Summary Fear behaviors are regulated by adaptive mechanisms that dampen their expression in the absence of danger. By studying circuits and the molecular mechanisms underlying this adaptive response, we show that cholinergic neurons of the medial habenula reduce fear memory expression through GABA B presynaptic excitation. Ablating these neurons or inactivating their GABA B receptors impairs fear extinction in mice, whereas activating the neurons or their axonal GABA B receptors reduces conditioned fear. Although considered exclusively inhibitory, here, GABA B mediates excitation by amplifying presynaptic Ca 2+ entry through Ca v2.3 channels and potentiating co-release of glutamate, acetylcholine, and neurokinin B to excite interpeduncular neurons. Activating the receptors for these neurotransmitters or enhancing neurotransmission with a phosphodiesterase inhibitor reduces fear responses of both wild-type and GABA B mutant mice. We identify the role of an extra-amygdalar circuit and presynaptic GABA B receptors in fear control, suggesting that boosting neurotransmission in this pathway might ameliorate some fear disorders.
