Exploring the Role of Infralimbic Cortex Inhibitory Circuits in Context-Dependent Extinction and Renewal of Fear

Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD). However, many patients experienced relapse of fear after treatment. Pavlovian fear conditioning and extinction are effective models to study the return of fear. During fear conditioning, an auditory conditioned stimulus (CS) is paired with an electric footshock (i.e., the unconditioned stimulus, US); after conditioning, the CS evoked a conditional fear response. Presenting the CS numerous times without the US causes an extinction of fear to the CS; however, the loss of fear to the CS is context-specific. That is, extinguished fear returns or “renews” outside of the extinction context. The hippocampus, the medial prefrontal cortex (mPFC) and the amygdala are thought to be essential for context-dependent extinction retrieval and fear renewal. However, how the mPFC, especially the infralimbic cortex (IL), regulates extinction memory is not clear. To clarify this question, I first used retrograde tracing techniques with immediate early gene expression to examine the activity of the mPFC-projecting neurons in the ventral hippocampus (VH) during extinction retrieval and fear renewal. Secondly, I pharmacologically manipulated GABAᴀ receptors in the IL during either extinction retrieval or fear renewal. Lastly, I examined the activity of the interneurons in IL in extinction memory retrieval and examined their contribution to memory retrieval using cell- and circuit-specific DREADD methods. The results showed that VH projections to the prelimbic cortex (PL) and IL were both engaged by fear renewal. This pattern of results suggested that VH inhibits IL via feed-forward inhibition, a finding that was confirmed by pharmacological manipulation of GABAᴀ receptors in IL. Specifically, GABAᴀ receptor agonists interfered with extinction retrieval in the extinction context, whereas GABAᴀ receptor antagonists reduced fear renewal in a different context. However, GAD-Fos immunohistochemistry did not reveal preferential recruitment of IL interneurons during renewal. Finally, the inactivation of putative IL interneurons or activation IL-> BLA pathway did not alter fear renewal. Together, these results suggested the regulating role of IL inhibitory circuits in the context-dependent memory of extinction. Future studies will be done to understand how subtypes of IL local interneurons and the GABA receptors subtypes modulate memory of extinction