Sex-dependent neuronal loss and apoptotic signaling in the anterior cingulate and anterior insular cortices associated with anxio-depressive-like behaviors in a late-stage monoiodoacetate mouse model of osteoarthritis

Osteoarthritis (OA) is a leading cause of disability worldwide, with chronic pain representing its most debilitating symptom and frequently accompanied by affective alterations. Increasing evidence implicates maladaptive supraspinal plasticity within cortical regions involved in pain affect, including the anterior cingulate cortex (ACC) and anterior insular cortex (AIC). However, the relationship between these behavioral impairments and neuronal alteration, as well as potential sex-specific vulnerability, remains poorly understood. Using a monosodium iodoacetate (MIA) model of knee OA in adult male and female mice, we examined the temporal progression of mechanical, thermal, functional and affective alterations at early (day 7) and advanced (day 28) stages of disease. Pain sensitivity, locomotor and gait changes, anxiety- and depression-like behaviors were assessed using established behavioral paradigms, followed by analyses of neuronal density and apoptotic signaling in the ACC and AIC. MIA induced robust mechanical and thermal hypersensitivity and gait impairment in both sexes, while early emotional alterations were not significant. In contrast, advanced OA was associated with pronounced anxiety- and depression-like behaviors. Notably, day 28 post-MIA analyses revealed significant neuronal loss and increased caspase-dependent apoptosis in both cortical regions, with females exhibiting greater vulnerability, particularly within the AIC, paralleling their more severe affective phenotypes. Together, these findings demonstrate that chronic OA pain is associated with progressive, sex-dependent neuronal loss within key cortical pain-affective circuits and highlight cortical neuronal remodeling as a critical substrate underlying the emotional burden of osteoarthritis pain.