Differential Alterations in Cortico-Amygdala Circuitry in Mice with Impaired Fear Extinction.

129S1/SvImJ (S1) mice exhibit selective impairments in fear extinction, though the mechanisms underlying these impairments are not fully understood. The medial prefrontal cortex (mPFC) consists of the prelimbic cortex (PL) and infralimbic cortex (IL), which are known to be involved in fear conditioning and extinction, respectively. The PL and IL project to the basolateral amygdala (BLA) that also plays an important role in both mechanisms. In the present study, we utilized optogenetic and electrophysiological approaches to measure inhibitory/excitatory ratios (I/E ratios) in mPFC-BLA circuits of S1 and control C57BL/6 (B6) mice following fear conditioning and extinction. As suggested previously, PL inputs to the BLA became more excitatory after fear conditioning in B6 mice. S1 mice also exhibited strengthened PL-BLA circuit following fear conditioning. Interestingly, fear extinction restored PL-BLA circuit strength to levels comparable to the baseline in B6 mice. However, PL-BLA circuit strength remained abnormally high even after extinction in S1 mice. The IL-BLA circuit became more inhibitory in B6 mice after fear extinction, whereas extinction failed to change the excitability of the IL-BLA circuit in S1 mice. These data suggest that the fear extinction impairments observed in S1 mice may be due to constantly decreased I/E balance in the PL-BLA circuit and lack of changes in I/E balance in the IL-BLA circuit. This further suggests that investigation of both pathways is instrumental in developing more effective therapeutics for psychopathologies that involve impairments in fear extinction, such as chronic pain and posttraumatic stress disorder.