Effects of treadmill running on anxiety- and craniofacial pain-like behaviors with histone H3 acetylation in the brain of mice subjected to social defeat stress

This study examined the effects of treadmill running (TR) regimens on craniofacial pain- and anxiety-like behaviors, as well as their effects on neural changes in specific brain regions of male mice subjected to repeated social defeat stress (SDS) for 10 days. Behavioral and immunohistochemical experiments were conducted to evaluate the impact of TR regimens on SDS-related those behaviors, as well as epigenetic and neural activity markers in the anterior cingulate cortex (ACC), insular cortex (IC), rostral ventromedial medulla (RVM), and cervical spinal dorsal horn (C2). Behavioral responses were quantified using multiple tests, while immunohistochemistry measured histone H3 acetylation, histone deacetylases (HDAC1, HDAC2), and neural activity markers (FosB and phosphorylated cAMP response element-binding protein (pCREB). The effects of both short-term TR (2 days, TR2) and long-term TR (10 days, TR10) regimens were conducted. TR10 significantly reduced anxiety- and formalin-evoked craniofacial pain-like behaviors in SDS mice. It normalized SDS-induced increases in histone H3 acetylation in both the anterior and posterior portions of the ACC, as well as the anterior portion of the IC. These inhibitory effects were also observed in SDS-related increases in HDAC1, FosB, and pCREB expression. Additionally, TR10 normalized increased histone H3 acetylation in the RVM and C2 regions, with specific effects on FosB and pCREB expression observed in the C2 region. In contrast, TR2 showed limited effects on craniofacial pain-like behaviors but reduced anxiety-like behaviors in SDS mice. Under sham conditions, TR2 had minimal impact on histone H3 acetylation. Paradoxically, TR2 increased formalin-evoked craniofacial pain-like behaviors during the early phase despite not altering acetylated histone H3 expression. In conclusion, the TR10 regimen is effective in attenuating SDS-induced craniofacial pain- and anxiety-like behaviors, likely by normalizing epigenetic modifications and neural activity in key brain regions.