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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    • "Moreover, mice engineered to express C-terminally truncated human DISC1 (Hikida et al., 2007; Li et al., 2007; Pletnikov et al., 2008; Shen et al., 2008), containing a targeted deletion of exons 2 and 3 (Kuroda et al., 2011), harbouring a naturally occurring 25 base pair deletion in the Disc1 gene (Gomez-Sintes et al., 2014; Juan et al., 2014) or carrying ENUinduced point mutations in Disc1 (Clapcote et al., 2007) all show behavioural abnormalities. Moreover, interactions between DISC1 and environmental factors have been shown to modulate behaviour (Abazyan et al., 2010; Haque et al., 2012; Ibi et al., 2010; Niwa et al., 2013). Therefore, the study of DISC1 biology may provide fundamental insight into the complex interplay between genetic, developmental and environmental factors that underlie mental illness. "
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    ABSTRACT: DISRUPTED-IN-SCHIZOPHRENIA (DISC1) has been one of the most intensively studied genetic risk factors for mental illness since it was discovered through positional mapping of a translocation breakpoint in a large Scottish family where a balanced chromosomal translocation was found to segregate with schizophrenia and affective disorders. While the evidence for it being central to disease pathogenesis in the original Scottish family is compelling, recent genome-wide association studies have not found evidence for common variants at the DISC1 locus being associated with schizophrenia in the wider population. It may therefore be the case that DISC1 provides an indication of biological pathways that are central to mental health issues and functional studies have shown that it functions in multiple signalling pathways. However, there is little information regarding factors that function upstream of DISC1 to regulate its expression and function. We herein demonstrate that Sonic hedgehog (Shh) signalling promotes expression of disc1 in the zebrafish brain. Expression of disc1 is lost in smoothened mutants that have a complete loss of Shh signal transduction, and elevated in patched mutants which have constitutive activation of Shh signalling. We previously demonstrated that disc1 knockdown has a dramatic effect on the specification of oligodendrocyte precursor cells (OPC) in the hindbrain and Shh signalling is known to be essential for the specification of these cells. We show that disc1 is prominently expressed in olig2-positive midline progenitor cells that are absent in smo mutants, while cyclopamine treatment blocks disc1 expression in these cells and mimics the effect of disc1 knock down on OPC specification. Various features of a number of psychiatric conditions could potentially arise through aberrant Hedgehog signalling. We therefore suggest that altered Shh signalling may be an important neurodevelopmental factor in the pathobiology of mental illness.
    Biology Open 09/2015; DOI:10.1242/bio.012005 · 2.42 Impact Factor
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    • "DISC1 has been found to play a role in the integration of cortical and hippocampal neuronal networks during the maturation of the prefrontal cortex (El-Hassar et al., 2014). Suppression of the expression of DISC1 during the neurodevelopmental process has been found alter dopamine transmission, with subsequent behavioral abnormalities (Niwa et al., 2013). Obstetric complications such as hypoxia have been found to increase the degradation of DISC1 (Barodia et al., 2015). "
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    ABSTRACT: Pre- and perinatal environmental factors have been shown to increase schizophrenia risk particularly when combined with genetic liability. The investigation of specific gene environment interactions in the etiology of psychiatric disorders has gained momentum. We used multivariate GEE regression modeling to investigate the interaction between genes of the DISC1 pathway and birth weight, in relation to schizophrenia susceptibility in a Finnish schizophrenia family cohort. The study sample consisted of 457 subjects with both genotype and birth weight information. Gender and place of birth were adjusted for in the models. We found a significant interaction between birth weight and two NDE1 markers in relation to increased schizophrenia risk: a four SNP haplotype spanning NDE1 (b=1.26, SE=0.5, p=0.012) and one of its constituent SNPs rs4781678 (b=1.33, SE=0.51, p=0.010). Specifically, high birth weight (>4000g) was associated with increased schizophrenia risk among subjects homozygous for the previously identified risk alleles. The study was based on a family study sample with high genetic loading for schizophrenia and thus our findings cannot directly be generalized as representing the general population. Our results suggest that the functions mediated by NDE1 during the early stages of neurodevelopment are susceptible to the additional disruptive effects of pre- and perinatal environmental factors associated with high birth weight, augmenting schizophrenia susceptibility.
    09/2015; DOI:10.1016/j.psychres.2015.08.038
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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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