Basomedial amygdala mediates top-down control of anxiety and fear

Activation of the ventral medial prefrontal cortex–basomedial amygdala pathway is shown to suppress anxiety and fear-related freezing in mice, thus identifying the basomedial amygdala (and not intercalated cells, as posited by earlier models) as a novel target of top-down control. Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC–BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway. Mechanism of regulation of anxiety and fear Regulation of fear and anxiety by the amygdala is thought to be subject to top-down control by the medial prefrontal cortex (mPFC), but the precise amygdala targets of mPFC subregions in this process are not well established. Karl Deisseroth and colleagues show here that the basomedial amygdala, rather than the intercalated cells, is a major target of the ventral mPFC in mice, and that activation of the ventral mPFC–basomedial amygdala pathway suppresses anxiety and fear-related freezing. This points to the basomedial amygdala as a novel target of top-down control.