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Abolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in mice
María Isabel Cuartero, … , Ignacio Lizasoain, María Ángeles Moro
María Isabel Cuartero, … , Ignacio Lizasoain, María Ángeles Moro
Published January 24, 2019
Citation Information: J Clin Invest. 2019;129(4):1536-1550. https://doi.org/10.1172/JCI120412.
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Research Article Neuroscience

Abolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in mice

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Abstract

Poststroke cognitive impairment is considered one of the main complications during the chronic phase of ischemic stroke. In the adult brain, the hippocampus regulates both encoding and retrieval of new information through adult neurogenesis. Nevertheless, the lack of predictive models and studies based on the forgetting processes hinders the understanding of memory alterations after stroke. Our aim was to explore whether poststroke neurogenesis participates in the development of long-term memory impairment. Here, we show a hippocampal neurogenesis burst that persisted 1 month after stroke and that correlated with an impaired contextual and spatial memory performance. Furthermore, we demonstrate that the enhancement of hippocampal neurogenesis after stroke by physical activity or memantine treatment weakened existing memories. More importantly, stroke-induced newborn neurons promoted an aberrant hippocampal circuitry remodeling with differential features at ipsi- and contralesional levels. Strikingly, inhibition of stroke-induced hippocampal neurogenesis by temozolomide treatment or using a genetic approach (Nestin-CreERT2/NSE-DTA mice) impeded the forgetting of old memories. These results suggest that hippocampal neurogenesis modulation could be considered as a potential approach for treatment of poststroke cognitive impairment.

Authors

María Isabel Cuartero, Juan de la Parra, Alberto Pérez-Ruiz, Isabel Bravo-Ferrer, Violeta Durán-Laforet, Alicia García-Culebras, Juan Manuel García-Segura, Jagroop Dhaliwal, Paul W. Frankland, Ignacio Lizasoain, María Ángeles Moro

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Figure 1

Cortical stroke impairs long-term memory in mice.

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Cortical stroke impairs long-term memory in mice.
(A) Experimental desig...
(A) Experimental design for panels B and C. Sham-operated and MCAO mice were subjected to CFC (0.6 mA × 3) and tested 28 and 60 days after training. (B and C) Remote memory retention after cerebral ischemia calculated as the percentage of freezing response 28 days (B, P < 0.05 vs. sham operated; sham operated, n = 37; MCAO, n = 63) and 60 days (C, *P < 0.05 vs. sham-operated group; sham operated, n = 8; MCAO, n = 8) after foot shocks. (D) Experimental design for panels E and F. (E) Percentage of freezing in control and MCAO groups after a weak (0.4 mA × 2; left columns; light orange panel; *P < 0.05 vs. sham-operated group; sham operated, n = 7; MCAO, n = 7) or a strong fear-conditioning paradigm (0.8 mA × 5; right columns; dark orange panel; P > 0.05 vs. sham-operated group; sham operated, n = 5; MCAO, n = 5). Retention for both types of conditioning was performed 28 days after training and 60 days after conditioning for the strong one. (F) Memory persistence at 2 months after strong fear-conditioning paradigm. Data are represented as percentage of freezing at 2 months versus that observed at 1 month (*P < 0.05 vs. sham-operated group; sham operated, n = 5; MCAO, n = 5). (G and H) Freezing response after conditioning (0.6 mA × 3) performed 48 hours before surgery (G, *P < 0.05 vs. sham operated; sham operated, n = 9; MCAO, n = 7) or 30 days after MCAO (H, *P < 0.05 vs. sham operated; sham operated, n = 15; MCAO, n = 15), respectively. Data are represented as mean ± SEM. Data were compared using nonparametric 2-tailed Mann-Whitney U test.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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