Adolescent Stress-Induced Epigenetic Control of Dopaminergic Neurons via Glucocorticoids

Department of Chemical Pharmacology, Meijo University Graduate School of Pharmaceutical Sciences, Nagoya 468-8503, Japan.
Science (Impact Factor: 33.61). 01/2013; 339(6117):335-339. DOI: 10.1126/science.1226931
Source: PubMed


Environmental stressors during childhood and adolescence influence postnatal brain maturation and human behavioral patterns
in adulthood. Accordingly, excess stressors result in adult-onset neuropsychiatric disorders. We describe an underlying mechanism
in which glucocorticoids link adolescent stressors to epigenetic controls in neurons. In a mouse model of this phenomenon,
a mild isolation stress affects the mesocortical projection of dopaminergic neurons in which DNA hypermethylation of the tyrosine
hydroxylase gene is elicited, but only when combined with a relevant genetic risk for neuropsychiatric disorders. These molecular
changes are associated with several neurochemical and behavioral deficits that occur in this mouse model, all of which are
blocked by a glucocorticoid receptor antagonist. The biology and phenotypes of the mouse models resemble those of psychotic
depression, a common and debilitating psychiatric disease.

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Available from: Hanna Jaaro-Peled, Jan 03, 2014
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    • "associative learning, and the pathophysiology of addiction , mood disorders, and schizophrenia (Wise and Bozarth, 1985; Schultz, 1998; Wise, 2004; Sesack and Grace, 2010; Howes et al., 2012). The dopamine system has been implicated in adolescent behavioral and illness vulnerabilities (Luciana et al., 2012; Matthews et al., 2013; Niwa et al., 2013), and aspects of dopamine transmission and VTA activity are different in adults and adolescents (Robinson et al., 2011; McCutcheon et al., 2012; Matthews et al., 2013). "
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    ABSTRACT: Immaturities in adolescent reward processing are thought to contribute to poor decision making and increased susceptibility to develop addictive and psychiatric disorders. Very little is known; however, about how the adolescent brain processes reward. The current mechanistic theories of reward processing are derived from adult models. Here we review recent research focused on understanding of how the adolescent brain responds to rewards and reward-associated events. A critical aspect of this work is that age-related differences are evident in neuronal processing of reward-related events across multiple brain regions even when adolescent rats demonstrate behavior similar to adults. These include differences in reward processing between adolescent and adult rats in orbitofrontal cortex and dorsal striatum. Surprisingly, minimal age related differences are observed in ventral striatum, which has been a focal point of developmental studies. We go on to discuss the implications of these differences for behavioral traits affected in adolescence, such as impulsivity, risk-taking, and behavioral flexibility. Collectively, this work suggests that reward-evoked neural activity differs as a function of age and that regions such as the dorsal striatum that are not traditionally associated with affective processing in adults may be critical for reward processing and psychiatric vulnerability in adolescents. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Developmental Cognitive Neuroscience 11/2014; 11. DOI:10.1016/j.dcn.2014.11.001 · 3.83 Impact Factor
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    • "Recently, it has also been shown that stress during adolescence induces epigenetic control of dopaminergic neurons via glucocorticoids (Niwa et al., 2013). Thus, the current literature suggests that stress has enduring effects on the brain, with a heightened impact on developing structures. "
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    ABSTRACT: The exposure to stress at different developmental time points has long been postulated to have a crucial impact on various brain structures involved in mental disorders. The long-term specific effects seem to emerge as a function of timing and duration of the exposure to stress, as well as the characteristics of the stressor. Previous studies have addressed this issue with an effort to describe a single "hyper-sensitive" time point, and have led to disagreement on a particular sensitive period for stress exposure. The primary aim of our study was to investigate the hypothesis that indeed there is a developmental stress risk window in male Wistar rats. We conducted a systematic mapping of the long-term effects of an acute stress protocol, applied both prenatal (gestational days 14-16) and postnatal (days 9-151), overall at 11 different time-points during development. Stress protocol consists of 3 days of either maternal separation (for rats at postnatal days 9-19) or exposure to the stressors forced swim, elevated plus maze and restraint (for both dams and males at postnatal days 24-151). Consequences in adulthood were measured by investigating the animals' behavior in both the open field and startle box, together with the physiological measure of corticosterone. We found both behaviorally and physiologically that the pubescence time points are the most vulnerable to stress compared to all other tested time points along the developmental trajectory. Carefully considering the comparison between rat and human age, our findings may imply the importance of childhood-to-adulthood transition, as a sensitive time-point which may exacerbate a predisposition for the development of stress-induced psychopathologies. Copyright © 2014. Published by Elsevier Ltd.
    Psychoneuroendocrinology 11/2014; 52C(1):168-175. DOI:10.1016/j.psyneuen.2014.11.012 · 4.94 Impact Factor
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    • "Research into the epigenetic impact of stress during this developmental stage has been relatively scant, however. This has begun to change recently, most notably with a study demonstrating that mild stress in adolescent mice causes a GR-dependent hypermethylation of the tyrosine hydroxylase promoter and changes in the mesolimbic dopamine system which lead to a number of behavioral deficits as well as altered HPA reactivity [79]. It is to be hoped that further work is done regarding this critical time period in brain development and disease susceptibility. "
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    Epigenetics in Psychiatry, 1st edited by Peedicayil, Grayson, Avramopoulos, 07/2014: pages 325-342; Academic Press., ISBN: 978-0-12-417115-5
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