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. PUBLIC HEALTH RELEVANCE: In many circumstances, subjects respond to fearful situations with avoidance. This is a useful coping strategy in situations where there is impending danger. However, avoidance responses can also be maladaptive. This is typical of many anxiety disorders, such as phobias (e.g. avoiding air transportation) and social anxiety (e.g. avoiding social situations). In fact, avoidance is a hallmark of most forms of pathological anxiety, in whic the tendency to avoid is so strong that it interferes with normal daily activities. Despite the obvious clinical relevance, very little is known about the neural circuits involved in the acquisition (learning) and expression (performance) of active avoidance. The goal of this research is to investigate the neural basis of active avoidance behavior.