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) 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 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 that there were no 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 of the HPA axis by the hippocampus. 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 immediate-early gene 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 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 studied gene regulation in the CA3, dentate gyrus and hypothalamus of animals lacking adult neurogenesis compared to wild-type animals. These studies have begun to provide us with further insight into the gene targets that are affected by loss of adult neurogenesis and which may be important in promoting stress resiliency. In addition we have conducted studies examining the role of newborn dentate gyrus granule cells on their innervation targets in the CA3 region of the hippocampus. Results of these studies show that suppression of adult hippocampal neurogenesis leads to dendritic remodeling of CA3 pyramidal cells. Messenger RNA and micro RNA expression studies showed changes in several genes that are involved in dendritic remodeling and are likely to be the underlying molecular causes for the observed remodeling. Furthermore, we have started examining the role of adult hippocampal neurogenesis on female behavior, especially pre- and postpartum behavioral adaptations of mood and anxiety. These studies are done in collaboration with Dr. Hen (Columbia University) who is supplying us with hippocampally irradiated females to validate our findings in the hGFAPtk transgenic animals. The hippocampus has long been noted as a site of structural and functional pathology in a variety of mental disorders. For example, depression, schizophrenia and post-traumatic stress disorder have been correlated with decreased hippocampal volume, deficits in learning and memory as well as mood perturbations. Improvement in some of the behavioral symptoms associated with these disorders has been linked to reversal of deficits in hippocampal plasticity and function. In particular, both correlative and direct evidence has linked the neuroplastic process of adult hippocamapal neurogenesis with the etiology and treatment of mental disorders. Our research, which is uncovering the neurobiological mechanisms linking hippocampal neurogenesis and dysregulation of the HPA-axis in stress-related disorders, has the potential to greatly aid our understanding of how dysregulation of hippocampal neurogenesis may be involved in mood disorders and in the antidepressant response.
|Schloesser, Robert J; Martinowich, Keri; Manji, Husseini K (2012) Mood-stabilizing drugs: mechanisms of action. Trends Neurosci 35:36-46|
|Schloesser, R J; Lehmann, M; Martinowich, K et al. (2010) Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol Psychiatry 15:1152-63|
|Schloesser, Robert J; Manji, Husseini K; Martinowich, Keri (2009) Suppression of adult neurogenesis leads to an increased hypothalamo-pituitary-adrenal axis response. Neuroreport 20:553-7|