Adult Hippocampal Neurogenesis along the Dorsoventral Axis Contributes Differentially to Environmental Enrichment Combined with Voluntary Exercise in Alleviating Chronic Inflammatory Pain in Mice.

Cognitive behavioral therapy, such as environmental enrichment combined with voluntary exercise (EE-VEx), is under active investigation as an adjunct to pharmaceutical treatment for chronic pain. However, the effectiveness and underlying mechanisms of EE-VEx remain unclear. In mice with intraplantar injection of complete Freund's adjuvant, our results revealed that EE-VEx alleviated perceptual, affective, and cognitive dimensions of chronic inflammatory pain. These effects of EE-VEx on chronic pain were contingent on the occurrence of adult neurogenesis in the dentate gyrus in a functionally dissociated manner along the dorsoventral axis: neurogenesis in the ventral dentate gyrus participated in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas neurogenesis in the dorsal dentate gyrus was involved in EE-VEx's cognitive-enhancing effects. Chronic inflammatory pain was accompanied by decreased levels of brain-derived neurotrophic factor (BDNF) in the dentate gyrus, which were reversed by EE-VEx. Overexpression of BDNF in the dentate gyrus mimicked the effects of EE-VEx. Our results demonstrate distinct contribution of adult hippocampal neurogenesis along the dorsoventral axis to EE-VEx's beneficial effects on different dimensions of chronic pain.SIGNIFICANCE STATEMENT Environmental enrichment combined with voluntary exercise (EE-VEx) is under active investigation as an adjunct to pharmaceutical treatment for chronic pain, but its effectiveness and underlying mechanisms remain unclear. In a mouse model of inflammatory pain, the present study demonstrates that the beneficial effects of EE-VEx on chronic pain depend on adult neurogenesis with a dorsoventral dissociation along the hippocampal axis. Adult neurogenesis in the ventral dentate gyrus participates in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas that in the dorsal pole is involved in EE-VEx's cognitive-enhancing effects in chronic pain.

Brain-derived neurotrophic factor in the infralimbic cortex alleviates inflammatory pain.

In chronic pain, it has been reported that the medial prefrontal cortex (mPFC) takes important regulatory roles, and may change functionally and morphologically in result of chronic pain. Brain-derived neurotrophic factor (BDNF) is well known as a critical modulator of neuronal excitability and synaptic transmission in the central nervous system. The aim of the present study is to investigate the role of BDNF in the infralimbic cortex and the prelimbic cortex of the mPFC in complete Freund's adjuvant (CFA)-induced inflammatory pain. We found that the BDNF level decreased in the infralimbic cortex, but not in the prelimbic cortex, 3days after the CFA induction of the inflammatory pain. BDNF infusion into bilateral infralimbic cortices to activate neuronal activities could alleviate inflammatory pain and accelerate long-term recovery from pain. In conclusion, BDNF in the infralimbic cortex of the mPFC could accelerate recovery from inflammatory pain.