Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma

Adverse childhood experiences (ACEs) may be referred to by other terms (e.g., early life adversity or stress and childhood trauma) and have a lifelong impact on mental and physical health. For example, childhood trauma has been associated with posttraumatic stress disorder (PTSD), anxiety, depression, bipolar disorder, diabetes, and cardiovascular disease. The heritability of ACE-related phenotypes such as PTSD, depression, and resilience is low to moderate, and, moreover, is very variable for a given phenotype, which implies that gene by environment interactions (such as through epigenetic modifications) may be involved in the onset of these phenotypes. Currently, there is increasing interest in the investigation of epigenetic contributions to ACE-induced differential health outcomes. Although there are a number of studies in this field, there are still research gaps. In this review, the basic concepts of epigenetic modifications (such as methylation) and the function of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response are outlined. Examples of specific genes undergoing methylation in association with ACE-induced differential health outcomes are provided. Limitations in this field, e.g., uncertain clinical diagnosis, conceptual inconsistencies, and technical drawbacks, are reviewed, with suggestions for advances using new technologies and novel research directions. We thereby provide a platform on which the field of ACE-induced phenotypes in mental health may build

Reduced Anxiety and Depression-Like Behaviours in the Circadian Period Mutant Mouse Afterhours

Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours.Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder.Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009).Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans

Lognormal Properties of SGR 1806-20 and Implications for Other SGR Sources

The time interval between successive bursts from SGR 1806-20 and the intensity of these bursts are both consistent with lognormal distributions. Monte Carlo simulations of lognormal burst models with a range of distribution parameters have been investigated. The main conclusions are that while most sources like SGR 1806-20 should be detected in a time interval of 25 years, sources with means about 100 times longer have a probability of about 5\% of being detected in the same interval. A new breed of experiments that operate for long periods are required to search for sources with mean recurrence intervals much longer than SGR 1806-20.Comment: 4 pages, latex with seperate file containing 2 uuencoded, gzip'ed, tarred, .eps figures. Replaced with file that does not use kluwer.sty to allow automatic postscript generation. To appear in proceedings of ESLAB 2

Interactions and switching field distributions of nanoscale magnetic elements

Magnetic nano-elements made from NiFe and Co have been investigated using magnetic imaging in the transmission electron microscope. Nano-elements like these have possible uses for in-plane patterned media or solid state memory. In both cases the elements will need to be patterned into closely spaced arrays and magnetostatic interactions between the elements will begin to become significant. Arrays must therefore be designed so that an element's interactions with its neighbors will be small compared to its coercivity. Arrays of NiFe elements 300 nm long, 50-100 nm wide, and 26 nm thick, were fabricated by electron beam lithography and lift-off patterning. Their switching behavior and the interactions between them were studied in detail. Magnetization sequences were recorded and hysteresis loops constructed. For rows of NiFe elements with the gap between elements the same as the element width or larger, the interactions turn out to be small, suggesting that denser arrays would be possible

Direct observation of magnetization reversal processes in micron-sized elements of spin-valve material

Simple calculations suggest that when continuous films of spin-valvematerial are patterned into micron-sized elements the magnetic properties should change markedly, depending on the element shape and size. We have used the differential phase contrast imaging mode of transmission electron microscopy to study directly the magnetization distributions supported by such elements in zero field and when subjected to an applied field in the pinning direction. For elements whose long axis is parallel to the pinning direction a parallel alignment of the free and pinned layers is favored. When subjected to a field a complex domain structure evolves and different irreversible paths are followed as the element is taken from negative to positive saturation and back again. By contrast, when the pinning direction is parallel to the short axis an antiparallel arrangement, where the magnetostatic contribution to the energy is effectively suppressed, can be preferred and simpler reversal mechanisms, with a higher degree of reversibility, are frequently seen

Magnetisation reversal in cobalt and permalloy nano-elements

We have investigated the domain structure and reversal mechanism in sub-micron sized magnetic elements using Lorentz microscopy in a transmission electron microscope (TEM). Acicular nano-elements were fabricated from thin films of Co and permalloy (NiFe) using electron beam lithography and lift-off techniques. The elements were 200 nm wide, 1.6-2.6 mu m long and 20-50 nm thick, with their ends either flat (rectangular) or pointed (triangular). Fresnel and Foucault techniques were used to image the domain structure in the elements in order to measure the switching fields and observe the reversal mechanisms. It was found that the magnetic properties depended strongly on the material, element width and film thickness, and on certain aspects of their shape. In particular the presence of two pointed ends greatly increased the switching field

Proteomic analysis of hippocampus and frontal cortex in a rat model of depression with gene-environment interaction and antidepressant treatment.

The wide-scale analysis of protein expression provides a powerful strategy for the exploration at a molecular level of complex pathophysiological mechanisms, such as the response to treatment with psychotropic agents. GENDEP is an Integrated Project that combines large-scale clinical pharmacogenomic studies on depressed patients with preclinical investigations on animal models of disease, focusing on treatment with antidepressants. In this work, the Flinders Sensitive Line (FSL), a genetically selected rat model of depression displaying good face, predictive and construct validity (Overstreet 2005) was investigated by a two dimensional proteomic approach. As a control, analyses were carried out on the corresponding Flinders Resistant Line (FRL), which does not show the depressive-like behaviour. To evaluate gene\u2013environment interactions, the FSL and FRL animals were subjected to maternal separation (MS), since early life trauma is considered to be an important antecedent of major depression. Following weaning, FSL and FRL rats were treated with escitalopram (ES), a selective serotonin reuptake inhibitor. FSL and FRL rats were subjected to 180 min. maternal separation from postnatal day 2 to 14. Control groups were not maternally separated. Both stressed and control animals were split into groups receiving ES admixed to food pellets (25 mg/kg/day) or vehicle for 30 days. One week before the end of treatments, the animals were subjected to the Porsolt swim test in order to assess the antidepressant effect of ES. After sacrifice, extracts were prepared from frontal cortex and hippocampus and proteins were separated by two-dimensional electrophoresis. Spots were detected by staining with a fluorescent dye. Image analysis was carried out on maps with PDQuest software to compare protein levels in different gels. Protein level comparisons were carried out with both univariate (Student\u2019s t test) and multivariate (Partial Least Squares) statistical analysis methods. Spots displaying statistically significant differences were cut and proteins were identified using peptide fingerprinting mass spectrometry. Comparisons were carried out between groups in different electrophoretic runs to detect changes induced by genetic background, stress exposure and pharmacological treatment in each brain region. Modified proteins were identified. By the comparison FRL vs FSL, information was gathered about genetic differences between the lines, which are probably involved in the depressive-like behaviour. In the comparison (FSL+noMS+vehicle) vs (FSL+no MS+ES) vs (FSL+MS+ES) the different effect of pharmacological treatment was revealed on control and maternally separated FSL. By the comparison (FSL+noMS+vehicle) vs (FSL+MS+vehicle) vs (FSL+MS+ES), information was collected about the effect of the pharmacological treatment on the modifications induced by maternal separation. The same designs were also analysed on the FRL. Proteins involved in the different pharmacological response in different genetic backgrounds were revealed in the comparison (FRL+MS+ES) vs (FSL+MS+ ES). Results on proteome analysis of ES treated rats allowed the identification of molecular correlates of vulnerability to the disease, the effect of early life stress and the response to pharmacological treatment