PV - Oligodendrocyte Interactions In the Infralimbic Cortex Promote Extracellular Plasticity after Safety Learning

The ability to differentiate between threat and safety cues is essential for adaptive behavior, yet this process is disrupted in psychiatric disorders such as post-traumatic stress disorder (PTSD), where safety cues fail to suppress fear expression. To uncover the neurobiological mechanisms of safety learning, we compared safety conditioning (SC) and contextual fear conditioning (CFC) in the infralimbic cortex (IL) of the medial prefrontal cortex (mPFC) across recent and remote memory retrieval in mice. We identify a novel mechanism whereby safety learning promotes neuro-glial interactions that may facilitate plasticity in the mPFC. SC promotes long-term suppression of contextual fear compared to CFC. At remote retrieval, SC animals show increased IL parvalbumin (PV) interneuron activity and reduced perineuronal net (PNN) density, suggesting that extracellular matrix (ECM) remodeling could support enhanced plasticity in this group. We further identify a critical role for oligodendrocyte lineage cells (OLCs) in PNN remodeling. Notably, safety retrieval recruits satellite oligodendrocyte lineage cells (i.e., satOlig2+ cells) to PV interneurons. In SC animals, this recruitment correlates with reduced PNN accumulation around PV-satOlig2 pairs, whereas CFC animals exhibit increased PNN density at remote retrieval. Open-source single-cell RNA sequencing reveals that oligodendrocyte precursor cells (OPCs) express PNN-building genes, mature oligodendrocytes (OLs) express PNN-degrading genes, and newly-formed oligodendrocytes (NFOLs) express both. Bulk RNAseq from SC animals shows reduced expression of OPC-related structural genes and increased expression of OL-related PNN-degrading genes in the mPFC. Notably, satOlig2 cells recruited during remote safety retrieval are predominantly CC1+ mature satellite OLs (satOLs), which we hypothesize degrade PNNs through expression of PNN degradation enzymes. Optogenetic inhibition of PV activity during safety learning blocks satOlig2 recruitment, maturation, and PNN degradation while restoring long-term contextual fear expression. These findings suggest a role for satOlig2 cells in promoting safety learning through dynamic PNN regulation. By maintaining PV interneuron activity and excitatory-inhibitory balance, satOlig2 cells may facilitate PNN remodeling, in support of fear suppression and adaptive behavior. This study provides critical insights into the mechanisms of safety learning and highlights potential OL- and ECM-based therapeutic targets for PTSD and related psychiatric disorders.