Brainstem Modulation of Proactive Coping

主动应对的脑干调节

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要虽然有些人能够很好地应对困难，但其他人却没有那么有弹性，尽管研究的重点是。恐惧反应的严重程度，临床证据表明反应冲突是适应不良的根源拟议的研究追求去甲肾上腺素的工作假设。 (NE)，一种在患有恐惧症和焦虑症的患者中观察到高水平的神经递质，引起该领域的工作主要集中在 NE 上。基底外侧杏仁核（BLA）中的释放，驱动恐惧调节范式中的情绪学习。然而，BLA 中的 NE 并不影响恐惧的表达（初步和已发表的反应）。另一方面，数据显示，中央杏仁核 (CeA) 的 NE 活动增加会支持威胁（恐惧）反应并反对主动行为。杏仁核接收来自脑干位点的强烈输入。蓝藻 (LC)，大脑中 NE 的主要来源。拟议的研究采用主动回避。范式（AA），其中动物学会发出主动反应以避免威胁，以研究 LC NE CeA 中的释放控制着冻结反应和适应性行动之间的平衡。将使用早期生命创伤范例，这可靠地产生无法执行 AA 的动物我们将在这些所谓的“差回避者”和“好回避者”控制中操纵 LCàCeA 电路，以达到以下目的：我们将测试 AA 的行为、电生理和分子机制。预测 LC 中 NE 的释放增加，以及由此导致的特定 CeA 靶神经元的变化，将在良好的回避者中产生不良的回避表型，而在不良的回避者中抑制该电路将“拯救”AA 我们还将评估细胞亚型的分子特性和电生理学特征。 CeA，它们在良好回避者和不良回避者中的功能有何不同，以及 LC 活性在这些中的作用总之，这些研究旨在改变该领域对 NE 系统的看法，从调节恐惧开始。 BLA 中的记忆形成，通过 CeA 中的动作控制防御反应选择。还将挑战占主导地位的方法论范式（例如，恐惧调节），这些范式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性反应与主动反应之间的竞争。成功完成这些研究将揭示 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，包括主动应对训练与药物结合以控制过度活跃的 NE 系统。