Recent work has identified stem cells in the central nervous system that are capable of proliferating into adulthood. While adult neuronal stem cells hold a great deal of therapeutic potential, to be a useful clinical tool, we must first understand the cellular and molecular mechanisms responsible for regulating proliferation and differentiation. Two month old male Sprague-Dawley rats were given one of three dietary treatments. Following 3 wks of zinc adequate (ZA, 30 ppm), zinc-deficient (ZD, 1 ppm), pair-fed (PF, 30 ppm), or zinc-supplemented (ZS, 180 ppm) diets, immunohistochemistry was used to quantify the number of Ki67 positive cells as a measure of newly proliferated cells in the dentate gyrus. Neurogenesis was determined by the co-localization of the neuronal marker, NeuN, with Ki67. ZD reduced the number of Ki67 positive cells to 50% of ZA controls (p<0.05) in both the subgranular zone (SGZ) and the granular cell layer (GCL) of the dentate gyrus. While ZD reduced the total number of cells that co-labeled with Ki67 and NeuN compared to ZS rats, dietary zinc did not alter the percentage of Ki67-positive cells that expressed NeuN. Because impairment in stem cell proliferation has been linked to alterations in mood, we hypothesized that ZD would lead to the development of depression-like behaviors in rodents. Consistent with depression ZD rats displayed anorexia (p<0.006), anhedonia (reduced saccharin: water intake, p<0.001), and anxiety-like behavior in a light-dark box test (p<0.05). Furthermore, the antidepressant drug fluoxetine (10 mg/kg body wt), reduced behavioral despair, as measured by the forced swim test, in ZA and ZS rats (p<0.002), but not in ZD rats. Thus, it appears that ZD not only induces depression, but also impairs the efficacy of antidepressant drugs. In an attempt to identify some of the molecular mechanisms that may be contributing to the impairment of drug efficacy in ZD rats, microarray analysis was performed to identify alterations in hippocampal gene expression following chronic fluoxetine administration in ZA and ZD rats. This work showed that ZD disrupts mitochondrial gene expression as well as important mediators of neurogenesis such as the receptor for transforming growth factor beta (TGF-â) and â-carotene 15,15 dioxygenase. Together these studies suggest that ZD-mediated changes in gene expression are responsible for a reduction in dentate stem cell proliferation, leading to the development of depression-like behaviors nthat are refractory to antidepressant treatment.