Dopaminergic neurons in the dorsal raphe nucleus are involved in the regulation of memory impairment in chronic pain.

Abstract

BACKGROUND: Chronic pain is a prevalent condition often associated with cognitive impairments, including memory deficits. The dorsal raphe nucleus (DRN) is implicated in both pain processing and memory regulation, yet the role of DRN dopaminergic (DAergic) neurons in chronic pain-induced memory impairment remains unclear. This study aimed to investigate whether DRN-DA neurons and their projections to the bed nucleus of the stria terminalis (BNST) contribute to memory deficits in a mouse model of chronic neuropathic pain. METHODS: Chronic constrictive injury (CCI) was induced in male C57BL/6J and DAT-Cre mice to establish neuropathic pain. Memory function was assessed using the novel object recognition (NOR) and fear conditioning tests (FCT). Neuronal activity was evaluated via c-Fos immunohistochemistry and whole-cell patch-clamp recordings. Chemogenetic and optogenetic techniques were employed to selectively manipulate DRN-DA neurons and their projections to the BNST. RESULTS: CCI mice exhibited significant memory impairments alongside reduced activity of DRN-DA neurons. Chemogenetic or optogenetic activation of DRN-DA neurons alleviated memory deficits in CCI mice. Optogenetic stimulation of DRN-DA terminals in the BNST similarly rescued memory performance, confirming the involvement of the DRN-BNST pathway in pain-related cognitive dysfunction. CONCLUSION: Our findings demonstrate that DRN-DA neurons play a critical role in regulating memory impairment induced by chronic pain, partly through projections to the BNST. Targeted activation of this pathway may represent a potential therapeutic strategy for alleviating cognitive deficits in chronic pain conditions.