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 虽然有些人能很好地应对困难，但另一些人则没有那么强的韧性。尽管研究的重点是 恐惧反应的大小，临床证据表明，反应冲突是适应不良的根源 应对精神疾病。这项拟议的研究追求的是去甲肾上腺素的工作假设 (NE)，一种在患有恐惧和焦虑症的患者中观察到的高水平神经递质，引起 与主动应对行为相冲突的行为反应。实地工作主要集中在东北地区 在杏仁基底外侧核(BLA)释放，在恐惧条件反射范式中驱动情绪学习。 然而，BLA中的去甲肾上腺素并不影响恐惧的表达(冰冻反应)。初稿和出版 数据显示，另一方面，杏仁中央核(CEA)去甲肾上腺素(NE)活动的增加支持威胁(恐惧) 反应和反对主动行为。杏仁核接受来自脑干部位的强输入。 蓝斑(LC)是脑内去甲肾上腺素的主要来源。这项拟议的研究使用了主动回避 范式(AA)，在这个范式中，动物学习发出主动反应以避免威胁，以研究LC NE是如何 在CEA中的释放控制着冻结反应和适应作用之间的平衡。要做到这一点， 将使用早期生命创伤范例，它可靠地产生不能执行AA AS的动物 成年人。我们将在这些所谓的“糟糕的回避者”和“优秀的回避者”控制中操纵LC？CEA电路 明确AA的行为、电生理和分子机制。我们将测试 预测LC中NE释放增加，以及由此导致的特定CEA靶神经元的变化，将 在好的回避者中产生一个糟糕的回避表型，而在糟糕的回避者中抑制这一回路将‘拯救’AA 行为。我们还将评估细胞亚型的分子同一性和电生理特征。 CEA，它们在好的和不好的回避者中的功能差异，以及LC活动在这些中的作用 改变。总之，这些研究的目的是改变能量场对NE系统的看法，从调节恐惧 BLA中的记忆形成，到通过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，恐惧条件作用)，这些范式错过了一个必要的 动物行为方面：对感知到的威胁的反应性和主动性反应之间的竞争。 这些研究的成功完成将揭示NE系统在适应性应对行为和 为适应不良应对的新疗法提供循证支持，包括积极的应对训练 结合药物来控制过度活跃的NE系统。