Neural mechanisms of active avoidance behavior

主动回避行为的神经机制

• 批准号: 10393704
• 负责人: Manuel A Castro-Alamancos
• 金额: $ 55.54万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393704
• 关键词: Air; Amygdaloid structure; Animals; Anxiety Disorders; Area; Aversive Stimulus; Avoidance Learning; Basal Ganglia; Behavior; Behavioral; Brain; Cell Nucleus; Cells; Conditioned Reflex; Conditioned Stimulus; Coping Skills; Corpus striatum structure; Cre-LoxP; Electrophysiology (science); Emotional; Emotions; Etiology; Event; Freezing; Fright; Ganglia; Glutamates; Goals; Heart Rate; Histologic; In Vitro; Learning; Lesion; Link; Measures; Mediating; Mental disorders; Methods; Midbrain structure; Modality; Modeling; Mouse Strains; Mus; Neurons; Outcome; Output; Pathological anxiety; Pathway interactions; Pedunculopontine Tegmental Nucleus; Performance; Pharmacology; Phobias; Procedures; Ramp; Research; Research Project Grants; Resolution; Role; Sensory; Signal Transduction; Slice; Stimulus; Structure; Substantia nigra structure; Testing; Thalamic structure; Transportation; Work; active control; avoidance behavior; base; behavioral response; clinically relevant; conditioned fear; conditioning; in vivo; learned behavior; millisecond; neural circuit; neural model; neuromechanism; neuronal circuitry; optogenetics; predictive modeling; relating to nervous system; response; sensory signal detection; sensory stimulus; social anxiety; social situation; superior colliculus Corpora quadrigemina; theories; tool

Summary Enormous progress has been made about the neural substrates of Pavlovian fear conditioning. In this paradigm, the association between an initially neutral sensory stimulus with an aversive event (footshock) leads to the transformation of the neutral stimulus into a conditioned stimulus (CS) that elicits fear responses in the form of immobility, potentiated startle, changes in heart rate, etc, which were not evoked by the neutral sensory stimulus. Ample evidence indicates that the CS must be transmitted through the modality-specific sensory thalamus to reach emotional processing centers in the amygdala, where the association with the aversive stimulus occurs and an output drives the conditioned responses. In contrast, little is known about the neural circuits involved in active avoidance behavior. In this paradigm, subjects learn to avoid an aversive event by producing an appropriate behavioral response (avoidance) during an interval signaled by the presentation of a CS. Understanding active avoidance behavior is important because it is present in most forms of pathological anxiety. Using optogenetics and chemogenetics, we recently found that the output of the basal ganglia through GABAergic neurons in the substantia nigra pars reticulata (SNr) fully controls active avoidance. SNr excitation blocks active avoidance without interfering with the ability to escape the harmful event, while SNr inhibition facilitates avoidance or can drive it in the absence of an external CS. With this work as a backdrop, we have developed a hypothetical model of the neural circuits involved in the performance (expression) of active avoidance behavior. Here we propose to test key aspects of this model. Our hypothesis is that SNr mediates active avoidance behavior though its projections to specific portions of the midbrain that drive the locomotor responses needed to avoid. Moreover, specific regions of the striatum control SNr activity during avoidance via striatonigral connections. We will employ a combination of behavioral, electrophysiological, optogenetics, chemogenetics, pharmacological and histological procedures to test these ideas. The long term objective of this research project is to reveal the neural substrates of active avoidance behavior, which has direct relevance to many psychiatric disorders.

总结 关于巴甫洛夫恐惧条件反射的神经基质已经取得了巨大的进展。在这 范式，最初中性感觉刺激与厌恶事件（电击脚）之间的关联 导致中性刺激转化为条件刺激（CS），激发恐惧反应， 不动的形式，增强惊吓，心率变化等，这些都不是由中性刺激引起的。 感官刺激大量的证据表明，CS必须通过特定的模态传输， 感觉丘脑到达杏仁核中的情绪处理中心，在那里， 出现厌恶刺激并且输出驱动条件反应。相比之下， 参与主动回避行为的神经回路在这个范例中，受试者学会避免一个令人厌恶的 通过在由事件发出信号的间隔期间产生适当的行为响应（回避）来控制事件。 介绍一个CS。了解主动回避行为很重要，因为它存在于大多数人中。 病理性焦虑利用光遗传学和化学遗传学，我们最近发现， 基底神经节通过黑质网状部（SNr）的GABA能神经元完全控制活性 回避SNr兴奋阻断主动回避，而不干扰逃避有害环境的能力。 事件，而SNr抑制有助于避免或可以在没有外部CS的情况下驱动它。通过这项工作 作为一个背景，我们已经开发了一个参与表演的神经回路的假设模型， 主动回避行为。在这里，我们建议测试这个模型的关键方面。我们的假设 SNr通过其投射到中脑的特定部分来介导主动回避行为， 驱动需要躲避的运动反应。此外，纹状体的特定区域控制SNr活性 通过纹状体黑质的联系来逃避。我们将采用行为， 电生理学、光遗传学、化学遗传学、药理学和组织学方法来测试这些 想法.本研究的长期目标是揭示主动回避的神经机制 行为，这与许多精神疾病直接相关。