The human tyrosine hydroxylase (hTH) gene has a 42†bp evolutionarily conserved region designated (CR) II at -7.24†kb, which bears 93% homology to the region we earlier identified as containing the glucocorticoid response element, a 7†bp activator protein-1 (AP-1)-like motif in the rat TH gene. We cloned this hTH-CRII region upstream of minimal basal hTH promoter in luciferase (Luc) reporter vector, and tested glucocorticoid responsiveness in human cell lines.
Elevated circulating levels of glucocorticoids are associated with psychiatric symptoms across several different conditions. It remains unknown if this hormonal abnormality is a cause or an effect of the psychiatric conditions. For example, the hypercortisolemia observed in a subset of patients with depression may have a direct impact on the symptoms of depression, but it is also possible that the hypercortisolemia merely reflects the stress associated with depression.
Epidemiological evidence links exposure to stress hormones during fetal or early postnatal development with lifetime prevalence of cardiac, metabolic, auto-immune, neurological and psychiatric disorders. This has led to the concept of 'developmental programming through stress'. Importantly, these effects (specifically, hypertension, hyperglycaemia and neurodevelopmental and behavioural abnormalities) can be reproduced by exposure to high glucocorticoid levels, indicating a crucial role of glucocorticoids in their causation.
Journal of the American Academy of Child and Adolescent Psychiatry
OBJECTIVE: Child and adolescent psychiatry is rife with examples of the sustained effects of early experience on brain function. The study of behavioral genetics provides evidence for a relation between genomic variation and personality and with the risk for psychopathology. A pressing challenge is that of conceptually integrating findings from genetics into the study of personality without regressing to arguments concerning the relative importance of genomic variation versus nongenomic or environmental influences.
RATIONALE: Early Life Stress (ELS) increases risk for both adult traumatization and posttraumatic stress disorder (PTSD). Adult PTSD may also reflect a continuation of a response to an earlier exposure to adversity. Given similarities between neuroendocrine aspects of PTSD and ELS, such as in reduced cortisol signaling and glucocorticoid receptor (GR) responsiveness, some aspects of the biology of PTSD may reflect biological correlates of risk.
Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic-pituitary-adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1(F) NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD).
Prenatal exposure to maternal stress can have lifelong implications for psychological function, such as behavioral problems and even the development of mental illness. Previous research suggests that this is due to transgenerational epigenetic programming of genes operating in the hypothalamic-pituitary-adrenal axis, such as the glucocorticoid receptor (GR). However, it is not known whether intrauterine exposure to maternal stress affects the epigenetic state of these genes beyond infancy.
BACKGROUND: A history of early adverse experiences is an important risk factor for adult psychopathology. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Preclinical work in rodents has linked low levels of maternal care to increased methylation of the promoter region of the glucocorticoid receptor (GR) gene, as well as to exaggerated hormonal and behavioral responses to stress.
Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Parental care influences development across mammals. In humans such influences include effects on phenotypes, such as stress reactivity, which determine individual differences in the vulnerability for affective disorders. Thus, the adult offspring of rat mothers that show an increased frequency of pup licking/grooming (ie, high LG mothers) show increased hippocampal glucocorticoid receptor (GR) expression and more modest hypothalamic-pituitary-adrenal responses to stress compared with the offspring of low LG mothers.
The likelihood of adult psychiatric problems is increased by childhood trauma, particularly so in carriers of certain alleles of certain genes. I discuss here a recent paper that sheds light on the mechanism of this effect, showing that specific demethylation occurring at the time of the initial trauma persists at adulthood and induces an increased reactivity to stress.