Prefrontal NMDA-receptor antagonism disrupts encoding or consolidation but not retrieval of incidental context learning.

The Context Preexposure Facilitation Effect (CPFE) is a variant of contextual fear conditioning in which learning about the context, acquiring a context-shock association, and retrieval of this association occur separately across three phases (context preexposure, immediate-shock training, and retention). We have shown that prefrontal inactivation or muscarinic-receptor antagonism prior to any phase disrupts retention test freezing during the CPFE in adolescent rats (Heroux et al., 2017; Robinson-Drummer et al., 2017). Furthermore, the medial prefrontal cortex (mPFC) is the only region in which robust learning-related expression of the immediate early genes c-Fos, Arc, Egr-1 and Npas4 is observed during immediate-shock training in the CPFE (Asok et al., 2013; Heroux et al., 2018; Schreiber et al., 2014). However, the role of prefrontal NMDA-receptor plasticity in supporting preexposure- and training-day processes of the CPFE is not known. Therefore, the current study examined the effects of intra-mPFC infusion of the NMDA-receptor antagonist MK-801 or saline vehicle prior to context preexposure (Experiment 1) or immediate-shock training (Experiment 2) in adolescent Long-Evans male and female rats. This infusion given prior to context preexposure but not training abolished retention test freezing, with no difference between MK-801-infused rats and non-associative controls preexposed to an alternative context (pooled across drug). These results demonstrate a role of prefrontal NMDA-receptor plasticity in the acquisition and/or consolidation of incidental context learning (i.e., encoded in the absence of reinforcement). In contrast, this plasticity is not required for context retrieval, or acquisition, expression, or consolidation of a context-shock association during immediate-shock training in the CPFE. These experiments add to a growing body of work implicating the mPFC in Pavlovian contextual fear conditioning processes in rodents.