Neural basis of active avoidance behavior

描述(由申请人提供)：关于巴甫洛夫恐惧条件作用的神经基础已经取得了巨大的进展。在这一范式中，最初的中性感觉刺激与厌恶事件(足底电击)之间的联系导致中性刺激转变为条件刺激(CS)，条件刺激引起的恐惧反应形式为静止不动、加强惊吓、心率变化等，而中性感觉刺激不会引起这些反应。大量证据表明，CS必须通过通道特有的感觉丘脑传递到杏仁核的情绪处理中心，在那里与厌恶刺激发生关联，输出驱动条件反应。相比之下，人们对参与主动回避行为的神经回路知之甚少。在这一范式中，受试者通过在呈现CS的间隔期间产生适当的行为反应(回避)来学习避免厌恶事件。理解主动回避行为很重要，因为它存在于大多数形式的病理性焦虑中。最近，我们在大鼠身上发现，丘脑感觉的损伤可以消除对通道相关CS的巴甫洛夫恐惧条件反射，但并不能消除对同一CS的主动回避。在这些动物中，上丘处理CS并调节主动回避。我们的一般假设是，上丘是一个早期中继站，用于快速检测具有重要行为意义并需要立即采取行动的感觉信号；一个非常适合调解主动回避的早期感觉运动中枢。以这项工作为背景，我们提出了一个涉及主动回避行为表现(表达)的神经回路的假设模型。在这里，我们建议测试该模型的两个关键方面。第一个目标是确定调节主动回避的输出通路。第二个目标是确定基底节在门控主动回避反应中的作用。我们将综合运用行为学、电生理学、药理学和组织学的方法来实现这些目标。这项研究的长期目标是揭示主动回避行为的神经基础，这与许多精神障碍有直接关系。

DESCRIPTION (provided by applicant): 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. Recently, using rats we found that lesions of the sensory thalamus that abolish Pavlovian fear conditioning to the modality-related CS do not abolish active avoidance to the same CS. In these animals, the superior colliculus processes the CS and mediates active avoidance. Our general hypothesis is that the superior colliculus serves as an early relay station for rapid detection of sensory signals that are behaviorally significant and require immediate action; an early sensorimotor hub well suited to mediate active avoidance. 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 two key aspects of this model. The first goal is to determine the output pathways that mediate active avoidance. The second goal is to determine the role of basal ganglia in gating active avoidance responses. We will employ a combination of behavioral, electrophysiological, pharmacological and histological procedures to reach these goals. 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.