Time-Restricted Feeding Alters Behavior in a Sex-Specific Manner in Mice With Neuropathic Pain

Evidence suggests that neuropathic pain (NP) and comorbid mood disorders are associated with circadian abnormalities. This suggests a role for chronotherapies, such as time-restricted feeding (TRF), to alleviate pain and comorbid anxiety. We investigated the effects of TRF on pain and anxiety-related behaviours in spared nerve injury (SNI) mice with NP and diurnal changes in the hypothalamus transcriptome, an important hub for modulating fear and anxiety. SNI male and female C57BL/6JRj mice received TRF during the dark active phase or ad libitum feeding (ALF) for three weeks post-surgery. Behavioral tests, von Frey, hot plate, light-dark box (LDT), and open field (OFT), were performed at baseline and post-surgery; hypothalamus tissues were dissected in the morning (zeitgeber time (ZT) 2-6) and afternoon (ZT 8-12). Male, but not female, SNI mice under TRF showed significantly reduced anxiety-like behaviors (LDT: p = 0.0259, Cohen's d = 1.245; OFT: p = 0.0054, Cohen's d = 1.643). Differentially expressed gene (DEG) analysis identified 33 DEGs in the hypothalamus in male SNI mice between TRF and ALF in the afternoon, with enriched anxiety-related, mitochondrial, and circadian genes. These findings support TRF as a potential therapeutic approach to alleviate comorbid anxiety in NP.