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

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 2

Long-term memory deficits after MCAO are hippocampus dependent.

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Long-term memory deficits after MCAO are hippocampus dependent. (A) Desi...
(A) Design for hippocampus inactivation with TTX before retrieval of fear memory. Sham-operated and MCAO mice were subjected to CFC (0.6 mA × 3) 7 days after surgery and tested 28 days after training (*P < 0.05 vs. sham operated; sham operated, n = 9; MCAO, n = 13). One day later, sham-operated and MCAO mice, allocated in 2 different groups, were bilaterally infused in the dorsal hippocampus with either vehicle or TTX. Three hours later, fear memory was evaluated as percentage of freezing (sham-operated vehicle, n = 4; MCAO vehicle, n = 5; sham-operated TTX, n = 5; MCAO TTX, n = 8; *P < 0.05 vs. sham-operated vehicle; #P < 0.05 vs. MCAO vehicle). (B) Representative images of c-Fos staining (green) in the hippocampus of untrained, sham-operated, and ischemic mice 90 minutes after a 10-minute retrieval session, 28 days after conditioning. Scale bar: 200 μm. (C–F) Barnes maze testing. (C) Experimental design. (D) Representative traces of the paths traveled during retrieval by mice in the Barnes maze obtained by EthoWatcher software. Time spent by sham-operated and MCAO mice around each quadrant (E) or around the target hole (F) in the Barnes maze platform 30 days after training. For E, 2-way ANOVA showed a significant interaction between quadrants and surgery (F(3,116) = 3.50; P = 0.0178) (Bonferroni’s post hoc: *P < 0.05 vs. sham-operated TQ; sham operated, n = 12; MCAO; n = 19). RQ, right quadrant; ATQ, antitarget quadrant; LQ, left quadrant. For F, *P < 0.05 vs. sham-operated group. Data are represented as mean ± SEM. Data were compared by using nonparametric 2-tailed Mann-Whitney U tests (A and F) or nonparametric 2-way ANOVA followed by Bonferroni’s post hoc testing (E).