Sex-specific frontal cortical circuit mechanisms mediating fear extinction

Strong evidence suggests synaptic plasticity is the critical cellular mechanism underlying learning and memory. Although the forms of synaptic plasticity used by different circuits vary, a widespread presumption is that the male and female brain has evolved to use the same form of plasticity within the same circuits during learning. We used complimentary approaches to determine how synaptic plasticity within the mouse frontal cortex supports extinction of associative memories. Here, we show that both male and female mice have similar ensemble dynamics in excitatory infralimbic cortical neurons during learning. However, activity in amygdala-projecting neurons was required for extinction memories only in male mice. Likewise, only male mice showed evidence for structural synaptic remodeling and clustering of dendritic spines on infralimbic-amygdala projection neurons. Projection-specific deletion of the glutamate receptor subunit GRIN2B blocked synaptic plasticity and impaired extinction memory in male but not female mice. These distinct mechanisms could be leveraged for precise therapies for mental health conditions relative to the present one-size-fits-all approach.