Adolescent Stress–Induced Epigenetic Control of Dopaminergic Neurons via Glucocorticoids

Abstract

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.

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…Furthermore, GAD1 suppression in CCK þ /CNR1 þ interneurons leads to dysfunctional amygdala-dependent behavior and aminergic signaling Schmidt et al, 2013). Finally, mild stress during development results in epigenetic-mediated reduction of dopaminergic cell function in DISC1 mutant mice (Niwa et al, 2013), whereas the loss of DISC1 in the frontal cortex of adult rats increased stress sensitivity and resulted in cognitive impairments that were not observed in rats with normal DISC1 expression (Gamo et al, 2013). These results establish an important G Â E interaction between DISC1 and stress and reinforce the importance of developmental timing of this interaction.…”

Effect of chronic stress during adolescence in prefrontal cortex structure and function

“…Chronic stress induces long-lasting changes in the brain and could contribute to an increased vulnerability to mental illness, especially during the so-called critical periods of cortical development [4,5]. Unfortunately, many adolescents are exposed to stressful situations around the world, including war [6] and extreme poverty (UNICEF, 2005).…”

Divergent anomaly in mesocorticolimbic dopaminergic circuits might be associated with different depressive behaviors, an animal study

“…Recently, several lines of evidence consistently indicated that dysregulation of dopamine receptors and DAT in the mesocorticolimbic dopaminergic system were associated with depression (Eisch et al., 2003; Niwa et al., 2013; Winter et al., 2007). However, their roles in the emergence of different depressive phenotypes remain unclear.…”