Ehsan Pishva

Defeat stress in rodents : From behavior to molecules

Mood and anxiety disorders are prevalent conditions affecting one out of four people during lifetime. The development of high validity animal models to study these disorders has been a major challenge in the past. When considering experimental approaches for studying affective disorders, the social defeat paradigm has been shown to have etiological, predictive and face validity. Here, we explain the general principle of social defeat stress paradigms, with a strong focus on the resident-intruder model and compare different experimental settings as published to date. We discuss behavioral changes described in defeated animals as well as changes in the animals physiological parameters. In addition, we provide an overview of the molecular adaptations that are found in animals subjected to defeat stress, with special attention to neural circuits and neuroendocrine signaling. Defeat produces specific behaviors resembling the signs and symptoms of humans with affective disorders, such as anhedonia, social avoidance, despair and anxiety. These can be linked to a wide range of physiological changes-ranging from cardiovascular changes to alterations in the immune system- or by disturbances in specific neurotransmitter systems, in particular serotonin and dopamine. The defeat stress model thus impacts on several functional domains of behavior and may mimic cardinal features of a multitude of psychiatric disorders including depression, post-traumatic stress disorder and schizophrenia. This manuscript critically reviews the core findings, strengths and limitations of the range of animal studies in this field and provides future perspectives.

The epigenome and postnatal environmental influences in psychotic disorders

ObjectivesSchizophrenia spectrum disorders and bipolar spectrum disorders are the product of both heritable and non-heritable factors, the impact of which converges at different biological levels. Recent evidence from molecular approaches has provided new insights about how environmental exposures cause persistent alterations in the regulation of gene expression, particularly by so-called epigenetic mechanisms. The aim of this review is to provide an overview of findings of epigenetic studies in psychotic disorders, summarizing findings of human and animal studies on epigenetic alterations due to postnatal environmental exposures associated with psychotic disorders.MethodsElectronic and manual literature search of MEDLINE, EMBASE and PSYCHINFO, using a range of search terms around epigenetics, DNA methylation, histone modifications, psychoses, schizophrenia, bipolar disorder and environmental risks associated with psychotic disorders as observed in human and experimental animal studies, complemented by review articles and cross-references.ResultsDespite several promising findings of differential epigenetic profiles in individuals with psychotic disorders in the studies published to date, the knowledge of the role of epigenetic processes in psychotic disorder remains very limited, and should be interpreted cautiously given various challenges in this rapidly evolving field of research.ConclusionsIntegration of epigenetic findings into biopsychosocial models of the etiology of psychotic disorders eventually may yield important insights into the biological underpinnings of the onset and course of psychotic disorders.

Epigenetic Genes and Emotional Reactivity to Daily Life Events: A Multi-Step Gene-Environment Interaction Study

Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery.

DNMT3A moderates cognitive decline in subjects with mild cognitive impairment: replicated evidence from two mild cognitive impairment cohorts

Epigenetic dysregulation has been associated with cognitive decline and Alzheimers disease. The present study investigated associations between common SNPs in genes regulating DNA methylation and age-related changes in cognitive decline in two independent prospective cohorts of patients suffering from mild cognitive impairment. An association between the rs1187120 SNP in DNMT3A and annual decline in cognitive functioning was discovered and replicated, suggesting that DNMT3A moderates cognitive decline in subjects with mild cognitive impairment.

Epigenetic epidemiology in psychiatry: A translational neuroscience perspective

Accumulating evidence from the field of neuroscience indicates a crucial role for epigenetic regulation of gene expression in development and aging of nervous system and suggests that aberrations in the epigenetic machinery are involved in the etiology of psychiatric disorders. Epidemiologic evidence on epigenetics in psychiatry, however, is currently very sparsely available, but is consistent with a mediating role for epigenetic mechanisms in bringing together inherited and acquired risk factors into a neurodevelopmental etiological model of psychiatric disorders. Here, we review evidence from the epidemiological and neuroscience literature, and aim to converge the evidence into an etiological model of psychiatric disorders that encompasses environmental, genetic and epigenetic contributions. Given the dynamic nature of the epigenetic machinery and the potential reversibility of epigenetic modifications, future well-designed interdisciplinary and translational studies will be of key importance in order to identify new targets for prevention and therapeutic strategies.

Neuroepigenetics of Aging and Age-Related Neurodegenerative Disorders

Neurodegenerative diseases are complex, progressive disorders and affect millions of people worldwide, contributing significantly to the global burden of disease. In recent years, research has begun to investigate epigenetic mechanisms for a potential role in disease etiology. In this chapter, we describe the current state of play for epigenetic research into neurodegenerative disorders including Alzheimers disease, Parkinsons disease and Huntingtons disease. We focus on the recent evidence for a potential role of DNA modifications, histone modifications and non-coding RNA in the etiology of these disorders. Finally, we discuss how new technological and bioinformatics advances in the field of epigenetics could further progress our understanding about the underlying mechanisms of neurodegenerative diseases.

PSYCHOSIS-ASSOCIATED EPIGENETIC VARIATION IN PATIENTS WITH ALZHEIMER’S DISEASE ACROSS CORTICAL BRAIN REGIONS

Figure 1. Data generation and analysis flow, (a) Illustration of nine DTI-feaByron Creese, Ehsan Pishva, Petroula Proitsi, Rebecca G. Smith, Clive Ballard, Daniel L. A. van den Hove, JonathanMill, Katie Lunnon, University of Exeter Medical School, Exeter, United Kingdom; Maastricht University, Maastricht, Netherlands; MRC Unit for Lifelong Health and Ageing at UCL, London, United Kingdom; University of Exeter, Exeter, United Kingdom. Contact e-mail: b.creese@exeter.ac.uk