Regulation of Adult Hippocampal Neurogenesis: Insights from Mouse Models of Dementia and Depression




Donovan, Michael Harry

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While neurogenesis is largely complete by birth, the subgranular zone (SGZ) in the adult hippocampus continues to produce functional young neurons. The last decade has produced a multitude of research demonstrating that the process of SGZ neurogenesis is dynamically regulated. Stimuli that negatively impact SGZ neurogenesis include stress, depression models, aging and models of neurodegenerative disease. Positive regulators of SGZ neurogenesis include antidepressants and hippocampal-dependent learning. These results have sparked tremendous speculation, both scientific and popular, that adult hippocampal neurogenesis might be critical for mood regulation and/or memory, and might be a promising target for the treatment of depression and dementia. However, we still know little about underlying mechanisms of how increases and decreases in SGZ neurogenesis occur. Here, I examine several manipulations of adult hippocampal neurogenesis, focusing on potential neuromechanisms underlying alterations in SGZ neurogenesis. First, in a mouse model of dementia, I find that in addition to agedependant decline in SGZ proliferation, these mice have retarded migration and maturation of new SGZ neurons and ectopic proliferation in a normally non-neurogenic region. Second, I explore how the antidepressant fluoxetine increases SGZ neurogenesis. I show that the increase occurs only after chronic administration and is not preceded by changes in cell death, cell-cycle or proliferating cell lineage. I next address the capacity of proliferating SGZ cells to respond to brain-derived neurotrophic factor (BDNF), a neurochemical implicated in antidepressant action and neurogenesis regulation. I find that most proliferating cells do not contain the necessary TrkB receptors in vivo, and thus BDNF action is likely indirect or through type-1 stem cells, which contain TrkB. Finally, I look at changes in neurogenesis in a social-defeat depression model. I find that, like other models of repeated stress, social-defeat stress appears to produce a stress-induced decrease in S-phase cells. However, closer analysis reveals that this decrease does not indicate decreased proliferation, and mice that are behaviorally sensitive to the stress actually show an increase in neurogenesis overall. Taken together, these results emphasize the complexity of the processes that comprise adult hippocampal neurogenesis, highlighting the importance of further investigation into the neuromechanisms of changes in neurogenesis.

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