Brain-derived neurotrophic factor (BDNF) is critical for establishing activity-related neural plasticity. There is increasing interest in the mechanisms of active avoidance and its extinction, but little is known about the role of BDNF in these processes. Using the platform-mediated avoidance task combined with local infusions of an antibody against BDNF, we show that blocking BDNF in either prelimbic (PL) or infralimbic (IL) medial prefrontal cortex during extinction training impairs subsequent recall of extinction of avoidance, differing from extinction of conditioned freezing. By combining retrograde tracers with BDNF immunohistochemistry, we show that extinction of avoidance increases BDNF expression in ventral hippocampal (vHPC) neurons, but not amygdala neurons, projecting to PL and IL. Using the CRISPR/Cas9 system, we further show that reducing BDNF production in vHPC neurons impairs recall of avoidance extinction. Thus, the vHPC may mediate behavioral flexibility in avoidance by driving extinction-related plasticity via BDNFergic projections to both PL and IL. These findings add to the growing body of knowledge implicating the hippocampal-prefrontal pathway in anxiety-related disorders and extinction-based therapies.

The long-lasting nature of fear memories is essential for survival, but the neural circuitry for retrieval of these associations changes with the passage of time. We previously reported a time-dependent shift from prefrontal-amygdalar circuits to prefrontal-thalamic circuits for the retrieval of auditory fear conditioning. However, little is known about the time-dependent changes in the originating site, the prefrontal cortex. Here we monitored the responses of prelimbic (PL) prefrontal neurons to conditioned tones at early (2 h) vs. late (4 days) timepoints following training. Using c-Fos, we find that PL neurons projecting to the amygdala are activated early after learning, but not later, whereas PL neurons projecting to the paraventricular thalamus (PVT) show the opposite pattern. Using unit recording, we find that PL neurons in layer V (the origin of projections to amygdala) showed cue-induced excitation at earlier but not later timepoints, whereas PL neurons in Layer VI (the origin of projections to PVT) showed cue-induced inhibition at later, but not earlier, timepoints, along with an increase in spontaneous firing rate. Thus, soon after conditioning, there are conditioned excitatory responses in PL layer V which influence the amygdala. With the passage of time, however, retrieval of fear memories shifts to inhibitory responses in PL layer VI which influence the midline thalamus.