Inhibition of prefrontal glutamatergic neuron activity during the recovery period following chronic stress disrupts fear memory in male rats: potential role of the infralimbic cortex.

Chronic stress typically leads to deficits in fear extinction. However, when a delay occurs from the end of chronic stress and the start of fear conditioning (a "recovery"), rats show improved context-cue discrimination, compared to recently stressed rats or nonstressed rats. The infralimbic cortex (IL) is important for fear extinction and undergoes neuronal remodeling after chronic stress ends, which could drive improved context-cue discrimination. Here, glutamatergic IL neurons of Sprague-Dawley male rats were targeted for inhibition using inhibitory designer receptors exclusively activated by designer drugs (DREADDs) and daily injections of clozapine N-oxide (CNO) during a 21-day recovery period from chronic stress. Histological verification confirmed DREADDs in the IL with some spread to nearby medial prefrontal cortex (PFC) regions. CNO administration was then discontinued before fear conditioning started and behavioral testing thereafter so that behavioral assessments occurred without neuronal inhibition. Fear conditioning involved presenting male rats with three tone-foot shock pairings on 1 day, which was followed by 2 days of 15 tone-alone extinction sessions. Daily and repeated inhibition of mainly IL neurons during the 21-day recovery period did not disrupt fear learning or fear extinction in all groups (controls, stressed rats without a recovery, and stressed rats with a recovery). However, chronically stressed rats given a recovery and with DREADD activation showed impaired spontaneous recovery, indicating a failure to form a tone-foot shock association. The findings show that daily inhibition of mainly IL neurons prior to fear conditioning and extinction depends upon the changes that occur during the recovery period following the end of chronic stress.