Stroke-Induced Neurogenesis in Aged Brain

Abstract

Background and Purpose-Stroke induced by middle cerebral artery occlusion (MCAO) triggers increased neurogenesis in the damaged striatum and nondamaged hippocampus of young adult rodents. We explored whether stroke influences neurogenesis similarly in the aged brain. Methods-Young adult (3 months) and old (15 months) rats were subjected to 1 hour of MCAO, and new cells were labeled by intraperitoneal injection of 5-bromo-2Ј-deoxyuridine 5Ј-monophosphate (BrdU), a marker for dividing cells, for 2 weeks thereafter. Animals were euthanized at 7 weeks after the insult, and neurogenesis was assessed immunocytochemically with antibodies against BrdU and neuronal markers with epifluorescence or confocal microscopy. Results-Young and old rats exhibited the same increased numbers of new striatal neurons after stroke, despite basal cell proliferation in the subventricular zone being reduced in the aged brain. In contrast, both the number of stroke-generated granule cells and basal neurogenesis in the dentate subgranular zone were lower in old compared with young animals. Also, the ability of newly formed cells to differentiate into neurons was impaired in the aged dentate gyrus. Conclusions-Basal neurogenesis is impaired in the subgranular and subventricular zones of aged animals, but both regions react to stroke with increased formation of new neurons. The magnitude of striatal neurogenesis after stroke is similar in young and old animals, indicating that this potential mechanism for self-repair also operates in the aged brain. Key Words: cerebral arteries Ⅲ hippocampus Ⅲ ischemia Ⅲ neuronal plasticity Ⅲ stem cells Ⅲ stroke, ischemic T he production of neurons in the mammalian brain continues throughout life. Neurons generated in the subventricular zone (SVZ) migrate to the olfactory bulb, and they differentiate into interneurons. Neurogenesis in the dentate subgranular zone (SGZ) gives rise to neurons in the granule cell layer (GCL). Basal hippocampal and olfactory bulb neurogenesis declines in aged animals, 1-4 but different treatments also increase the production of new neurons in old brains. 1,5,6 Stroke induced by middle cerebral artery occlusion (MCAO) in young adult rodents triggers increased neurogenesis in the SGZ/GCL and SVZ. [7][8][9][10][11] This insult causes neuronal loss in the striatum and cerebral cortex, whereas hippocampal formation is spared. The SVZ neuroblasts migrate into the damaged striatal area and adopt the phenotype of projection neurons. 8 -10 Stroke leads to deficits in hippocampus-associated spatial memory, 12 and the increase in SGZ neurogenesis might aim to counteract cognitive impairments. Striatal neurogenesis, therefore, may contribute to recovery of stroke-impaired motor function.Ischemic stroke occurs more often in aged humans. It is therefore of major clinical interest to explore whether the aged brain retains the capacity for stroke-induced neurogenesis. Here we show that both basal and stroke-induced hippocampal neurogenesis is attenuated in old animals. In contrast, despite redu...

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“…However, neurogenesis does not compensate for neuronal loss in age-related neurodegenerative disorders, which may be caused by impaired neurogenesis. A reduction in basal levels of neurogenesis may contribute to the pathogenesis of such disorders (Darsalia et al, 2005;Haughey et al, 2002). Our data show that SVZ neural progenitor cells are capable of proliferation and self-renewal, but these functions are significantly decreased with age, and exhibit decreased neurosphere formation and BrdU incorporation.…”

“…Cell growth and neuronal progenitor cell proliferation Cameron and McKay, 1999;Darsalia et al, 2005;Kuhn et al, 1996;McDonald and Wojtowicz, 2005), which may be attributed to a decreased telomerase activity (Cherif et al, 2003). Neurogenesis declines dramatically with age, which in part is due to decreased levels of mitogens, and a decrease in the progenitor pool resulting from a reduction of factors which support brain plasticity (Shetty et al, 2005).…”

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“…Focal cerebral ischemia following experimental stroke, induces similar magnitudes of neurogenesis in young (3 mo) and old (15 mo) rats. 75 Furthermore, activation of neurogenesis occurs in the human brain following cerebral ischemia in patients up to 84 y old, [24][25][26] despite a mere trickle of neurogenesis in aged healthy brain. 72 These data highlight the continued validity of ion channels as targets for repair in the aged brain.…”

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“…Ageing is the greatest negative regulator of hippocampal neurogenesis (Kuhn et al, 1996), and adult neurogenesis may be required for hippocampal-dependent learning and memory (Zhao et al, 2008). Increased neurogenesis in rodents is seen following ischaemia (Takagi et al, 1999), stroke (Darsalia et al, 2005) and after seizures (Parent et al, 1997). These increases may be an attempt at brain self-repair and treatments that enhance neurogenesis and survival of new neurons in adults may provide a novel therapeutic approach to the treatment of neurodegenerative diseases.…”