Adult hippocampal neurogenesis poststroke: More new granule cells but aberrant morphology and impaired spatial memory

Abstract

Stroke significantly stimulates neurogenesis in the adult dentate gyrus, though the functional role of this postlesional response is mostly unclear. Recent findings suggest that newborn neurons generated in the context of stroke may fail to correctly integrate into pre-existing networks. We hypothesized that increased neurogenesis in the dentate gyrus following stroke is associated with aberrant neurogenesis and impairment of hippocampus-dependent memory. To address these questions we used the middle cerebral artery occlusion model (MCAO) in mice. Animals were housed either under standard conditions or with free access to running wheels. Newborn granule cells were labelled with the thymidine analoque EdU and retroviral vectors. To assess memory performance, we employed a modified version of the Morris water maze (MWM) allowing differentiation between hippocampus dependent and independent learning strategies. Newborn neurons were morphologically analyzed using confocal microscopy and Neurolucida system at 7 weeks. We found that neurogenesis was significantly increased following MCAO. Animals with MCAO needed more time to localize the platform and employed less hippocampus-dependent search strategies in MWM versus controls. Confocal studies revealed an aberrant cell morphology with basal dendrites and an ectopic location (e.g. hilus) of new granule cells born in the ischemic brain. Running increased the number of new neurons but also enhanced aberrant neurogenesis. Running, did not improve the general performance in the MWM but slightly promoted the application of precise spatial search strategies. In conclusion, ischemic insults cause hippocampal-dependent memory deficits which are associated with aberrant neurogenesis in the dentate gyrus indicating ischemia-induced maladaptive plasticity in the hippocampus.

Compensatory hippocampal neurogenesis in the absence of cognitive impairment following experimental hippocampectomy in adult rats

“…The presence of neuroblasts in the hippocampal hilus may represent ectopic migration of adult-born cells to this hippocampal region. This has been reported after status epilepticus (Yang et al, 2008) and stroke (Woitke et al, 2017).…”

Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons

“…To our knowledge this is the first study showing that obesity/T2D impairs stroke-induced hippocampal neurogenesis. The functional role of hippocampal neurogenesis in the overall recovery of impaired hippocampal function after stroke is largely unknown, although studies suggest it is limited or even harmful, mainly due to the limited ability of new neurons to integrate in neuronal networks properly [51,78]. However, recent animal studies have shown that T2D decreases cognitive functions after stroke [10,79], also by employing HFD feeding [22,80].…”

Abolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in mice

“…14,15). Although subgranular zone (SGZ) neurogenesis could promote cognitive function recovery after cerebral ischemia (16,17), stroke also modifies the morphology of newborn granule cells (18,19), concomitant to hippocampus-dependent memory deficits, suggesting a role of hippocampal neurogenesis in poststroke cognitive impairment. Furthermore, higher levels of hippocampal neurogenesis promote forgetting of old memories, which are otherwise strengthened by reducing neurogenesis (9,20).…”