Another process impaired in normal aging is neurogenesis within the granule cell layer (GCL) in the hippocampus. Neurogenesis continues to occur throughout the life predominantly in the subgranular zone (SGZ) of the dentate gyrus in the hippo-campal formation and in the subventricular zone (SVZ). Neural stem cells in the SGZ give rise to progenitor cells that migrate in the granule cell layer and differentiate into neuronal or glial phenotype. Progenitors in the SVZ migrate into the olfactory bulb through the rostral migratory stream and differentiate into interneurons. Newly generated hippocampal granule cells acquire the morphological and biochemical properties of neurons, develop synapses on their cell bodies and dendrites, and extend axonal projection along the mossy fibers into the hippocampal CA3 region.55 Newborn granule neurons are electrically active and capable of firing action potentials and receive synaptic inputs.56 However, the functional significance of adult neurogenesis is still unclear. The finding that increased hippocampal neurogenesis occurs in the brain of patients with Alzheimer's disease and after cerebral ischemia, have suggested that new neurons may integrate into existing brain circuitry and contribute to repair.57,58
An increasing amount of evidence suggests that neurogenesis is involved in hippocampal-dependent learning and memory. The Shors laboratory has shown a strong correlations between the number of new neurons and performance on some forms of hippocampal-dependent memory tasks, such as the trace eye-blink conditioning task,59 as well as, observing a deficit in a hippocampal-dependent memory task by reducing the generation of new neurons with an anti-mitotic agent.60 The correlation between neurogenesis and learning is not without controversy as other reports, either failed to find a correlation between the number of newly generated neurons and performance on a memory task, or observed that aged animals who perform better on a hippocampal-dependent memory task have fewer new neurons compared with animals that perform worse.61'62 The precise reasons for age-related decreases in neurogenesis are unknown, as the production of new neurons in adult hippocampus depends on multiple factors. The above observations suggest that the age-related decrease in neurogenesis is due to the overall age-related alteration in the microenvironment of the brain. The importance of the microenvironment was supported in a study that showed that the subgranuler zone of the dentate gyrus of a young Fisher 344 rats contains around 50,000 Sox-2+ progenitor cells and that this population of cells is intact in the aged animal.63 The decrease in hippocampal neurogenesis during aging appears to be an outcome of increased quiescence of neural stem cells due to changes in neural stem cell environment.63 Indeed, a recent report suggests that stem cells in aged animals can be rejuvenated. In this study parabi-osis between aged and young mice demonstrated that muscle satellite cells from the aged mice increased proliferative rates when exposed to serum of young rats.64 This report suggests that the environment in aged animals may play a significant role in the reduced proliferative capacity of stem cells. A decrease in multiple stem/progenitor cell proliferation factors, insulin growth factor-1, fibroblast growth factor -2, and brain derived neurotrophic factor has been identified as important facts for the alteration of the microenvironment of the aged brain. Inflammation within the brain is also a potent inhibitor of neurogenesis.65 Inflammation in the brain, as well as increased oxidative stress, have been indicated as factors responsible for the alteration in the aged brain microenvironment. It has been shown that nutritional treatments that aim to decrease oxidants and inflammation, such as feeding with blueberry, can improve cognitive function66 and can also increase neurogenesis.67,68 Preliminary studies from our laboratory have indicated that pretreatment with Spirulina may have the potential to combat inflammation caused by LPS in the young hippocampus of the rat.69 In addition, Spirulina may also have the ability to assist with neurogenesis in the aged rat hippocampus.70
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