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.
Transient and permanent focal cerebral ischemia results in a series of typical pathophysiologic events. These consequences evolve in time and space and are not limited to the lesion itself, but they can be observed in perilesional (penumbra) and widespread ipsi- and sometimes contralateral remote areas (diaschisis). The extent of these areas is variable depending on factors such as the type of ischemia, the model, and the functional modality investigated. This review describes some typical alterations attributable to focal cerebral ischemia using the following classification scheme to separate different lesioned and perilesional areas: (1) The lesion core is the brain area with irreversible ischemic damage. (2) The penumbra is a brain region that suffers from ischemia, but in which the ischemic damage is potentially, or at least partially, reversible. (3) Remote brain areas are brain areas that are not directly affected by ischemia. With respect to the etiology, several broad categories of remote changes may be differentiated: (3a) remote changes caused by brain edema; (3b) remote changes caused by waves of spreading depression; (3c) remote changes in projection areas; and (3d) remote changes because of reactive plasticity and systemic effects. The various perilesional areas are not necessarily homogeneous; but a broad differentiation of separate topographic perilesional areas according to their functional state and sequelae allows segregation into several signaling cascades, and may help to understand the functional consequences and adaptive processes after focal brain ischemia.
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