Visceral hypersensitivity following adult chronic social defeat stress is associated with microglial remodeling in the anterior cingulate cortex.

Abstract

Stress contributes significantly to visceral pain hypersensitivity in irritable bowel syndrome (IBS). Although stress during critical developmental periods, such as chronic social defeat stress (CSDS) in adolescence or early-life adversities, like maternal separation, has been extensively researched and is known to increase visceral pain sensitivity, little is known about the effects of CSDS on visceral pain processing in full adulthood. This gap is important because IBS onset and exacerbation of symptoms frequently occur in adults experiencing chronic psychosocial stress. Using a CSDS protocol in adult mice, we examined changes in visceral pain thresholds, anxiety-like behavior, and neuroimmune plasticity, particularly focusing on microglia linked to pain and emotions. CSDS-exposed mice exhibited significantly reduced visceral pain thresholds and heightened visceral sensitivity, accompanied by adrenal gland hypertrophy, thymic atrophy, and elevated anxiety-like behavior. Morphological analysis revealed pronounced microglial process shrinkage and decreased branching within the anterior cingulate cortex (ACC) after CSDS, without considerable changes in traditional inflammation-associated mRNA levels. No microglial remodeling was detected in other regions. Microglial depletion with PLX3397 partially reduced visceral hypersensitivity, producing an intermediate phenotype, but did not improve anxiety-like behavior. Our findings suggest that microglia play a modulatory, but not exclusive role in stress-induced visceral pain. Regional differences indicate the ACC acts as a hub for chronic pain plasticity, governed by complex microglial and circuit-level mechanisms.