Highlights d Phospho-tau is accumulated in DG GABAergic interneurons of AD patients and mice d Interneuron overexpressing human tau impairs adult hippocampal neurogenesis d Tau accumulation reduces GABA, disinhibits local circuits, and promotes astrogliosis d THIP, a d-GABA A R agonist, improves neurogenesis and cognition in AD 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. 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.
Highlights d Ventral hippocampal CA1-infralimbic cortex (vCA1-IL) connectivity is involved in pain d Persistent spontaneous pain in rats with inflammation disrupts vCA1-IL connectivity d Activating vCA1-IL alleviates spontaneous pain and promotes overall pain recovery d BDNF expression correlates with behavior and activity changes in spontaneous pain
A genome editing technique based on the clustered regularly interspaced short palindromic repeats (CRISPR)associated endonuclease Cas9 enables efficient modification of genes in various cell types, including neurons. However, neuronal ensembles even in the same brain region are not anatomically or functionally uniform but divide into distinct subpopulations. Such heterogeneity requires gene editing in specific neuronal populations. We developed a CRISPR-SaCas9 system-based technique, and its combined application with anterograde/ retrograde AAV vectors and activity-dependent cell-labeling techniques achieved projection-and function-specific gene editing in the rat brain. As a proof-of-principle application, we knocked down the cbp (CREB-binding protein), a sample target gene, in specific neuronal subpopulations in the medial prefrontal cortex, and demonstrated the significance of the projection-and function-specific CRISPR-SaCas9 system in revealing neuronal and circuit basis of memory. The high efficiency and specificity of our projection-and function-specific CRISPR-SaCas9 system could be widely applied in neural circuitry studies. Development of a CRISPR-SaCas9 system for projection-and function-specific gene editing in the rat brain. Sci. Adv. 6, eaay6687 (2020).
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