The hippocampus has been identified 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 hippocampal neurogenesis with the etiology and treatment of mental disorders. Increasing evidence supports the view that adult hippocampal neurogenesis is a physiologically important event. However, despite our growing understanding of the mechanisms regulating adult neurogenesis, the precise functional roles of newly generated cells and their impact on brain function remains elusive. Physical activity, environmental enrichment, antidepressant administration and learning can increase proliferation and survival of new neurons while age and exposure to stress decrease neurogenesis. Exposure to chronic stress is also capable of inducing retraction of apical dendrites in CA3 pyramidal neurons. These studies were designed to follow up on our recent findings that suppression of adult neurogenesis results in 1) misregulation of the acute response to stress, leading to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis response and 2) an inability to recover normally from depressive-like behaviors induced from exposure to psychosocial stress. The current studies showed that suppression of neurogenesis in the adult mouse is sufficient to cause substantial changes in dendrite morphology in the CA3 region of the hippocampus, effects that mimic the phenotype observed after exposure to chronic stress. These cellular events are correlated with the induction of a program of coordinated gene regulation changes of transcripts that are localized to and have known function in remodeling activity at the post-synaptic density. The data from these studies contribute to the theory that that newly born neurons are an integral component in the proper functioning of this circuit. These studies also showed that expression of brain-derived neurotrophic factor (BDNF) is decreased in the dentate gyrus after suppression of neurogenesis. High concentrations of BDNF protein have been localized to the mossy fiber pathway and immunodetection is increased in CA3 terminals following seizure activity. BDNF is thus well positioned to regulate both the direct excitatory and indirect feed-forward inhibitory inputs to CA3 pyramidal cells. Since proper synaptic regulation of the mossy fiber-CA3 synapse is important for the maintenance and stabilization of CA3 pyramidal cell dendrites, our data suggest that the decreased levels of DG BDNF following suppression of adult neurogenesis may contribute to the observed changes in CA3 gene expression and dendrite morphology by modulating the ability of DG-derived BDNF to regulate synaptic efficacy at mossy-fiber bouton-CA3 pyramidal cell contacts. A second project in collaboration with the Laboratory of Cellular &Molecular Regulation, NIMH, examined the intersection between adult neurogenesis, regulation of the hypothalamic-pituitary-adrenal axis and exposure to chronic psychosocial stress. These studies have provided preliminary evidence that causal relationships exist between proper regulation of the acute stress response, rates of adult neurogenesis and exposure to chronic stress.

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U.S. National Institute of Mental Health
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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