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 - 丘脑回路调节回避行为 抽象的 焦虑症是美国最常见的精神疾病，影响约18％的人群。然而， 与焦虑相关的基本机制仍然难以捉摸。最近的证据已经确定了媒体 前额叶皮层（MPFC）是动画和MPFC介导的执行功能的关键调节器 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。 一项形态学研究表明，PFC中多巴胺β-羟化酶（DBH）静脉曲张的密度更高 比其他皮质。但是，MPFC如何对其他大脑区域进行自上而下的控制以调节 动画避免行为以及是否以及如何通过去甲肾上腺素调节（NE） 保持不清楚。该项目将测试MPFC的创新概念 - 旁牙丘脑（MPFC-PVT） 电路是焦虑和决策的重要目标。我们的试点研究建议 通过Dreadd Viral Victor抑制MPFC-PVT途径的化学遗传学大大增加了时间 在高架迷宫的张开手臂上花费，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具有活性， 驱动避免行为并引起动画依赖性行为。我们将探讨 前额叶NE信号传导调节了这种效果。我们将调查这两个区域之间的沟通 通过使用钙成像，对动物行为的详细深度插曲分析（AIM 1）结合了G- 蛋白质偶联受体（GPCR）基于激活的去甲肾上腺素（grab-ne）传感器（AIM 2）用于动画样 行为。抢夺将使我们能够在自由言论的动物中实时监视前额叶NE动力学。 DeepLabcut™将使用子毫米临时性提供对动物姿势的详细分析 可以用来确定动物情绪状态变化的解决方案。总而言之，我们解决这些问题 使用最先进的方法在概念上具有创新的问题，这些方法允许精确，因果关系 以投影特异性的方式进入体内和离体的角色。