Role of adult neurogenesis in regulation of the HPA axis and stress resiliency

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The dentate gyrus of the hippocampus is one of two regions in the brain that retains the capacity to generate new neurons throughout the lifespan. The survival of these newly born neurons is negatively regulated by stress exposure and increased glucocorticoids. Recent studies have proposed that the ongoing production of neurons during adulthood in the hippocampus may be linked to the development of depressive disorders as well as their treatment with antidepressants. For example, it has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in an animal model of depression. To further understand the impact of adult neurogenesis on mood and anxiety-related behaviors , we (in collaboration with the Unit on Neural Plasticity, Dr. Heather Cameron) developed a mouse model that allows for the conditional ablation of adult neural progenitors. Conditional ablation of adult neural progenitor cell proliferation in this model is achieved by expression of herpes simplex virus thymidine kinase (HSV-tk) under the control of the human GFAP promoter. Administration of the antiviral drug valganciclovir (VGCV) causes prevention of cells expressing HSV-tk from re-entering the cell cycle. Baseline physiological and pathological observations of this mouse model revealed no differences indicating adverse side effects by the treatment or a combination of treatment and insertion of the transgene. Further, behavioral observations did not show increases in baseline anxiety or depressive-like behavior in animals without neurogenesis. We discovered that animals lacking adult neurogenesis show an increased hypothalamic pituitary adrenal (HPA) axis response when exposed to mild stress. These results suggest that newly born neurons in the hippocampus are important for the negative regulation that the hippocampus has over the HPA axis. We have now initiated studies to understand the physiological role of these newly born neurons in providing this inhibitory control. These studies include studying c-fos activation following mild stress in the paraventricular nucleus of the hypothalamus in animals lacking neurogenesis. We have also extended our studies to look at the role of newly born neurons in regulating the response to chronic stress. In a study conducted in collaboration with the Laboratory of Cellular and Molecular Regulation we showed that recovery from psychosocial stress, which can be achieved by housing animals in an enriched environment, is dependent on intact adult neurogenesis. Based on these results we believe that these newly born neurons in the hippocampus may be a critical component of the stress recovery and resiliency program, which is at least partially mediated through the impact of these newly born neurons on inhibitory control of the HPA axis. To better understand the impact of these newly born neurons on primary target regions, e.g. the hypothalamus and the medial prefrontal cortex, we have begun to study pathway specific gene regulation using a combination of pathway-specific PCR arrays in animals lacking adult neurogenesis compared to wild type animals. We anticipate that the results of these studies will provide further insight into the gene targets that are affected by loss of adult neurogenesis and which may be important in promoting stress resiliency.