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

Denholtz, L. E.; Liu, J.; Nahmoud, I.; Casaccia, P.; Likhtik, E.

doi:10.1101/2025.07.25.666881

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bioRxiv · 10.1101/2025.07.25.666881

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

Denholtz, L. E.·Liu, J.·Nahmoud, I.·Casaccia, P.·Likhtik, E.

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Abstract

Safety learning is mediated by the infralimbic region (IL) of the medial prefrontal cortex, but its cellular mechanisms are poorly understood. Here we show that safety learning improves cognitive flexibility in the long-term, which is associated with recruitment of oligodendrocyte progenitor cells to a satellite position at parvalbumin (PV) interneurons in the IL and their maturation into oligodendrocytes (OLs), as well as a decrease in perineuronal nets (PNNs) surrounding PVs paired with satellite OLs. Using scRNA transcriptomic data mining, we demonstrate that immature OLs primarily express PNN assembly genes, whereas mature OLs express PNN degradation enzymes. We then demonstrate that inhibiting IL PVs during safety learning prevents safety-induced cognitive flexibility, satellite OL maturation, and PNN degradation around IL PV. Thus, we propose that safety learning drives a novel form of neuro-glial plasticity that helps degrade PNNs around PV interneurons via OL recruitment and maturation, thereby shaping IL long-term activity.

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Denholtz, L. E., Liu, J., Nahmoud, I., Casaccia, P., Likhtik, E.. 2025-07-31. PV - Oligodendrocyte Interactions in the Infralimbic Cortex Promote Extracellular Plasticity after Safety Learning. https://doi.org/10.1101/2025.07.25.666881

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