Dopamine D2 receptors in the extended amygdala scale the optimization of seeking and avoidance behaviors

Abstract In mammals, the ability to optimize and select behavioral strategies is a cardinal and conserved psychophysiological feature for maximizing the chances of survival. However, the neural circuits and underlying mechanisms regulating this flexible feature remain yet unsolved. Here, we demonstrate that such optimization relies on dopamine D2 receptors (D2R) within a subcircuit spanning across the extended amygdala (EA) and the tail of the striatum (TS). Using a mouse model carrying a temporally controlled deletion of D2R within a subcircuit defined by WFS1 neurons, we found that intact EA D2R signaling is necessary to regulate homeostasis-dependent food-seeking behaviors in both male and female mice as well as active avoidance learning and innate escape responses in males. Altogether, these findings identify EA and TS D2R signaling as a novel hub through which dopamine optimizes appetitive behaviors and regulates the switch from passive to active defensive behaviors, regardless of learned or innate threats.