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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE285736 | GEO | 2025/08/13

REPOSITORIES: GEO

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Project description:Background: Extinction-based exposure therapy is used in treating anxiety- and trauma-related disorders, however there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to facilitate the inadequate protection against return-of-fear phenomena. Methods: Spontaneous recovery and fear renewal tests, assessed persistence and context-independence of treatments rescuing deficient fear extinction in 129S1/SvImJ mice. To reveal neurobiological mechanisms supporting long-lasting extinction rescue, whole-genome expression profiling, qRT-PCR, immunohistochemistry and chromatin immunoprecipitation were used. Results: Persistent and context-independent rescue of deficient fear extinction induced by dietary zinc-restriction was associated with enhanced expression of dopamine-related genes, such as genes encoding the dopamine- D1 (Drd1a) and -D2 (Drd2) receptor in the medial prefrontal cortex (mPFC) and amygdala. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a possibly involved gene regulatory mechanism. While enhancing histone acetylation, via administering the HDAC inhibitor MS275, does not induce successful fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated. This was associated with enhanced neuronal histone acetylation in the mPFC and amygdala. Finally, as a proof of principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. Conclusion: Current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear inhibitory memory.

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

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