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 naïve 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.

中文翻译：

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慢性疼痛通过中海马 BDNF 信号传导介导的神经发生中断来损害记忆形成

背景慢性疼痛患者经常抱怨他们的记忆力差。慢性疼痛相关记忆障碍的潜在机制仍然难以捉摸，并且几乎没有可用于这种情况的临床治疗策略。方法在雄性小鼠坐骨神经慢性缩窄性损伤诱导的神经病理性疼痛模型中，我们使用电路特异性电生理记录，结合化学遗传学、分子学和药理学方法，研究慢性疼痛相关记忆的电路和分子机制。减值。结果 我们目前的结果表明，慢性神经性疼痛损害了空间记忆的获得，同时减少了齿状回的成人神经发生。实验性地减少齿状回神经发生模拟了这种疼痛诱导对幼稚小鼠空间记忆形成的影响。此外，海马神经发生和记忆形成的疼痛相关损伤分别通过腹侧被盖区多巴胺能投射的化学发生激活或失活来挽救或模拟，腹侧被盖区释放脑源性神经营养因子是必需的。重要的是，我们发现慢性而非急性系统性地施用亚麻醉剂量的氯胺酮，虽然不能缓解疼痛，但可能通过挽救脑源性神经营养因子介导的齿状回神经发生来改善空间记忆形成的慢性疼痛相关损伤。结论 这些发现提供了一种新颖的、