• Tomohiro Ohgomori and Shozo Jinno.
• Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Rehabilitation, Osaka Kawasaki Rehabilitation University, Kaizuka 597-0104, Japan.
• Neuroscience. 2021 Sep 15; 472: 90-102.

AbstractRecent studies have emphasized that adult hippocampal neurogenesis impairment may be associated with cognitive problems. Because cuprizone (CPZ), a copper-chelating reagent, was shown to decrease the production of new neurons, we aimed to further understand the involvement of adult hippocampal neurogenesis impairment in cognitive function by using a short-term (2-week) CPZ exposure paradigm. The CPZ-fed mice showed cognitive deficits, i.e., impaired sensorimotor gating and reduced social novelty preference, compared to normal-fed mice. Although a long-term (e.g., 5-week) CPZ exposure paradigm was found to cause demyelination, we encountered that the labeling for myelin in the hippocampus was unaffected by 2-week CPZ exposure. The densities of neuronal progenitor cells (NPCs) and newborn granule cells (NGCs) were lower in CPZ-fed mice than in normal-fed mice, while those of neural stem cells (NSCs) were comparable between groups. We then examined whether short-term CPZ exposure might induce activation of signal transducer and activator of transcription 3 (STAT3), which plays a major role in cytokine receptor signaling. The densities of phosphorylated STAT3-positive (pSTAT3+) NSCs were higher in CPZ-fed mice than in normal-fed mice, while those of pSTAT3+ NPCs/NGCs were very low in both groups. Interestingly, the densities of bromodeoxyuridine-positive (BrdU+) NSCs were higher in CPZ-fed mice than in normal-fed mice 2 weeks after BrdU injection, while those of BrdU+ NPCs/NGCs were lower in CPZ-fed mice than in normal-fed mice. These findings suggest that short-term CPZ exposure inhibits differentiation of NSCs into NPCs via activation of STAT3, which may in part underlie cognitive deficits.Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

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