SUMMARY Precise regulation of cellular metabolism is hypothesized to constitute a vital component of the developmental sequence underlying the life-long generation of hippocampal neurons from quiescent neural stem cells (NSCs). The identity of stage-specific metabolic programs and their impact on adult neurogenesis are largely unknown. We show that the adult hippocampal neurogenic lineage is critically dependent on the mitochondrial electron transport chain and oxidative phosphorylation machinery at the stage of the fast proliferating intermediate progenitor cell. Perturbation of mitochondrial complex function by ablation of the mitochondrial transcription factor A (Tfam) reproduces multiple hallmarks of aging in hippocampal neurogenesis, whereas pharmacological enhancement of mitochondrial function ameliorates age-associated neurogenesis defects. Together with the finding of age-associated alterations in mitochondrial function and morphology in NSCs, these data link mitochondrial complex function to efficient lineage progression of adult NSCs and identify mitochondrial function as a potential target to ameliorate neurogenesis-defects in the aging hippocampus.

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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.

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Background and Purpose-Environmental stimulation consistently increases dentate neurogenesis in the adult brain and improves spatial learning. We tested the hypothesis whether specific rehabilitative training of an impaired forelimb influences these processes after focal cortical infarcts. Methods-Focal cortical infarcts were induced in the forelimb sensorimotor cortex using the photothrombosis model. One group of infarcted animals and sham-operated controls housed in standard cages received one daily session of skilled reaching training of the impaired or dominant forelimb, respectively. A second group was transferred to an enriched environment, whereas a third group remained in the standard cages without further treatment. Bromodeoxyuridine was administered from day 2 until day 6 postinfarct. Proliferation and differentiation of newborn cells was analyzed at day 10 and 42 using immunocytochemistry with neuronal and glial markers and confocal laser scanning microscopy. Spatial learning was tested in the Morris water maze between days 35 and 41. Results-After cortical infarcts in the forelimb sensorimotor cortex, environmental enrichment as well as daily reaching training of the impaired paw both increase dentate neurogenesis and improve functional performance in the Morris water maze. Nevertheless, the reaching training-induced neurogenic response was significantly greater in nonlesioned controls associated with the best spatial learning performance in the water maze. Conclusions-Skilled forelimb training effectively stimulates dentate neurogenesis and spatial learning in the infarcted and healthy brain. However, this reaching training-induced increase in neurogenesis was reduced after cortical infarcts.