Neuropharmacology. 2025 Oct 31:110755. doi: 10.1016/j.neuropharm.2025.110755. Online ahead of print.
ABSTRACT
BACKGROUND: Chronic pain and depression are highly comorbid conditions that pose a significant clinical challenge, yet the underlying neural circuitry mechanisms are poorly understood. The ventral hippocampal CA1 (vCA1) has been implicated in both pain and affective processing, but its specific role in this comorbidity remains unclear.
METHODS: We combined immunofluorescence, whole-cell patch-clamp recordings, and pathway-specific chemogenetic and optogenetic manipulations to investigate the role of vCA1 glutamatergic neurons and their downstream targets in a chronic constriction injury (CCI) mouse model. Behavioral assays were used to assess nociceptive, depressive, and anxiety-related phenotypes.
RESULTS: We observed reduced excitability of vCA1 and ventral dentate gyrus (vDG) neurons in the comorbidity model. Inhibition or ablation of vCA1 glutamatergic neurons in naïve mice induced both nociceptive hypersensitivity and depression-like behaviors, whereas suppression of vDG neurons elicited depression-like behaviors without altering nociceptive sensitivity. Conversely, optogenetic and chemogenetic activation of vCA1 glutamatergic neurons alleviated CCI-induced nociceptive hypersensitivity and depression behaviors. A functional divergence was identified in the downstream pathways of vCA1: projections to the nucleus accumbens (NAc) and thalamic reticular nucleus (TRN) selectively modulated nociceptive hypersensitivity, whereas projections to the lateral septum (LS) specifically regulated depression-like behaviors.
CONCLUSION: These findings establish vCA1 glutamatergic neurons as a critical hub in pain-depression comorbidity, and delineate distinct pathways that differentially govern nociceptive and depressive behaviors.
PMID:41177517 | DOI:10.1016/j.neuropharm.2025.110755
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