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.
Highlights
Stroke is one of the leading causes of death and disability worldwide, affecting millions of lives every year
The aberrant features of newborn neurons previously detected in Sholl analysis or in mean apical dendrite length were not observed at this time point (Supplemental Figure 12, B and C), 30.5% of the ipsilesional newborn population still displayed apical dendrite growth alterations, an effect that might lead to an incorrect integration of axonal projections coming from entorhinal cortex (EC). All these results indicate that ischemic stroke promotes an increase in neurogenesis that gives rise to the generation of differential populations of newborn neurons with altered morphological features depending on their ipsi- or contralesional location, an effect that remains, at a lower intensity, when the levels of neurogenesis become normalized
We have investigated the mechanisms underlying long-term memory deficits driven by cortical ischemic stroke
Summary
Stroke is one of the leading causes of death and disability worldwide, affecting millions of lives every year. Whereas motor impairment may ameliorate during the chronic phase of stroke, cognitive deficits tend to worsen [2, 3]. More than one-third of patients may develop cognitive impairment or even dementia later after stroke [4,5,6]. Despite this high prevalence, mechanisms underlying poststroke cognitive impairment and dementia remain unclear [2, 4, 7]
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