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-背外侧前额叶皮质(DlPFC)调节工作记忆和自上而下的控制，但 因急性或慢性压力而受损，在大多数精神障碍中是功能失调的。压力暴露增加 去甲肾上腺素(NE)释放，通过(β-AR和α1-AR)加强杏仁核的情绪反应，但 通过α1-AR减弱dlPFC，而β-AR的作用(S)尚不清楚。在此基础上，提出了通用的α1-AR 拮抗剂哌唑嗪和β-AR拮抗剂心得安用于治疗创伤后应激障碍 (创伤后应激障碍)。然而，哌唑嗪和心得安并不总是有效的，研究结果表明，某些亚型 α1-AR和β-AR的表达可能有利于PFC，因此阻断所有亚型的拮抗剂可能会适得其反。 拟议的研究将对α1-AR(α1A-AR、α1B-AR、α1D-AR)和β-AR(β1-AR、β2-AR)进行首次研究 AR，β3-AR)亚型在恒河猴dlPFC中的作用，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的AR和β-AR亚型 以揭示超微结构的位置，例如在突触前释放部位或在第三层dlPFC的树突棘上。我们 将使用离子导入结合单个单位记录的dlPFC神经元在猴子中执行一项工作 记忆任务，以确定刺激α1-AR和β-AR亚型如何改变任务相关神经元的放电，以及 他们的第二个信使行动。我们还将使用α1-AR和β-AR亚型的系统给药 选择性拮抗剂阻断应激诱导的工作记忆缺陷，并测试选择性拮抗剂(S)是否 比目前使用的非选择性药物哌唑嗪或心得安更有效和有效，以及是否 低剂量的更具选择性的拮抗剂可以恢复认知，副作用更少。目标1将描述 α1-AR亚型的作用，检查它们的定位(目标1A)，dlPFC中的生理作用(目标1B)， 以及在轻度、急性应激源时对工作记忆表现的影响(目标1C)。初步数据显示 α1A-AR亚型显著减少与工作记忆相关的dlPFC神经元放电，并且选择性 α1A-AR拮抗剂有效地阻断了应激诱导的认知障碍，提示了一种更好的治疗策略 治疗学。目标2将描述β-AR亚型，检查它们的定位(目标2A)、生理学 DlPFC中的行为(AIM 2B)，以及在轻度、急性应激源(AIM)下对工作记忆表现的影响 2C)。初步数据表明，β1-AR亚型显著降低了与工作记忆相关的dlPFC 神经元放电，以及选择性的β1-AR拮抗剂阻断应激诱导的认知障碍。在心肌中， β1-AR开放电压门控Cav1.2Ca~(2+)通道介导“战斗或逃跑”应激反应 (由CACNA1C编码)，我们的初步数据表明，在灵长类动物dlPFC中，有害的β1-AR作用 涉及类似的行为，有助于解释为什么CACNA1C功能获得突变会增加精神分裂症的风险 DlPFC功能受损的疾病，包括创伤后应激障碍。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应激相关精神障碍的方法。