ABSTRACT
Environmental factors, including stress, that are experienced during early life (ELS) or adolescence are potential risk factors for the development of behavioral and mental disorders later in life. The endocannabinoid system plays a major role in the regulation of stress responses and emotional behavior, thereby acting as a mediator of stress vulnerability and resilience. Among the critical factors, which determine the magnitude and direction of long-term consequences of stress exposure is age, i.e., the maturity of brain circuits during stress exposure. Thus, the present study addressed the hypotheses that ELS and adolescent stress differentially affect the expression of regulatory elements of the endocannabinoid system, cannabinoid receptor 1 (CB1R) and fatty acid amide hydrolase (FAAH) in the medial prefrontal cortex (mPFC) of adult female rats. We also tested the hypothesis that the proposed gene expression changes are epigenetically modulated via altered DNA-methylation. The specific aims were to investigate if (i) ELS and adolescent stress as single stressors induce changes in CB1R and FAAH expression (ii) ELS exposure influences the effect of adolescent stress on CB1R and FAAH expression, and (iii) if the proposed gene expression changes are paralleled by changes of DNA methylation. The following experimental groups were investigated: (1) non-stressed controls (CON), (2) ELS exposure (ELS), (3) adolescent stress exposure (forced swimming; FS), (4) ELS + FS exposure. We found an up-regulation of CB1R expression in both single-stressor groups and a reduction back to control levels in the ELS + FS group. An up-regulation of FAAH expression was found only in the FS group. The data indicate that ELS, i.e., stress during a very immature stage of brain development, exerts a buffering programming effect on gene expression changes induced by adolescent stress. The detected gene expression changes were accompanied by altered DNA methylation patterns in the promoter region of these genes, specifically, a negative correlation of mean CB1R DNA methylation with gene expression was found. Our results also indicate that ELS induces a long-term "(re)programming" effect, characterized by CpG-site specific changes within the promoter regions of the two genes that influence gene expression changes in response to FS at adolescence.
ABSTRACT
BACKGROUND: ADHD is a common neurodevelopmental disorder with a pediatric prevalence of 5.2%.While medication treatment for ADHD is effective, it does not address all symptoms and a small but notable subgroup does not respond to medications. Adverse effects limit its use and some parents and participants resist use of medication. Thus, limitations of medication treatment for ADHD motivate searching for other therapeutic options. Transcranial Direct Current Stimulation (tDCS) has been suggested as a treatment for children with ADHD, with mixed results to date. Protocol variables employed, including combined use of cognitive training (CT) and scheduling of sessions, may explain diverse findings to date. The aim of this study was to examine safety, feasibility and efficacy of tDCS combined with CT provided three-times-per week for one-month to treat children with ADHD. METHODS: In a double blind, randomized, sham-controlled pilot study, 25 children with ADHD were randomized to receive 12 sessions of either anodal tDCS or sham-tDCS for 20 min combined with CT three-times-per-week for four weeks. The tDCS anode was over left dorsolateral prefrontal cortex (DLPFC) and cathode over vertex. Assessments were obtained prior to, after 6 sessions, 12 sessions and one-month after intervention. RESULTS: No significant post-intervention differences were found between those receiving tDCS or sham-tDCS. Both groups demonstrated significant improvement on questionnaire measures of ADHD and executive function with mixed results seen on computerized performance measures. Overall, adverse effects were mild with no significant difference between groups. However, three children, all from the tDCS group, experienced headaches with two requiring temporary cessation and one requiring removal from the study. CONCLUSIONS: Anodal tDCS to the DLPFC using the above protocol in children with ADHD did not demonstrate additional treatment benefits beyond that of CT.
