A novel role for the infralimbic cortex in conditioned fear responding

Freezing during Pavlovian fear conditioning is the most commonly used indicator of learned fear in rodents. Although freezing and its neural underpinnings have been widely studied, the field has largely ignored other potential indicators of learned fear. Darting, an escape-like conditioned fear response, occurs more frequently in females and is reliably predicted by a distinct behavioral phenotype: heightened shock response and decreased freezing compared to rodents that do not engage in darting. The experiments in this study sought to expand the field's understanding of conditioned fear by investigating the neural correlates of conditioned darting, focusing on the infralimbic cortex (IL) and longitudinal columns of the periaqueductal gray (PAG) due to their known roles in modulating defensive responses, including conditioned freezing. We find that fear conditioning elicits greater neural activity (measured by quantification of cFos expression) in the IL of females compared to males, but that IL activation corresponds to freezing only in Darters. We next used chemogenetic tools to excite or inhibit either the IL alone or IL-PAG projections prior to fear conditioning. IL manipulations in either direction reduced freezing in both males and females, while IL inhibition increased darting and shock response in females only, and the effects of circuit-specific manipulations were minimal. Together, our findings suggest a novel, role for the IL in driving defensive responses during fear conditioning that is not dependent on IL-PAG connectivity.