Brief Treatment With the Glucocorticoid Receptor Antagonist Mifepristone Normalises the Corticosterone-Induced Reduction of Adult Hippocampal Neurogenesis
ABSTRACT The glucocorticoid receptor antagonist mifepristone has been shown to rapidly and effectively ameliorate symptoms of psychotic major depression. To better understand its mechanism, we investigated mifepristone's cellular effects, and found that it rapidly reversed a chronic corticosterone-induced reduction of adult neurogenesis in rats. Unlike other antidepressants, mifepristone is particularly potent in a high corticosterone environment. These data indicate that similarly to its clinical efficacy, mifepristone's effects on adult neurogenesis are rapid and positive, and may therefore be important for its mechanism of action.
Full-textDOI: · Available from: Paul J Lucassen, Aug 16, 2015
- SourceAvailable from: Arnaud Tanti
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- "Some of them do not integrate into the functional network and thus undergo apoptosis, while others survive (survival). Rodent studies have shown that a large number of factors associated with increased risk of MDD, such as unpredictable stress (Alonso et al., 2004; Mineur et al., 2007), elevated glucocorticoids (Mayer et al., 2006; Wong and Herbert, * Correspondence to: A. Tanti, INSERM U 930, Universite´Franc¸ois Rabelais, Faculte´des Sciences et Techniques, Parc Grandmont, Tours F-37200, France. Tel: +33-2-47-36-70-01. "
ABSTRACT: In recent years, both major depression and antidepressant therapy have been linked to adult hippocampal neurogenesis. The hippocampus is not a homogeneous brain area, and a converging body of evidence indicates a functional dissociation along its septo-temporal axis, the dorsal part being involved more in learning/memory and spatial navigation, while the ventral sub-region is linked more to emotional behavior and regulation of the neuroendocrine stress axis. Research has therefore been conducted in an attempt to relate effects of models of depression and of antidepressant therapies to adult neurogenesis along the septo-temporal axis of the hippocampus. The present paper reviews the current literature addressing this question and discusses the possible mechanisms involved and the functional significance of such regional effects. This review shows that animal models of depression elicit an effect restricted to the ventral hippocampus more frequently than a dorsal-specific effect. However, this is also stage specific, and concerns neurogenesis, rather than cell proliferation or survival. Surprisingly, the same does not apply regarding the effects of selective serotonin re-uptake inhibitors that act in a more uniform way on dorsal and ventral adult neurogenesis in most studies. Some recently introduced clinical compounds (e.g., agomelatine) or putative antidepressants have a specific action on the ventral sub-region, indicating that an action restricted to this part of the brain may be sufficient to achieve remission. Finally, non-pharmacological manipulations that are also endowed with antidepressant effects, such as environmental enrichment or physical exercise, also act on both subdivisions, although some studies pointed to specificity of dorsal neurogenesis. The different treatments, acting either on the dorsal or on the ventral sub-regions, could promote recovery by improving either ventral- or dorsal-related functions, both contributing in a different way to treatment efficacy.Neuroscience 08/2013; 252. DOI:10.1016/j.neuroscience.2013.08.017 · 3.33 Impact Factor
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- "It is likely that the involvement of steroid hormones in stable behavioural trait characteristics depends heavily on long-lasting effects on neural plasticity. In mammals, it has been shown that corticosteroids inhibit brain cell proliferation      and survival of newly formed cells  , suppress long-term potentiation (LTP)  , cause retraction and simplification of dendrites , and even kill neurons . Despite the numerous reports of corticosteroid-induced remodelling of the mammalian brain, surprisingly few studies have investigated the effects of stress and cortisol on the fish brain. "
ABSTRACT: Physiological and behavioural responses to environmental change are individually variable traits, which manifest phenotypically and are subject to natural selection as correlated trait-clusters (coping styles, behavioural syndromes, or personality traits). Comparative research has revealed a range of neuroendocrine-behavioural associations which are conserved throughout the vertebrate subphylum. Regulatory mechanisms universally mediate a switch between proactive (e.g. active / aggressive) and reactive (e.g. conservation/withdrawal) behaviour in response to unpredictable and uncontrollable events. Thresholds for switching from active coping to behavioural inhibition are individually variable, and depend on experience and genetic factors. Such factors affect physiological stress responses as well as perception, learning, and memory. Here we review the role of an important contributor to neural processing, the set of biochemical, molecular, and structural processes collectively referred to as neural plasticity. We will concentrate on work in teleost fishes, while also elucidating conserved aspects. In fishes, environmental and physiological control of brain cell proliferation and neurogenesis has received recent attention. This work has revealed that the expression of genes involved in CNS plasticity is affected by heritable variation in stress coping style, and is also differentially affected by short- and long-term stress. Chronic stress experienced by subordinate fishes in social hierarchies leads to a marked suppression of brain cell proliferation. Interestingly, typically routine dependent and inflexible behaviour in proactive individuals is also associated with low transcription of neurogenesis related genes. The potential for these findings to illuminate stress-related neurobiological disorders in other vertebrates is also discussed.General and Comparative Endocrinology 12/2012; 181(1). DOI:10.1016/j.ygcen.2012.12.003 · 2.67 Impact Factor
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- "DATSON ET AL. chronic stress-and chronic corticosterone-induced reduction in adult neurogenesis in the DG (Mayer et al., 2006; Oomen et al., 2007). Therefore, we investigated whether GR-blockade with RU486 would also be effective in reversing the effects of stress exposure on gene expression in the DG. "
ABSTRACT: The dentate gyrus (DG) of the hippocampus plays a crucial role in learning and memory. This subregion is unique in its ability to generate new neurons throughout life and integrate these new neurons into the hippocampal circuitry. Neurogenesis has further been implicated in hippocampal plasticity and depression. Exposure to chronic stress affects DG function and morphology and suppresses neurogenesis and long-term potentiation (LTP) with consequences for cognition. Previous studies demonstrated that glucocorticoid receptor (GR) blockade by a brief treatment with the GR antagonist mifepristone (RU486) rapidly reverses the stress and glucocorticoid effects on neurogenesis. The molecular pathways underlying both the stress-induced effects and the RU486 effects on the DG are, however, largely unknown. The aim of this study was therefore (1) to investigate by microarray analysis which genes and pathways in the DG are sensitive to chronic stress and (2) to investigate to what extent blockade of GR can normalize these stress-induced effects on DG gene expression. Chronic stress exposure affected the expression of 90 genes in the DG (P < 0.01), with an overrepresentation of genes involved in brain development and morphogenesis and synaptic transmission. RU486 treatment of stressed animals affected expression of 107 genes; however, mostly different genes than those responding to stress. Interestingly, we found CREBBP to be normalized by RU486 treatment to levels observed in control animals, suggesting that CREB-signaling may play a central role in mediating the chronic stress effects on neurogenesis, LTP and calcium currents. The identified genetic pathways provide insight into the stress-induced adaptive plasticity of the hippocampal DG that is so central in learning and memory and will direct future studies on the functional outcome and modulation of these stress effects.Hippocampus 02/2012; 22(2):359-71. DOI:10.1002/hipo.20905 · 4.30 Impact Factor