Monoamine oxidase A (MAOA) harbours a polymorphic upstream variable-number tandem repeat (u-VNTR). The MAOA-L allele of the u-VNTR leads to decreased gene expression levels in vitro and has been found to increase the risk of conduct disorder in males with childhood adversities. Early-life adversities have been associated with hypermethylation of the glucocorticoid receptor (NR3C1). In this study, we first performed a genetic association analysis of the MAOA u-VNTR using individuals with depression (n = 392) and controls (n = 1276). Next, DNA methylation analyses of MAOA and NR3C1 were performed using saliva samples of depressed and control subgroups. Adult MAOA-L females with childhood adversities were found to have a higher risk of developing depression (p = 0.006) and overall MAOA methylation levels were decreased in depressed females compared to controls (mean depressed, 42% vs. mean controls, 44%; p = 0.04). One specific childhood adversity [early parental death (EPD)] was associated with hypermethylation of NR3C1 close to an NGFI-A binding site (mean EPD, 19% vs. mean non-EPD, 14%; p = 0.005). Regression analysis indicated that this association may be mediated by the MAOA-L allele (adjusted R² = 0.24, ANOVA: F = 23.48, p < 0.001). Conclusively: (1) depression in females may result from a gene × childhood-adversity interaction and/or a dysregulated epigenetic programming of MAOA; (2) childhood-adversity subtypes may differentially impact DNA methylation at NR3C1; (3) baseline MAOA-genotypic variations may affect the extent of NR3C1 methylation.

Natural behaviors such as eating, drinking, reproduction and exercise activate brain reward pathways and consequently the individual engages in these behaviors to receive the reward. However, drugs of abuse are even more potent to activate the reward pathways. Rewarding behaviors and addictive drugs also affect other parts of the brain not directly involved in the mediation of reward. For instance, running increases neurogenesis in hippocampus and is beneficial as an antidepressant in a genetic animal model of depression and in depressed humans. Here we discuss and compare neurochemical and functional changes in the brain after addictive drugs and exercise with a focus on brain reward pathways and hippocampus.

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Formation of lasting memories is believed to rely on structural alterations at the synaptic level. We had found that increased neuronal activity down-regulates Nogo receptor-1 (NgR1) in brain regions linked to memory formation and storage, and postulated this to be required for formation of lasting memories. We now show that mice with inducible overexpression of NgR1 in forebrain neurons have normal long-term potentiation and normal 24-h memory, but severely impaired month-long memory in both passive avoidance and swim maze tests. Blocking transgene expression normalizes these memory impairments. Nogo, Lingo-1, Troy, endogenous NgR1, and BDNF mRNA expression levels were not altered by transgene expression, suggesting that the impaired ability to form lasting memories is directly coupled to inability to down-regulate NgR1. Regulation of NgR1 may therefore serve as a key regulator of memory consolidation. Understanding the molecular underpinnings of synaptic rearrangements that carry lasting memories may facilitate development of treatments for memory dysfunction.behavior ͉ hippocampus ͉ long-term potentiation ͉ myelin inhibitors ͉ synaptic plasticity