Temporal Dynamics of Parvalbumin Interneurons and Perineuronal Nets During Learned Helplessness

Abstract This study followed the recruitment of medial prefrontal cortex parvalbumin (PV + ) interneurons and their perineuronal nets (PNN) across the two stages of the learned helplessness (LH) paradigm: the initial uncontrollable stress experience and the later expression of helpless or resilient coping. Combining TRAP2-based activity mapping with a staggered-endpoint design, three main findings emerged on the functional and structural neuronal correlates in prelimbic (PL) and infralimbic (ILA) subregions during LH paradigm. First, prefrontal recruitment during the first inescapable shock session already predicted the coping strategy that would be expressed two days later during escape avoidance test, before any behavioral divergence was observable. Second, the expression of parvalbumin protein (PV) in this cortical subpopulation of interneurons followed a dynamic trajectory rather than a static stress change, transiently reduced across all shocked animals at the escape test, and back to baseline over the following week in both PL and ILA, except in animals that went on to be classified as “helpless”. Third, PNN intensity temporal patterns did not track stress exposure in either subregion, yet PNN and PV became correlated with one another specifically in ILA in stressed animals, pointing to a stress-induced structural coupling rather than a constitutive relationship between the two markers.