钙成像，对动物行为的详细DeepLabCut分析（目标1）结合G- 蛋白偶联受体（GPCR）基于激活的去甲肾上腺素（GRAB-NE）传感器（Aim 2） 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™将以亚毫秒的时间间隔提供动物姿势的详细分析， 可以用来确定动物的情绪状态变化的分辨率。总之，我们解决这些问题 使用最先进的方法提出概念上创新的问题，允许进行精确的因果询问 以投射特异性的方式在体内和离体地研究该回路的作用。