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      Adult hippocampal neurogenesis buffers stress responses and depressive behavior

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          Summary

          Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness 1, 2 . In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis 3 . Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking 4, 5 . Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioral components of the stress response. Using transgenic and radiation methods to specifically inhibit adult neurogenesis, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice compared with intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis 6, 7 . Relative to controls, neurogenesis-deficient mice showed increased food avoidance in a novel environment after acute stress, increased behavioral despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

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          Most cited references27

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          Reconsidering anhedonia in depression: lessons from translational neuroscience.

          Anhedonia is a core symptom of major depressive disorder (MDD), the neurobiological mechanisms of which remain poorly understood. Despite decades of speculation regarding the role of dopamine (DA) in anhedonic symptoms, empirical evidence has remained elusive, with frequent reports of contradictory findings. In the present review, we argue that this has resulted from an underspecified definition of anhedonia, which has failed to dissociate between consummatory and motivational aspects of reward behavior. Given substantial preclinical evidence that DA is involved primarily in motivational aspects of reward, we suggest that a refined definition of anhedonia that distinguishes between deficits in pleasure and motivation is essential for the purposes of identifying its neurobiological substrates. Moreover, bridging the gap between preclinical and clinical models of anhedonia may require moving away from the conceptualization of anhedonia as a steady-state, mood-like phenomena. Consequently, we introduce the term "decisional anhedonia" to address the influence of anhedonia on reward decision-making. These proposed modifications to the theoretical definition of anhedonia have implications for research, assessment and treatment of MDD. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression.

            Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.
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              Subventricular zone astrocytes are neural stem cells in the adult mammalian brain.

              Neural stem cells reside in the subventricular zone (SVZ) of the adult mammalian brain. This germinal region, which continually generates new neurons destined for the olfactory bulb, is composed of four cell types: migrating neuroblasts, immature precursors, astrocytes, and ependymal cells. Here we show that SVZ astrocytes, and not ependymal cells, remain labeled with proliferation markers after long survivals in adult mice. After elimination of immature precursors and neuroblasts by an antimitotic treatment, SVZ astrocytes divide to generate immature precursors and neuroblasts. Furthermore, in untreated mice, SVZ astrocytes specifically infected with a retrovirus give rise to new neurons in the olfactory bulb. Finally, we show that SVZ astrocytes give rise to cells that grow into multipotent neurospheres in vitro. We conclude that SVZ astrocytes act as neural stem cells in both the normal and regenerating brain.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                22 July 2011
                3 August 2011
                25 February 2012
                : 476
                : 7361
                : 458-461
                Affiliations
                National Institute of Mental Health, NIH, Bethesda, MD, 20892
                Author notes

                Author Contributions J.S. performed histological, endocrine, and behavioral experiments, analyzed data and wrote the paper; A.S. performed behavioral experiments and analyzed behavioral data; H.C. performed endocrine experiments, analyzed data and wrote the paper; J.P. and M.B. generated the transgenic mice.

                Author for correspondence: H.A.C. heathercameron@ 123456mail.nih.gov , 301-496-3814
                Article
                nihpa313013
                10.1038/nature10287
                3162077
                21814201
                37cccbe9-b757-4c46-9c4b-b7ba4674759a

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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