Chronic Pain Impairs Memory Formation via Disruption of Neurogenesis Mediated by Mesohippocampal Brain-Derived Neurotrophic Factor Signaling

BACKGROUND: Chronic pain patients often complain of their poor memory. The mechanisms underlying chronic pain-related memory impairment remain elusive, and there are few clinical therapeutic strategies available for this condition. METHODS: In a neuropathic pain model induced by chronic constrictive injury of the sciatic nerve in male mice, we used circuit-specific electrophysiological recording, combined with chemogenetic, molecular, and pharmacologic methods, to examine the circuit and molecular mechanisms underlying chronic pain-related memory impairment. RESULTS: Our current results show that chronic neuropathic pain impaired the acquisition of spatial memory and, meanwhile, reduced adult neurogenesis in the dentate gyrus. Experimentally reducing dentate gyrus neurogenesis mimicked this pain-induced effect on spatial memory formation in naive mice. Furthermore, pain-associated impairments of both hippocampal neurogenesis and memory formation were rescued or mimicked by chemogenetic activation or deactivation, respectively, of the ventral tegmental area dopaminergic projection, through which ventral tegmental area-released brain-derived neurotrophic factor was required. Importantly, we found that chronic, but not acute, systematic administration of subanesthetic doses of ketamine, while without relieving pain, ameliorated chronic pain-related impairment of spatial memory formation, potentially by rescuing brain-derived neurotrophic factor-mediated dentate gyrus neurogenesis. CONCLUSIONS: These findings provide a novel, circuit-based mechanistic link between chronic pain and memory formation deficit, and potential new therapeutic options for chronic pain-related learning deficit and memory impairment.