Persistent anxiety after a psychological trauma is a hallmark of many anxiety disorders. However, the neural circuits mediating the extinction of traumatic fear memories remain incompletely understood. We show that selective, in vivo stimulation of the ventromedial prefrontal cortex (vmPFC)–amygdala pathway facilitated extinction memory formation, but not retrieval. Conversely, silencing the vmPFC-amygdala pathway impaired extinction formation and reduced extinction-induced amygdala activity. Our data demonstrate a critical instructional role for the vmPFC-amygdala circuit in the formation of extinction memories. These findings advance our understanding of the neural basis of persistent fear, with implications for posttraumatic stress disorder and other anxiety disorders.
Chronic stress contributes to the neuropathology of mental health disorders, including those associated with anxiety. The basolateral amygdala (BLA) coordinates emotional behavioral responses through glutamatergic outputs to downstream regions such as the prefrontal cortex (PFC), nucleus accumbens core (NAcc) and bed nucleus of the stria terminalis (BNST). We explored the effects of chronic stress on BLA outputs to the PFC, NAcc and BNST using slice electrophysiology combined with optogenetics in two inbred mouse strains with distinct stress-induced anxiety responses. We found that ten consecutive days of chronic restraint stress enhanced pre-synaptic glutamate release at BLA-to-PFC synapses in C57BL/6J mice, but reduced pre-synaptic glutamate release at these synapses in DBA/2J mice. To assess the behavioral relevance of enhanced glutamate output at BLA-to-PFC synapses, we approximated the effects of chronic stress on the BLA-PFC circuit using optogenetics. We found that photostimulation of the BLA-PFC circuit in unstressed C57BL/6J mice produced persistent (i.e., post-stimulation) increased anxiety-like behavior and hyperactivity in the elevated plus-maze - a profile consistent with prototypical behavioral responses of stressed C57BL/6J mice. These data demonstrate that chronic stress dysregulates the BLA-PFC circuit by altering pre-synaptic glutamate release from BLA outputs, and provide a mechanism by which chronic stress can lead to increased anxiety.
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