Neural substrates for expectation-modulated fear learning in the amygdala and periaqueductal gray

A form of aversively motivated learning called fear conditioning occurs when a neutral conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US). US-evoked depolarization of amygdala neurons may instruct Hebbian plasticity that stores memories of the CS-US association, but the origin of US inputs to the amygdala is unknown. Theory and evidence suggest that instructive US inputs to the amygdala will be inhibited when the US is expected, but this has not been demonstrated during fear conditioning. Here we investigated neural pathways that relay US information to the amygdala by recording neurons in the amygdala and periaqueductal gray (PAG) during fear conditioning. US-evoked responses in both amygdala and PAG were inhibited by expectation. Pharmacological inactivation of the PAG attenuated US-evoked responses in the amygdala and impaired acquisition of fear conditioning, indicating that PAG may be an important part of the pathway that relays instructive signals to the amygdala.