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.

项目总结/摘要 虽然有些人能很好地应对困难，但其他人则没有那么有弹性。尽管研究集中在 恐惧反应的程度，临床证据表明反应冲突是适应不良的根源 应对精神疾病拟议的研究追求的工作假设，去甲肾上腺素 (NE)在患有恐惧和焦虑症的患者中观察到高水平的神经递质， 与积极应对行为相冲突的行为反应。该领域的工作重点是NE 在基底外侧杏仁核（BLA）中释放，这在恐惧条件反射范式中驱动情绪学习。 然而，BLA中的NE不影响恐惧的表达（冻结反应）。初步和公布 另一方面，数据显示中央杏仁核（CeA）中NE活性的增加支持威胁（恐惧） 反应并反对积极主动的行为。杏仁核接受来自脑干位点的强烈输入 蓝斑核（LC）是脑内NE的主要来源。这项研究采用了主动回避的方法， 模式（AA），其中动物学会发出积极主动的反应，以避免威胁，以调查如何LC NE CeA中的释放控制着冻结反应和适应行动之间的平衡。为了实现这一点， 将使用早期生活创伤范例，其可靠地产生无法进行AA的动物， 成年人了我们将在这些所谓的“不良回避者”和“良好回避者”控制中操纵LCàCeA回路， 确定行为，电生理，和AA的分子机制。我们将测试 预测从LC释放的NE升高，以及在特定CeA靶神经元处产生的变化， 在良好的回避者中产生一个不良的回避表型，而在不良的回避者中抑制这个回路将“拯救”AA 行为我们还将评估细胞亚型的分子特性和电生理特征， 他们是如何在功能上不同的好与坏的回避，以及LC活动的作用，在这些 变化总之，这些研究旨在改变场如何看待NE系统，从调节恐惧， BLA中的记忆形成，通过CeA中的动作控制防御反应选择。这些研究 也将挑战占主导地位的方法论范式（例如，恐惧条件反射），这错过了一个重要的 动物行为的一个方面：对感知到的威胁的反应与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， 为适应不良应对的新疗法提供基于证据的支持，包括积极应对训练 结合药物来控制过度活跃的NE系统。