The Impact of Chronic Morphine on Adult Hippocampal Progenitor Cells and the Neurogenic Niche
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The birth of new neurons persists in the adult hippocampal subgranular zone (SGZ). Adult neurogenesis is dynamically regulated and thought to be important for certain types of spatial learning and memory. SGZ proliferation and neurogenesis are decreased by chronic morphine, yet how this alteration occurs is unknown. It is unclear if morphine causes alterations in cell cycle progression, progenitor cell maturation, or indirectly inhibits progenitor cells by altering the hippocampal neurogenic niche. I first examined a time course of morphine's effect on the progenitor cell cycle, cell death and immature SGZ neurons. I found that S phase cycling cells were vulnerable to morphine at early time points with a concurrent increase in cell death. I found that although the total population of SGZ immature neurons remained unchanged, the proportion of progenitor cells that progressed to a more mature stage decreased. I next asked whether decreased levels of proliferation resulted from shortened S phase length. Using a modified double injection paradigm of halogenated thymidine analogs, I found that chronic morphine did not alter the length of S phase of progenitor cells. Next, I asked if chronic morphine could have an indirect inhibitory effect on progenitor cells by altering growth factors and neurovasculature within the hippocampal neurogenic niche. I found that protein levels of factors within the niche were maintained or upregulated (e.g. vascular endothelial growth factor) to compensate for the morphine-induced decrease in proliferation. Lastly, I asked whether chronic morphine would decrease proliferation in an inducible nestin-CreERT2/R26R-yellow fluorescent protein transgenic mouse. I found that proliferation in this transgenic mouse was not altered after a particular paradigm of morphine exposure. Together these findings suggest that morphine alters adult hippocampal proliferation through multiple effects: both on the progenitor cells themselves (cell cycle, maturation) and indirectly by alteration of the neurogenic niche. Additional work is needed to understand the mechanism of the morphine-induced changes in progenitor cell cycle and the neurogenic niche. The present findings will benefit both the addiction field by offering new avenues for treatment and neural stem cell biology by demonstrating stages of neurogenesis that are more vulnerable to exogenous stimuli.