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 - 背侧前额叶皮层（DLPFC）介导工作内存和自上而下的控制 受到急性或慢性压力的损害，并且在大多数精神疾病中功能失调。压力暴露增加 去甲肾上腺素（NE）释放，它可以通过（β-ar和α1-ar来强调杏仁核情绪反应，但 通过α1-AR削弱DLPFC，而β-AR的作用尚不清楚。基于这项工作，一般的α1-ar 拮抗剂，肾和β-AR拮抗剂普萘洛尔用于治疗创伤后应激障碍 （PTSD）。但是，丙二醇和普萘洛尔并不总是有效的，发现表明某些亚型 α1-AR和β-AR的含量可能使PFC受益，因此阻断所有亚型的拮抗剂可能会适得其反。 拟议的研究将进行α1-AR（α1A-AR，α1b-ar，α1d-ar）和β-ar（β1-AR，β2-，β2-）的首次研究。 恒河猴DLPFC中的AR，β3-ar）亚型作用，使用多个标记免疫荧光来定位α1- 锥体细胞，GABA能中间神经元，星形胶质细胞和小胶质细胞的AR和β-AR亚型以及免疫胶质细胞 揭示超微结构位置，例如在突触前释放位点或第三层DLPFC中的树突状刺。我们 将使用与猴子中DLPFC神经元的单个单位记录相结合的猴子的离子噬菌体 记忆任务以确定α1-AR和β-AR亚型的刺激如何改变与任务相关的神经元的放电，并如何改变 他们的第二个使者行动。我们还将使用α1-AR和β-AR亚型的系统给药 选择性拮抗剂阻止应力引起的工作记忆定义，并测试选择性剂是否为 比当前使用的非选择性剂，prazosin或propranolol以及是否具有更大的潜力和高效 低剂量的选择性拮抗剂可以恢复认知，副作用较少。 AIM 1将表征 α1-ar亚型的作用，检查了它们的定位（AIM 1A），在DLPFC中的身体作用（AIM 1B）， 以及对轻度急性压力源期间工作记忆表现的影响（AIM 1C）。初步数据指示 α1A-AR亚型显着降低了与工作记忆相关的DLPFC神经元触发，并且是选择性的 α1A-AR拮抗剂可能会阻止应力引起的认知缺陷，这表明了卓越的策略 AIM 2将表征β-AR亚型，检查其定位（AIM 2A），生理 DLPFC（AIM 2B）中的动作，以及对轻度急性压力源期间工作记忆表现的影响（AIM 2C）。初步数据表明β1-AR亚型显着降低了与工作记忆相关的DLPFC 神经元的发射，并且选择性β1-AR拮抗剂阻止了应力引起的认知缺陷。在心肌中， “战斗或飞行”应力响应是通过电压门控CAV1.2 Ca2+通道的β1-AR介导的 （由CACNA1C编码），我们的初步数据表明灵长类动物DLPFC中有害的β1-AR作用 涉及类似的行动，有助于解释为什么CACNA1C中的功能收益突变增加了精神的风险 DLPFC功能受损的疾病，包括PTSD。识别α1-ar和β-ar的亚型 损害DLPFC功能将有助于设计与压力相关的精神障碍的更有效的疗法。