WHOLE-BRAIN MAPPING OF NEURONAL ACTIVATION UNDERLYING PAIN-DEPRESSION COMORBIDITY AND KETAMINE MODULATION IN MICE

Pain and depression are highly comorbid conditions that exacerbate each other. A large proportion of the population suffers from chronic pain and depression, each representing a debilitating condition with a major socioeconomic burden. Current treatments mainly rely on symptomatic approaches, with limited efficacy and significant side effects. This situation reflects an incomplete understanding of how pain and depression-related networks interact within the central nervous system. Interestingly, antidepressant drugs, including sub-anesthetic doses of ketamine, have been shown to clinically improve both depressive and pain symptoms in patients. These observations suggest that such compounds provide a valuable tool to investigate the neural circuits underlying pain-depression comorbidity. The present study aims to characterize brain-wide activity patterns and identify functional networks engaged during pain-depression comorbidity, as well as their modulation by ketamine. We performed whole-brain c-Fos immunostaining combined with light-sheet microscopy and automated atlas-based registration to generate activity maps in mice subjected to chronic restraint stress-induced depressive-like states and mechanical and thermal hypersensitivity. Behavioral analyses confirmed the presence of depressive-like phenotypes and hypersensitivity in this model. Brain-wide activity mapping revealed a distinct pattern of regional activation during depression-induced hypersensitivity, involving brain areas previously implicated in both pain and depression. Ketamine selectively reversed activity changes in a subset of these regions, while others remained unaffected, indicating a region-specific modulation of comorbidity-related networks. Together, these results show that pain-depression comorbidity engages a specific and distributed brain-wide activity signature that can be partially reversed by ketamine, providing a foundation for future circuit-level studies of pain-depression interactions.