Neural mechanisms of active avoidance behavior

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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.