Brainstem Modulation of Proactive Coping

主动应对的脑干调节

• 批准号: 10660652
• 负责人: Robert Milton Sears
• 金额: $ 70.98万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660652
• 关键词: Active Learning; Adrenergic beta-Antagonists; Adult; Amygdaloid structure; Animal Behavior; Animals; Anxiety; Anxiety Disorders; Behavior; Behavior Control; Behavioral; Brain; Brain Stem; Brain region; CRISPR/Cas technology; Cells; Clinical; Conflict (Psychology); Coping Behavior; Coping Skills; Data; Early-life trauma; Electrophysiology (science); Emotional; Equilibrium; Evidence based treatment; Exhibits; Exposure to; Freezing; Fright; Functional disorder; Future; Goals; Heart; Human; Individual; Infusion procedures; Intervention; Lateral; Learning; Measures; Mediating; Mental disorders; Methodology; Microdialysis; Molecular; Neurobiology; Neurons; Neurotransmitters; Norepinephrine; Norepinephrine Receptors; Panic; Patients; Perception; Performance; Pharmaceutical Preparations; Phenotype; Photometry; Population; Predisposition; Propranolol; Psychopathology; Publishing; Rattus; Reaction; Research; Role; Shock; Signal Transduction; Somatostatin; Source; Stimulus; Techniques; Testing; Training; Trauma; Whole-Cell Recordings; Work; antagonist; beta-adrenergic receptor; comparison control; conditioned fear; coping; early life stress; evidence base; fear memory; improved; in vivo; locus ceruleus structure; neural circuit; norepinephrine system; novel; optogenetics; pharmacologic; prevent; receptor; resilience; response; single-cell RNA sequencing; treatment strategy

Project Summary/Abstract While some individuals cope well with hardship, others are not as resilient. Although studies have focused on the magnitude of fear reactions, clinical evidence suggests that response conflict is at the root of maladaptive coping in psychiatric disease. The proposed research pursues the working hypothesis that norepinephrine (NE), a neurotransmitter observed in high levels in patients suffering from fear and anxiety disorders, elicits behavioral reactions that are in conflict with proactive coping behavior. Work in the field has focused on NE release in the basolateral amygdala (BLA), which drives emotional learning in fear conditioning paradigms. However, NE in the BLA does not affect the expression of fear (freezing reactions). Preliminary and published data show that increased NE activity in the central amygdala (CeA), on the other hand, supports threat (fear) reactions and opposes proactive behaviors. The amygdala receives strong input from the brainstem locus coeruleus (LC), the major source of NE in the brain. The proposed research uses an active avoidance paradigm (AA), in which animals learn to emit a proactive response to avoid a threat, to investigate how LC NE release in the CeA controls the balance between freezing reactions and adaptive actions. To accomplish this, an early life trauma paradigm will be used, which reliably yields animals that are unable to perform AA as adults. We will manipulate the LCàCeA circuit in these so-called ‘poor avoiders’ and ‘good avoider’ controls to identify the behavioral, electrophysiological, and molecular mechanisms underlying AA. We will test the prediction that elevated NE release from LC, and the resulting changes at specific CeA target neurons, will yield a poor avoider phenotype in good avoiders, whereas inhibiting this circuit in poor avoiders will ‘rescue’ AA behavior. We will also assess the molecular identity and electrophysiological profiles of cell subtypes in the CeA, how they are functionally different in good versus poor avoiders, and the role of LC activity in these changes. Together, these studies aim to change how the field views the NE system, from modulating fear memory formation in the BLA, to controlling defensive response selection via action in the CeA. These studies will also challenge the dominant methodological paradigms (e.g., fear conditioning), which miss an essential aspect of animal behavior: the competition between reactive versus proactive responses to perceived threats. Successful completion of these studies will uncover the NE system’s role in adaptive coping behaviors and provide evidence-based support for novel treatments of maladaptive coping, including active coping training combined with drugs to control an overactive NE system.

项目摘要/摘要 虽然有些人很好地应对艰辛，但其他人并没有那么韧性。尽管研究重点是 临床证据表明，恐惧反应的幅度表明，反应冲突是适应不良的根源 精神病的应对。拟议的研究追求了去甲肾上腺素的工作假设 （NE），在患有恐惧和焦虑症的患者中观察到的神经递质，引起 与主动应对行为相抵触的行为反应。该领域的工作重点是NE 在基础型杏仁核（BLA）中释放，该杏仁核在恐惧调节范式中驱动情绪学习。 但是，BLA中的NE不会影响恐惧的表达（冻结反应）。初步和出版 数据表明，另一方面，中央杏仁核（CEA）的NE活动增加了威胁（恐惧） 反应并反对主动行为。杏仁核从脑干基因座收到强大的输入 Coeruleus（LC），大脑中NE的主要来源。拟议的研究使用主动回避 范式（AA），动物学会发出积极的反应以避免威胁，以调查LC NE如何 在CEA中释放控制冷冻反应与自适应作用之间的平衡。为此， 将使用早期生命创伤范式，可靠地产生无法执行AA的动物 成年人。我们将在这些所谓的“穷人避免人”和“良好的Avoider”控件中操纵LCàcea电路 确定AA背后的行为，电生理和分子机制。我们将测试 预测LC的NE释放升高，并且在特定CEA靶神经元处产生的变化将 在良好的避难所中产生差的Avoider表型，而抑制穷人的这一电路会“营救” AA 行为。我们还将评估细胞亚型的分子身份和电生理特征 CEA，它们在良好与穷人避免人方面的功能不同，以及LC活性在这些方面的作用 更改。这些研究共同旨在改变领域的看法，从调节恐惧。 BLA中的记忆形成，以通过CEA中的动作来控制防御响应选择。这些研究 还将挑战主要的方法论范式（例如，恐惧条件），这错过了必不可少的 动物行为的方面：反应性与对感知威胁的主动反应之间的竞争。 这些研究的成功完成将揭示NE系统在适应性应对行为中的作用和 为适应不良应对的新型治疗提供基于证据的支持，包括主动应对培训 与药物结合使用以控制过度活跃的NE系统。