BEHAVIORAL, MOLECULAR AND EPIGENETIC CONSEQUENCES OF EARLY LIFE STRESS EXPOSURE AND THEIR IMPACT ON ADULT PSYCHOPATHOLOGY

There is now consistent evidence that psychiatric diseases may often represent the consequence of exposure to adverse events early in life, which may disrupt the correct program of brain maturation thus leading to long-lasting changes in brain function. Accordingly, exposure to stress during gestation in rats has a strong impact on brain development and can cause long-term abnormalities in adult behavior (Fumagalli et al., 2007; Seckl, 1998). In this context, the study of environmental manipulations in animal models offers the possibility to investigate the mechanisms that may be responsible for functional deterioration, with the advantage of keeping the influence of various factors such as the timing and intensity of the adverse condition, the growth environment and the genetic background under control. Given all these premises, in this study we first set up and employed a paradigm of prenatal stress in rodents in order to reproduce early life adversities that may encompass pregnancy and early postnatal life. Indeed, gestational stress has long-lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis and on the behavior of the dams, suggesting that alterations in maternal behavior following exposure to prenatal stress could also contribute to the long-term effects (Maccari et al., 2003; Maccari and Morley-Fletcher, 2007) of this environmental stressor. In particular, the paradigm we employed consisted in restraining the dams during the last week of gestation for 45 minutes three times a day under bright light, from gestation day 14 until delivery. We next sacrificed the pups, both males and females, at different postnatal time points, in order to create a time profile of the modifications under investigation. First, we tested the cognitive functionality of adult animals with the object recognition test, since cognitive disabilities are one of the common symptoms that characterize different psychiatric conditions (Disner et al., 2011; Lapiz-Bluhm et al., 2008; Lesh et al., 2011; Lewis et al., 2012). Next, we performed a detailed analysis of two candidate systems whose deterioration could contribute to the development of the diseased phenotype, namely the glucocorticoid receptor (GR) and the neurotrophin brain-derived neurotrophic factor (BDNF), through basal and functional analyses at gene and protein levels. These two systems have emerged as the most vulnerable elements of exposure to stress during development and can be considered markers of the dysfunctions associated with psychiatric disorders. The HPA axis is involved in the response to stressful events (Maccari et al., 2003), whereas neuronal plasticity represents an array of mechanisms involved in the adaptive capacity to environmental changes (Calabrese et al., 2009; Duman and Monteggia, 2006). We performed the analyses at various stages of development, trying to establish how early the molecular alterations become manifest and their persistence in time. Notably this bears the possibility to evaluate the potential of early pharmacological interventions that may prove effective in preventing the molecular and functional alterations set in motion by prenatal stress exposure, leading to long-term beneficial effects on the brain function. Several animal models and human studies suggest that the effect of exposure to stress early in life on lifelong phenotypes is mediated by epigenetic regulation of gene expression involving changes in DNA methylation (McGowan and Szyf, 2010; Weaver, 2007). A further aspect of this experimental work was thus to determine the methylome profile of the hippocampus and the prefrontal cortex of adult rats exposed to prenatal stress. In order to do this, we combined methylated DNA immunoprecipitation (MeDIP) followed by the hybridization on a custom designed high-density oligonucleotide arrays, in order to identify, with an unbiased approach, the genes that are persistently affected by gestational exposure to stress at expression level through changes in the methylation of their promoters. Last, we aimed at identifying novel candidate markers in a translational approach, by comparing the methylome results obtained in the rat model with a non-human primate model based on different rearing condition, and with a human model of maternal adversities. The identification of genes that show a similar response to early adversities in the brain and in peripheral tissues, in three different species and across the lifespan, is critical for the development of novel diagnostic tools and for therapeutic interventions

Sex-Specific Effects of Prenatal Stress on Bdnf Expression in Response to an Acute Challenge in Rats : a Role for Gadd45β

Exposure to early adversities represents a major risk factor for psychiatric disorders. We have previously shown that exposure to prenatal stress (PNS) in rats alters the developmental expression of brain-derived neurotrophic factor (Bdnf) with a specific temporal profile. However, exposure to early-life stress is known to alter the ability to cope with challenging events later in life, which may contribute to the enhanced vulnerability to stress-related disorders. Since Bdnf is also an important player for activity-dependent plasticity, we investigated whether the exposure to PNS in rats could alter Bdnf responsiveness to an acute challenge at adulthood. We found that exposure to PNS produces significant changes in Bdnf responsiveness with brain region- and gender-specific selectivity. Indeed, exposure to an acute stress upregulates Bdnf expression in the prefrontal cortex, but not in the hippocampus, of control animals. Moreover, such modulatory activity is selectively impaired in PNS female rats, an effect that was associated with changes in the modulation of the DNA demethylase Gadd45\u3b2. Our results suggest that exposure to PNS may reprogram gene transcription through epigenetic mechanisms reducing the ability to cope under adverse conditions, a trait that is disrupted in psychiatric diseases

Inducible forebrain-specific ablation of the transcription factor Creb during adulthood induces anxiety but no spatial/contextual learning deficits

The cyclic AMP (cAMP)-response element binding protein (CREB) is an activity-dependent transcription factor playing a role in synaptic plasticity, learning and memory, and emotional behavior. However, the impact of Creb ablation on rodent behavior is vague as e.g. memory performance of different Creb mutant mice depends on the specific type of mutation per se but additionally on the background and learning protocol differences. Here we present the first targeted ablation of CREB induced during adulthood selectively in principal forebrain neurons in a pure background strain of C57BL/6 mice. All hippocampal principal neurons exhibited lack of CREB expression. Mutant mice showed a severe anxiety phenotype in the openfield and novel object exploration test as well as in the Dark-Light Box Test, but unaltered hippocampus-dependent long-term memory in the Morris water maze and in context dependent fear conditioning. On the molecular level, CREB ablation led to CREM up regulation in the hippocampus and frontal cortex which may at least in part compensate for the loss of CREB. BDNF, a postulated CREB target gene, was down regulated in the frontal lobe but not in the hippocampus; neurogenesis remained unaltered. Our data indicate that in the adult mouse forebrain the late onset of CREB ablation can, in case of memory functionality, be compensated for and is not essential for memory consolidation and retrieval during adulthood. In contrast, the presence of CREB protein during adulthood seems to be pivotal for the regulation of emotional behavior

Comparison of 30 THz impulsive burst time development to microwaves, H-alpha, EUV, and GOES soft X-rays

The recent discovery of impulsive solar burst emission in the 30 THz band is raising new interpretation challenges. One event associated with a GOES M2 class flare has been observed simultaneously in microwaves, H-alpha, EUV, and soft X-ray bands. Although these new observations confirm some features found in the two prior known events, they exhibit time profile structure discrepancies between 30 THz, microwaves, and hard X-rays (as inferred from the Neupert effect). These results suggest a more complex relationship between 30 THz emission and radiation produced at other wavelength ranges. The multiple frequency emissions in the impulsive phase are likely to be produced at a common flaring site lower in the chromosphere. The 30 THz burst emission may be either part of a nonthermal radiation mechanism or due to the rapid thermal response to a beam of high-energy particles bombarding the dense solar atmosphere.Comment: accepted to Astronomy and Astrophysic

Generalised models for torsional spine and fan magnetic reconnection

Three-dimensional null points are present in abundance in the solar corona, and the same is likely to be true in other astrophysical environments. Recent studies suggest that reconnection at such 3D nulls may play an important role in the coronal dynamics. In this paper the properties of the torsional spine and torsional fan modes of magnetic reconnection at 3D nulls are investigated. New analytical models are developed, which for the first time include a current layer that is spatially localised around the null, extending along either the spine or the fan of the null. These are complemented with numerical simulations. The principal aim is to investigate the effect of varying the degree of asymmetry of the null point magnetic field on the resulting reconnection process - where previous studies always considered a non-generic radially symmetric null. The geometry of the current layers within which torsional spine and torsional fan reconnection occur is found to be strongly dependent on the symmetry of the magnetic field. Torsional spine reconnection still occurs in a narrow tube around the spine, but with elliptical cross-section when the fan eigenvalues are different, and with the short axis of the ellipse being along the strong field direction. The spatiotemporal peak current, and the peak reconnection rate attained, are found not to depend strongly on the degree of asymmetry. For torsional fan reconnection, the reconnection occurs in a planar disk in the fan surface, which is again elliptical when the symmetry of the magnetic field is broken. The short axis of the ellipse is along the weak field direction, with the current being peaked in these weak field regions. The peak current and peak reconnection rate in this case are clearly dependent on the asymmetry, with the peak current increasing but the reconnection rate decreasing as the degree of asymmetry is increased

Morc1 knockout evokes a depression-like phenotype in mice

Morc1 gene has recently been identified by a DNA methylation and genome-wide association study as a candidate gene for major depressive disorder related to early life stress in rodents, primates and humans. So far, no transgenic animal model has been established to validate these findings on a behavioral level. In the present study, we examined the effects of a Morc1 loss of function mutation in female C57BL/6N mice on behavioral correlates of mood disorders like the Forced Swim Test, the Learned Helplessness Paradigm, O-Maze and Dark-Light-Box. We could show that Morc1(-/-) mice display increased depressive-like behavior whereas no behavioral abnormalities regarding locomotor activity or anxiety-like behavior were detectable. CORT plasma levels did not differ significantly between Morc1(-/-) mice and their wildtype littermates, yet - surprisingly - total Bdnf mRNA-levels in the hippocampus were up-regulated in Morc1(-/-) animals. Although further work would be clarifying, Morc1(-/-) mice seem to be a promising epigenetically validated mouse model for depression associated with early life stress

Risk factors for postoperative depression in 150 subjects treated for drug-resistant focal epilepsy.

Objective.The primary goal was to identify risk factors for post-surgical depression in subjects operated on for drug-resistant epilepsy. Secondary goals were to confirm the high rate of depression in subjects suffering from epilepsy (prior to surgery) and to look for first post-surgical depressive episode.Methods.Case series study of 150 subjects surgically treated for partial epilepsy (side of surgery: 72 right, 78 left; site of surgery: 97 Unilobar Temporal, 17 Unilobar Frontal, 14 Posterior, 22 Multilobar). All subjects routinely had three psychiatric evaluations: before surgery (baseline) and at 6 and 12 months after surgery. Psychiatric diagnoses were made according to DSM-IV-TR criteria. Bivariate (Fisher exact test and Kruskal–Wallis rank sum test) and multivariate (logistic regression model fitting) analyses were performed.Results.Thirty-three (22%) subjects had post-surgical depressive episodes, 31 of them in the first 6 months. Fourteen out of 33 experienced depression for the first time. Post-surgical depressive episodes are not associated with gender, outcome on seizures, side/site of surgical resection, histological diagnosis, psychiatric diagnoses other than depression. Depressive episodes before surgery and older age at surgery time are risk factors for post-surgical depression (p = 0.0001 and 0.01, respectively, at logistic regression analysis). No protective factors were identified.Conclusions.Our data show that lifetime depressive episodes and older age at surgery time are risk factors for post-surgery depression. Moreover, a prospective study could be useful in order to assess whether depression is really a consequence of surgery

Modulation of BDNF expression by repeated treatment with the novel antipsychotic lurasidone under basal condition and in response to acute stress

It is known that long-term treatment with antipsychotic drugs (APDs) produces neuroadaptive changes through the modulation of different proteins that, by enhancing neuronal plasticity and cellular resiliency, may improve core disease symptoms. The aim of this study was to investigate the ability of chronic treatment with the novel antipsychotic lurasidone to modulate BDNF expression in hippocampus and prefrontal cortex, under basal conditions or in response to an acute stress, a major precipitating element in psychiatric disorders. By means of real-time PCR, we found that (1) chronic lurasidone treatment increases total BDNF mRNA levels in rat prefrontal cortex and, to less extent, in hippocampus; (2) the modulation of BDNF mRNA levels in response to acute swim stress in lurasidone-treated rats was markedly potentiated in hippocampus, and to less extent in prefrontal cortex, through the selective regulation of different neurotrophin isoforms. The increase of BDNF mRNA levels in prefrontal cortex was paralleled by an enhancement of mature BDNF protein levels. In conclusion, repeated exposure to lurasidone regulates BDNF expression, through a finely tuned modulation of its transcripts. This effect may contribute to the amelioration of functions, such as cognition, closely associated with neuronal plasticity, which are deteriorated in schizophrenia patients