Nucleus Accumbens MEF2C Mediates the Maintenance of Peripheral Nerve Injury-induced Physiological and Behavioral Maladaptations

Pre-clinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling. Mef2c overexpression also reversed SNI-induced neuronal hyperexcitability and sensitized dopamine release after phasic stimulation. Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain. Overall design: C57BL/6J or DBA/2J mice (8-9 weeks old) were obtained from Jackson Laboratories and maintained on a 12-hour light/dark cycle with ad libitum access to food and water. Tibial SNI was performed on the left sciatic nerve under inhaled isoflurane. In Sham-operated mice, the same procedure was followed, but the nerves were left untouched. Stereotaxic coordinates for bilateral viral vector injections into the NAc were as follows with respect to bregma: AP, +1.60mm; ML: ±1.50mm; DV, -4.40mm at an angle of 10° from the midline. AAV8-hSyn-Mef2c-Egfp and AAV8-hSyn-Egfp were supplied by the Akbarian Lab at the Icahn School of Medicine at Mount Sinai. Approximately 7x10^9 viral particles were administered into the NAc of each hemisphere.