Prefrontal impairment with stress- NE receptor subtype mechanisms.

与压力-NE受体亚型机制有关的前额损伤。

• 批准号: 10655735
• 负责人: AMY F.T. ARNSTEN
• 金额: $ 83.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655735
• 关键词: ADRB1 gene; Acute; Affinity; Amygdaloid structure; Animals; Astrocytes; Automobile Driving; Brain; Cardiac; Catecholamines; Cells; Chronic stress; Cognition; Cognitive; Cognitive deficits; Confocal Microscopy; Coupled; Cyclic AMP; Data; Dendritic Spines; Disease; Dissection; Dose; Emotional; Exposure to; Family; Goals; Heart; Human; Hypotensives; Immunoelectron Microscopy; Immunofluorescence Immunologic; Impairment; Interneurons; Iontophoresis; Label; Length; Location; Macaca mulatta; Mediating; Memory impairment; Mental disorders; Microglia; Molecular; Monkeys; Myocardium; Neurons; Nightmare; Norepinephrine; Norepinephrine Receptors; Patients; Performance; Physiological; Post-Traumatic Stress Disorders; Potassium Channel; Prazosin; Prefrontal Cortex; Primates; Propranolol; Pyramidal Cells; Research; Risk; Risk Factors; Role; Schizophrenia; Second Messenger Systems; Sensory; Short-Term Memory; Site; Stress; Techniques; Testing; Therapeutic; Vertebral column; Work; acute stress; antagonist; biological adaptation to stress; cell type; design; effective therapy; fighting; gain of function mutation; mental representation; presynaptic; receptor; response; sedative; side effect; stress reduction; stressor; treatment strategy; voltage

Abstract- The dorsolateral prefrontal cortex (dlPFC) mediates working memory and top-down control, but is impaired by acute or chronic stress, and is dysfunctional in most mental disorders. Stress exposure increases norepinephrine (NE) release, which strengthens amygdala emotional responses via (β-AR and α1-AR, but weakens the dlPFC via α1-AR, while the role(s) of β-AR are unknown. Based on this work, the general α1-AR antagonist, prazosin, and β-AR antagonist, propranolol, are used to treat Post-Traumatic Stress Disorder (PTSD). However, prazosin and propranolol are not always effective, and findings suggest that some subtypes of α1-AR and β-AR may benefit PFC, and thus antagonists that block all subtypes may be counterproductive. The proposed research will perform the first study of α1-AR (α1A-AR, α1B-AR, α1D-AR) and β-AR (β1-AR, β2- AR, β3-AR) subtype actions in rhesus monkey dlPFC, using multiple label immunofluorescence to localize α1- AR and β-AR subtypes on pyramidal cells, GABAergic interneurons, astrocytes and microglia, and immunoEM to reveal ultrastructural locations, e.g. at pre-synaptic release sites or on dendritic spines in layer III dlPFC. We will use iontophoresis coupled with single unit recordings of dlPFC neurons in monkeys performing a working memory task to determine how stimulation of α1-AR and β-AR subtypes alters task-related neuronal firing, and their second messenger actions. We will also use systemic administration of α1-AR and β-AR subtype selective antagonists to block stress-induced working memory deficits, and test whether selective agent(s) are more potent and efficacious than the currently used, nonselective agents, prazosin or propranolol, and whether low doses of more selective antagonists can restore cognition with fewer side effects. Aim 1 will characterize the roles of α1-AR subtypes, examining their localization (Aim 1A), physiological actions in dlPFC (Aim 1B), and effects on working memory performance during a mild, acute stressor (Aim 1C). Preliminary data indicate that the α1A-AR subtype markedly reduces working memory-related dlPFC neuronal firing, and that a selective α1A-AR antagonist potently blocks stress-induced cognitive deficits, suggesting a superior strategy for therapeutics. Aim 2 will characterize β-AR subtypes, examining their localization (Aim 2A), physiological actions in dlPFC (Aim 2B), and effects on working memory performance during a mild, acute stressor (Aim 2C). Preliminary data indicate that the β1-AR subtype markedly reduces working memory-related dlPFC neuronal firing, and that a selective β1-AR antagonist blocks stress-induced cognitive deficits. In heart muscle, the “fight or flight” stress response is mediated by β1-AR opening of voltage-gated Cav1.2 Ca2+ channels (encoded by CACNA1C), and our preliminary data indicate that detrimental β1-AR actions in primate dlPFC involve similar actions, helping to explain why gain-of-function mutations in CACNA1C increase risk of mental disorders with impaired dlPFC function, including PTSD. Identifying the subtypes of α1-AR and β-AR that impair dlPFC function will help the design of more effective therapies for stress-related mental disorders.

摘要：背外侧前额叶皮层（dlPFC）介导工作记忆和自上而下的控制，但 受到急性或慢性压力的损害，并且在大多数精神障碍中都会出现功能障碍。 去甲肾上腺素（NE）释放，通过（β-AR和α1-AR增强杏仁核的情绪反应，但是 通过 α1-AR 削弱 dlPFC，而 β-AR 的作用尚不清楚。根据这项工作，一般的 α1-AR。 拮抗剂哌唑嗪和 β-AR 拮抗剂普萘洛尔用于治疗创伤后应激障碍 （创伤后应激障碍）然而，哌唑嗪和普萘洛尔并不总是有效，研究结果表明某些亚型 α1-AR 和 β-AR 的作用可能有益于 PFC，因此阻断所有亚型的拮抗剂可能会适得其反。 拟议的研究将首次研究α1-AR（α1A-AR、α1B-AR、α1D-AR）和β-AR（β1-AR、β2- AR，β3-AR）亚型在恒河猴 dlPFC 中的作用，使用多标记免疫荧光定位 α1- 锥体细胞、GABA能中间神经元、星形胶质细胞和小胶质细胞以及免疫EM的AR和β-AR亚型 揭示超微结构位置，例如突触前释放位点或第 III 层 dlPFC 中的树突棘。 将使用离子电渗疗法结合猴子 dlPFC 神经元的单个单元记录来执行工作 记忆任务以确定α1-AR和β-AR亚型的刺激如何改变任务相关的神经放电，以及 我们还将使用 α1-AR 和 β-AR 亚型进行全身给药。 选择性拮抗剂来阻止压力引起的工作记忆缺陷，并测试选择性药物是否 比目前使用的非选择性药物哌唑嗪或普萘洛尔更有效，以及是否 低剂量、更具选择性的拮抗剂可以恢复认知，同时副作用更少，这是目标 1 的特征。 α1-AR 亚型的作用，检查其定位（目标 1A），dlPFC 中的生理作用（目标 1B）， 以及在轻度、急性压力源下对工作记忆表现的影响（初步数据表明）。 α1A-AR 亚型显着降低工作记忆相关的 dlPFC 神经放电，并且选择性 α1A-AR 拮抗剂可有效阻止压力引起的认知缺陷，这表明这是一种更好的策略 目标 2 将表征 β-AR 亚型，检查其定位（目标 2A）、生理学。 dlPFC 的活动（目标 2B），以及在轻度、急性应激源期间对工作记忆表现的影响（目标 2C) 初步数据表明 β1-AR 亚型显着降低了工作记忆相关的 dlPFC。 神经放电，并且选择性 β1-AR 拮抗剂可以阻止应激引起的心肌认知缺陷， “战斗或逃跑”应激反应是由电压门控 Cav1.2 Ca2+ 通道的 β1-AR 打开介导的 （由 CACNA1C 编码），我们的初步数据表明，灵长类 dlPFC 中的苦恼 β1-AR 作用 涉及类似的行为，有助于解释为什么 CACNA1C 的功能获得突变会增加精神疾病的风险 dlPFC 功能受损的疾病，包括 PTSD 识别 α1-AR 和 β-AR 的亚型。 损害 dlPFC 功能将有助于设计更有效的治疗压力相关精神障碍的疗法。