Stress-induced perinatal and transgenerational epigenetic programming of brain development and mental health

Research efforts during the past decades have provided intriguing evidence suggesting that stressful experiences during pregnancy exert long-term consequences on the future mental wellbeing of both the mother and her baby. Recent human epidemiological and animal studies indicate that stressful experiences in utero or during early life may increase the risk of neurological and psychiatric disorders, arguably via altered epigenetic regulation. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications are prone to changes in response to stressful experiences and hostile environmental factors. Altered epigenetic regulation may potentially influence fetal endocrine programming and brain development across several generations. Only recently, however, more attention has been paid to possible transgenerational effects of stress. In this review we discuss the evidence of transgenerational epigenetic inheritance of stress exposure in human studies and animal models. We highlight the complex interplay between prenatal stress exposure, associated changes in miRNA expression and DNA methylation in placenta and brain and possible links to greater risks of schizophrenia, attention deficit hyperactivity disorder, autism, anxiety- or depression-related disorders later in life. Based on existing evidence, we propose that prenatal stress, through the generation of epigenetic alterations, becomes one of the most powerful influences on mental health in later life. The consideration of ancestral and prenatal stress effects on lifetime health trajectories is critical for improving strategies that support healthy development and successful aging.     

Psychiatrische Erkrankungen in Schwangerschaft und Stillzeit

The peripartum period represents a critical phase for the onset and course of mental disorders. During this phase, mental disorders occur as first onset or, more often, as recurrent or ongoing chronic conditions with onset and further course of illness in- or outside the peripartal period. No clear risk increase exists for the more prevalent mental disorders such as depressive and anxiety disorders during this period, whereas there is an increased risk for bipolar disorder. Peripartal mental disorders may impact fetal and child development through different mechanisms. The International Statistical Classification of Diseases and Related Health Problems (ICD-10) does not sufficiently take into account particularities of peripartal disorders with possible prognostic relevance. The present article gives an overview on prevalence, course, and clinical diagnostics and presents a proposal for consistent categorization of peripartal mental disorders.     

DNA Modifications and Neurological Disorders

Mounting evidence has recently underscored the importance of DNA methylation in normal brain functions. DNA methylation machineries are responsible for dynamic regulation of methylation patterns in discrete brain regions. In addition to methylation of cytosines in genomic DNA (5-methylcytosine; 5mC), other forms of modified cytosines, such as 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, can potentially act as epigenetic marks that regulate gene expression. Importantly, epigenetic modifications require cognate binding proteins to read and translate information into gene expression regulation. Abnormal or incorrect interpretation of DNA methylation patterns can cause devastating consequences, including mental illnesses and neurological disorders. Although DNA methylation was generally considered to be a stable epigenetic mark in post-mitotic cells, recent studies have revealed dynamic DNA modifications in neurons. Such reversibility of 5mC sheds light on potential mechanisms underlying some neurological disorders and suggests a new route to correct aberrant methylation patterns associated with these disorders.     

Epigenetische Pathomechanismen der Epileptogenese

Recent studies point to a pathogenic role of epigenetic chromatin modifications during epileptogenesis. Epigenetic mechanisms are covalent posttranslational modifications of histone proteins and DNA, which can produce lasting alterations in chromatin structure and gene expression. They are increasingly recognized as fundamental regulatory processes in central nervous system development, synaptic plasticity, and memory, and also play a role in neurological disorders, such as schizophrenia or spinal muscular atrophy. The authors propose that the “methylation hypothesis??addresses the intriguing issue of seizure-induced epigenetic chromatin modifications, which aggravate the epileptogenic condition by targeting candidate epileptogenesis gene expression. Unravelling epigenetic pathomechanisms will open also new strategies to identify molecular targets for pharmacological treatment in epilepsies. This project will be supported by EpiGENet, one of four consortia from the newly established European EuroEPINOMICS initiative.     

Epigenetic alterations in depression and antidepressant treatment

Epigenetic modifications control chromatin structure and function, and thus mediate changes in gene expression, ultimately influencing protein levels. Recent research indicates that environmental events can induce epigenetic changes and, by this, contribute to long-term changes in neural circuits and endocrine systems associated with altered risk for stress-related psychiatric disorders such as major depression. In this review, we describe recent approaches investigating epigenetic modifications associated with altered risk for major depression or response to antidepressant drugs, both on the candidate gene levels as well as the genome-wide level. In this review we focus on DNA methylation, as this is the most investigated epigenetic change in depression research.     

Virtuelle Expositionstherapie bei Angststörungen

Anxiety disorders are among the most prevalent mental disorders in Germany. Exposure therapy has proven effective in treating anxiety disorders. During exposure therapy, patients are systematically confronted with the feared stimulus or situation. Exposure therapy can be conducted in vivo or in sensu. Recently, a considerable amount of research on virtual reality exposure therapy (VRET) in the treatment of anxiety disorders—especially phobias—has been published. During virtual reality exposure therapy, patients are confronted with a virtual representation of the feared stimulus or situation. There are many studies showing that virtual reality exposure therapy is effective—especially in treating specific phobias. One major advantage of virtual reality exposure therapy is that therapists can easily control the feared object or situation. Furthermore, virtual reality exposure therapy requires less organizational effort and is less time-consuming than exposure therapy in vivo. The principal disadvantage of virtual reality exposure therapy is the danger of cyber sickness. With the development of affordable user-friendly systems, therapists may increasingly use virtual reality exposure therapy to treat patients suffering from anxiety disorders. With respect to the future development of virtual reality exposure therapy, augmented reality seems to be a promising treatment alternative. Future studies need to confirm the efficacy of augmented reality exposure therapy in treating anxiety disorders.     

Role of epigenetics in mental disorders

The purpose of this paper was to selectively review the literature on the role of epigenetics in mental illnesses. Aberrant epigenetic regulation has been clearly implicated in the aetiology of some human illnesses. In recent years a growing body of evidence has highlighted the possibility that epigenetics may also play a key role in the origins and expression of mental disorders. Epigenetic phenomena may help explain some of the complexity of mental illnesses and provide a basis for discovering novel pharmacological targets to treat these disorders.     

Epigenetic dysregulation in cognitive disorders

Epigenetic mechanisms are not only essential for biological functions requiring stable molecular changes such as the establishment of cell identity and tissue formation, they also constitute dynamic intracellular processes for translating environmental stimuli into modifications in gene expression. Over the past decade it has become increasingly clear that both aspects of epigenetic mechanisms play a pivotal role in complex brain functions. Evidence from patients with neurodegenerative and neurodevelopmental disorders such as Alzheimer's disease and Rett syndrome indicated that epigenetic mechanisms and chromatin remodeling need to be tightly controlled for proper cognitive functions, and their dysregulation can have devastating consequences. However, because they are dynamic, epigenetic mechanisms are also potentially reversible and may provide powerful means for pharmacological intervention. This review outlines major cognitive disorders known to be associated with epigenetic dysregulation, and discusses the potential of 'epigenetic medicine' as a promising cure.     

Epileptogenesis: Can the Science of Epigenetics Give Us Answers?

Epigenetic mechanisms are regulatory processes that control gene expression changes involved in multiple aspects of neuronal function, including central nervous system development, synaptic plasticity, and memory. Recent evidence indicates that dysregulation of epigenetic mechanisms occurs in several human epilepsy syndromes. Despite this discovery of a potential role for epigenetic mechanisms in epilepsy, few studies have fully explored their contribution to the process of epilepsy development known as epileptogenesis. The purpose of this article is to discuss recent findings suggesting that the process of epileptogenesis may alter the epigenetic landscape, affecting the gene expression patterns observed in epilepsy. Future studies focused on a better characterization of these aberrant epigenetic mechanisms hold the promise of revealing novel treatment options for the prevention and even the reversal of epilepsy.The underlying cause of epilepsy in patients is still largely unknown, leaving 1 to 2% of the population without a cure and making the search for new treatments ever more urgent. Current treatment options for the epilepsies have been largely focused on and are effective at controlling seizure activity in most cases; however, cures for these disorders have been elusive. This is largely owing to the very complex progression of the disease state and the multiple inherited and acquired factors that can influence the onset and progression of epilepsy disorders. An emerging idea is that exploring epigenetic mechanisms, including covalent modifications of histones and DNA, may provide insight into how inherited or acquired alterations in the steady-state expression patterns of genes in the brain contribute to epileptogenesis.During the past decade the science of epigenetics has advanced our understanding of the complex relationship between genetic and environmental factors that orchestrate expression of genes under numerous physiologic conditions. Accordingly, aberrant epigenetic regulation of genes has been implicated in several CNS disorders, including stroke, Alzheimer disease, schizophrenia, and depression (1, 2). Epilepsy is no exception, in that abnormalities in the expression and regulation of epigenetic factors offer a provocative locus for the integration of common pathways that may reveal novel insights into the development of this disease.     

Epigenetic regulation of Th1 and Th2 cell development

All cells of the body, regardless of the tissue type, contain the same genetic material, but express this genetic material differently. Epigenetics is one process by which differential gene expression within a cell is regulated. Epigenetic mechanisms involve postsynthetic modifications to DNA and/or DNA-associated histones that do not change the DNA sequence itself, but which remodel chromatin, are passed along at each cell division, and occur during and after early development. The CD4⁺ T cell best represents a cell in which epigenetic mechanisms are used to affect mature cell physiology. As a naïve CD4⁺ T cell develops into either a Th1 or Th2 cell that secretes predominantly IFN-γ or IL-4, respectively, the expression of one cytokine gene and the permanent silencing of the other is orchestrated using epigenetic mechanisms. Because there appears to be an association between Th1/Th2 cell immunity, behavior, and/or disease, it is possible that an environmentally induced epigenetic change that occurs during Th1/Th2 cell development could explain how certain Th1/Th2-associated conditions develop. This article will review basic epigenetic mechanisms and what is known about how these mechanisms influence cytokine gene expression in a naïve CD4⁺ T cell as it develops into a Th1 or Th2 cell.     

Monodramatherapie mit Borderline-PatientInnen

The borderline disorder is considered to be one of the most severe mental disorders. It is a complex traumatic disturbance and at the same time a particularly severe personality disorder. The borderline disorder is characterised by a structural dissociation of the personality, which explains the particularly serious identity and relationship disturbance underlying the borderline symptoms. The complexity and specific dynamic of the borderline disorder requires a therapy strategy, which meets all these factors: the requirement of the maturation of the personality, the processing/integration of the underlying traumata, the attachment and relationship disturbance as well as the identity problems. In a non-residential ambulatory setting, treatment in form of individual therapy is the best choice for borderline therapy, at least during the first years of therapy. The theoretical considerations, which form the basis for the psychodramatic treatment for borderline patients in an individual setting is the content of this article.     

Epigenetic regulation of myelination in health and disease

Myelin is lipid‐rich structure that is necessary to avoid leakage of electric signals and to ensure saltatory impulse conduction along axons. Oligodendrocytes in central nervous system (CNS) and Schwann cells in peripheral nervous system (PNS) are responsible for myelin formation. Axonal demyelination after injury or diseases greatly impairs normal nervous system function. Therefore, understanding how the myelination process is programmed, coordinated, and maintained is crucial for developing therapeutic strategies for remyelination in the nervous system. Epigenetic mechanisms have been recognized as a fundamental contributor in this process. In recent years, histone modification, DNA modification, ATP‐dependent chromatin remodeling, and non‐coding RNA modulation are very active area of investigation. We will present a conceptual framework that integrates crucial epigenetic mechanisms with the regulation of oligodendrocyte and Schwann cell lineage progression during development and myelin degeneration in pathological conditions. It is anticipated that a refined understanding of the molecular basis of myelination will aid in the development of treatment strategies for debilitating disorders that involve demyelination, such as multiple sclerosis in the CNS and neuropathies in the PNS.     

Das Monodrama im Coaching von Menschen mit geistigem Handicap beim Übergang von der Schule auf den ersten Arbeitsmarkt

The monodrama technique with its focus on a single person provides a valuable tool in coaching people with mental handicaps. This article describes three sessions with a young woman who makes her way from a special school to the first job market. Her topics in these coaching sessions are finding a professional role and identity, accepting given limitations and managing conflicts. The coaching concentrates on activating personal und system resources, opportunities of support and developing a focus on solution.     

Approach to epigenetic analysis in language disorders

Language and learning disorders such as reading disability and language impairment are recognized to be subject to substantial genetic influences, but few causal mutations have been identified in the coding regions of candidate genes. Association analyses of single nucleotide polymorphisms have suggested the involvement of regulatory regions of these genes, and a few mutations affecting gene expression levels have been identified, indicating that the quantity rather than the quality of the gene product may be most relevant for these disorders. In addition, several of the candidate genes appear to be involved in neuronal migration, confirming the importance of early developmental processes. Accordingly, alterations in epigenetic processes such as DNA methylation and histone modification are likely to be important in the causes of language and learning disorders based on their functions in gene regulation. Epigenetic processes direct the differentiation of cells in early development when neurological pathways are set down, and mutations in genes involved in epigenetic regulation are known to cause cognitive disorders in humans. Epigenetic processes also regulate the changes in gene expression in response to learning, and alterations in histone modification are associated with learning and memory deficits in animals. Genetic defects in histone modification have been reversed in animals through therapeutic interventions resulting in rescue of these deficits, making it particularly important to investigate their potential contribution to learning disorders in humans.     

Epigenetic aspects of multiple sclerosis and future therapeutic options

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease accompanied by demyelination of neurons in the central nervous system that mostly affects young adults, especially women. This disease has two phases including relapsing-remitting form (RR-MS) by episodes of relapse and periods of clinical remission and secondary-progressive form (SP-MS), which causes more disability. The inheritance pattern of MS is not exactly identified and there is an agreement that it has a complex pattern with an interplay among environmental, genetic and epigenetic alternations. Epigenetic mechanisms that are identified for MS pathogenesis are DNA methylation, histone modification and some microRNAs’ alternations. Several cellular processes including apoptosis, differentiation and evolution can be modified along with epigenetic changes. Some alternations are associated with epigenetic mechanisms in MS patients and these changes can become key points for MS therapy. Therefore, the aim of this review was to discuss epigenetic mechanisms that are associated with MS pathogenesis and future therapeutic approaches.