Lifetime stress experience: transgenerational epigenetics and germ cell programming

The transgenerational epigenetic programming involved in the passage of environmental exposures to stressful periods from one generation to the next has been examined in human populations, and mechanistically in animal models. Epidemiological studies suggest that gestational exposures to environmental factors including stress are strongly associated with an increased risk of neurodevelopmental disorders, including attention deficit-hyperactivity disorder, schizophrenia, and autism spectrum disorders. Both maternal and paternal life experiences with stress can be passed on to offspring directly during pregnancy or through epigenetic marks in the germ cell. Animal models of parental stress have examined relevant offspring phenotypes and transgenerational outcomes, and provided unique insight into the germ cell epigenetic changes associated with disruptions in neurodevelopment. Understanding germline susceptibility to exogenous signals during stress exposure and the identification of the types of epigenetic marks is critical for defining mechanisms underlying disease risk.     

Chromatin regulation in drug addiction and depression

Alterations in gene expression are implicated in the pathogenesis of several neuropsychiatrie disorders, including drug addiction and depression, increasing evidence indicates that changes in gene expression in neurons, in the context of animal models of addiction and depression, are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular, and bioinformatic approaches that are being used to understand the complex epigenetic regulation of gene expression in brain by drugs of abuse and by stress. These advances promise to open up new avenues for improved treatments of these disorders.     

The epigenetic dimension of Alzheimer's disease: causal,consequence, or curiosity?

Early-onset, familial Alzheimer''s disease (AD) is rare and may be attributed to disease-causinq mutations. By contrast, late onset, sporadic (non-Mendelian) AD is far more prevalent and reflects the interaction of multiple genetic and environmental risk factors, together with the disruption of epigenetic mechanisms controlling gene expression. Accordingly, abnormal patterns of histone acetylation and methylation, as well as anomalies in global and promoter-specific DNA methylation, have been documented in AD patients, together with a deregulation of noncoding RNA. In transgenic mouse models for AD, epigenetic dysfunction is likewise apparent in cerebral tissue, and it has been directly linked to cognitive and behavioral deficits in functional studies. Importantly, epigenetic deregulation interfaces with core pathophysiological processes underlying AD: excess production of Aβ42, aberrant post-translational modification of tau, deficient neurotoxic protein clearance, axonal-synaptic dysfunction, mitochondrial-dependent apoptosis, and cell cycle re-entry. Reciprocally, DNA methylation, histone marks and the levels of diverse species of microRNA are modulated by Aβ42, oxidative stress and neuroinflammation. In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes. While some epigenetic shifts oppose the evolution of AD, most appear to drive its progression. Epigenetic changes are of irrefutable importance for AD, but they await further elucidation from the perspectives of pathogenesis, biomarkers and potential treatment.     

Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function

We review studies with human and nonhuman species that examine the hypothesis that epigenetic mechanisms, particularly those affecting the expression of genes implicated in stress responses, mediate the association between early childhood adversity and later risk of depression. The resulting studies provide evidence consistent with the idea that social adversity, particularly that involving parent-offspring interactions, alters the epigenetic state and expression of a wide range of genes, the products of which regulate hypothalamic-pituitary-adrenal function. We also address the challenges for future studies, including that of the translation of epigenetic studies towards improvements in treatments.     

Opposite effects of stressful experience on memory formation in males versus females

It has become increasingly clear that males and females differ even more dramatically than we previously thought. Not only do they exhibit differing responses to stress and environmental experience, but they can also respond in opposite directions. In rats, it has been shown that exposure to an acute stressful event can enhance subsequent learning in males while dramatically impairing learning in females. These opposite effects of stress on memory formation are accompanied by similarly opposite effects on neuroanatomical measures, such as dendritic spines in the hippocampal formation. Moreover, these opposite effects of stress are mediated by different hormonal systems between the sexes. These unique responses to stressful experience in male versus female rats may be used to model sex differences in mental illness, such as those that exist for depression and posttraumatic stress disorder.     

From shell shock and war neurosis to posttraumatic stress disorder: a history of psychotraumatology

The term posttraumatic stress disorder (PTSD) has become a household name since its first appearance in 1980 in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-lll) purblished by the American Psychiatric Association, In the collective mind, this diagnosis is associated with the legacy of the Vietnam War disaster. Earlier conflicts had given birth to terms, such as "soldier's heart, " "shell shock," and "war neurosis." The latter diagnosis was equivalent to the névrose de guerre and Kriegsneurose of French and German scientific literature. This article describes how the immediate and chronic consequences of psychological trauma made their way into medical literature, and how concepts of diagnosis and treatment evolved over time.     

Serotonin-related pathways and developmental plasticity: relevance for psychiatric disorders

Risk for adult psychiatric disorders is partially determined by early-life alterations occurring during neural circuit formation and maturation. In this perspective, recent data show that the serotonin system regulates key cellular processes involved in the construction of cortical circuits. Translational data for rodents indicate that early-life serotonin dysregulation leads to a wide range of behavioral alterations, ranging from stress-related phenotypes to social deficits. Studies in humans have revealed that serotonin-related genetic variants interact with early-life stress to regulate stress-induced cortisol responsiveness and activate the neural circuits involved in mood and anxiety disorders. Emerging data demonstrate that early-life adversity induces epigenetic modifications in serotonin-related genes. Finally, recent findings reveal that selective serotonin reuptake inhibitors can reinstate juvenile-like forms of neural plasticity, thus allowing the erasure of long-lasting fear memories. These approaches are providing new insights on the biological mechanisms and clinical application of antidepressants.     

Neuropsychological and neuroimaging findings in traumatic brain injury and post-traumatic stress disorder

Advances in imaging technology, coupled with military personnel returning home from Iraq and Afghanistan with traumatic brain injury (TBI) and/or post-traumatic stress disorder (PTSD), have increased interest in the neuropsychology and neurobiology of these two conditions. There has been a particular focus on differential diagnosis. This paper provides an overviev of findings regarding the neuropsychological and neurobiological underpinnings of TBI and for PTSD. A specific focus is on assessment using neuropsychological measures and imaging techniques. Challenges associated with the assessment of individuals with one or both conditions are also discussed. Although use of neuropsychological and neuroimaging test results may assist with diagnosis and treatment planning, further work is needed to identify objective biomarkers for each condition. Such advances would be expected to facilitate differential diagnosis and implementation of best treatment practices.     

Post-traumatic stress disorder diagnosis in children: challenges and promises

Children and adolescents experience high rates of potentially traumatic experiences. Many children subsequently develop mental health problems, including post-traumatic stress disorder (PTSD) symptoms. Accurately diagnosing PTSD in children is challenging. This paper reviews the following important issues: (i) the specificity of the PTSD diagnosis; (ii) children who are symptomatic and impaired but do not have enough symptoms for the diagnosis of PTSD; (iii) developmental considerations for preschool and schooi-age children; and (iv) a variety of assessment challenges that reflect the difficulty and complexity of interviewing children and caregivers about these symptoms. Despite these challenges, PTSD remains the best construct for clinical and research work with trauma survivors. Pediatric PTSD criteria are valuable for identifying children at risk and in need of treatment and can be even more helpful when developmentally modified in ways that are discussed.     

Biomarkers in development of psychotropic drugs

Biomarkers have been receiving increasing attention, especially in the field of psychiatry In contrast to the availability of potent therapeutic tools including pharmacotherapy, psychotherapy, and biological therapies, unmet needs remain in terms of onset of action, stability of response, and further improvement of the clinical course. Biomarkers are objectively measured characteristics which serve as indicators of the causes of illnesses, their clinical course, and modification by treatment. There exist a variety of markers: laboratory markers which comprise the determination of genetic and epigenetic markers, neurotransmitters, hormones, cytokines, neuropeptides, enzymes, and others as single measures; electrophysiological markers which usually comprise electroencephalography (EEG) measures, and in particular sleep EEG and evoked potentials, magnetic encephalography, electrocardiogram, facial electromyography, skin conductance, and others; brain imaging techniques such as cranial computed tomography, magnetic resonance imaging, functional MRI, magnetic resonance spectroscopy, positron emission tomography, and single photon emission computed tomography; and behavioral approaches such as cue exposure and challenge tests which can be used to induce especially emotional processes in anxiety and depression. Examples for each of these domains are provided in this review. With a view to developing more individually tailored therapeutic strategies, the characterization of patients and the courses of different types of treatment will become even more important in the future.     

Increased DNA methylation in the suicide brain

Clinical studies find that childhood adversity and stress-ful life events in adulthood increase the risk for major depression and for suicide. The predispositions to either major depression or suicide are thought to depend on genetic risk factors or epigenetic effects. We investigated DNA methylation signatures postmortem in brains of suicides with diagnosis of major depressive disorder. DNA methylation levels were determined at single C-phosphate-G (CpG) resolution sites within ventral prefrontal cortex of 53 suicides and nonpsychiatric controls, aged 16 to 89 years. We found that DNA methylation increases throughout the lifespan. Suicides showed an 8-fold greater number of methylated CpG sites relative to controls (P<2.2x10-16), with greater DNA methylation changes over and above the increased methylation observed in normal aging. This increased DNA methylation may be a significant contributor to the neuropathology and psychopathology underlying the risk of suicide in depression.     

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.     

Early biomarkers of psychosis

Biological traits that are predictive of the later development of psychosis have not yet been identified. The complex, multidetermined nature of schizophrenia and other psychoses makes it unlikely that any single biomarker will be both sensitive and specific enough to unambiguously identify individuals who will later become psychotic. However, current genetic research has begun to identify genes associated with schizophrenia, some of which have phenotypes that appear early in life. While these phenotypes have low predictive power for identifying individuals who will become psychotic, they do serve as biomarkers for pathophysiological processes that can become the targets of prevention strategies. Examples are given from work on the role of the alpha(T)nicotinic receptor and its gene CHRNA7 on chromosome 15 in the neurobiology and genetic transmission of schizophrenia.     

The psychobiology of resilience and vulnerability to anxiety disorders: implications for prevention and treatment

Much of the research on the neurobiology of human anxiety disorders has focused on psychopaihological abnormalities in patients with anxiety disorders. While this line of research is obviously important, more investigation is needed to elucidate the psychobiology of resilience to extreme stress. Study of the psychobiology of resilience has the potential to identify neurochemical, neuropeptide, and hormonal mediators of vulnerability and resilience to severe stress. In addition, the relevance of neural mechanisms of reward and motivation, fear responsiveness, and social behavior to character traits associated with risk and resistance to anxiety disorders may be clarified. These areas of investigation should lead to improved methods of diagnosis, novel approaches to prevention, and new targets for antianxiety drug discovery.     

Post-traumatic stress disorder: the neurobiological impact of psychological trauma

The classic fight-or-flight response to perceived threat is a reflexive nervous phenomenon thai has obvious survival advantages in evolutionary terms. However, the systems that organize the constellation of reflexive survival behaviors following exposure to perceived threat can under some circumstances become dysregulated in the process. Chronic dysregulation of these systems can lead to functional impairment in certain individuals who become "psychologically traumatized" and suffer from post-traumatic stress disorder (PTSD), A body of data accumulated over several decades has demonstrated neurobiological abnormalities in PTSD patients. Some of these findings offer insight into the pathophysiology of PTSD as well as the biological vulnerability of certain populations to develop PTSD, Several pathological features found in PTSD patients overlap with features found in patients with traumatic brain injury paralleling the shared signs and symptoms of these clinical syndromes.     

Personal genomes in progress: from the Human Genome Project to the Personal Genome Project

The cost of a diploid human genome sequence has dropped from about $70M to $2000 since 2007- even as the standards for redundancy have increased from 7x to 40x in order to improve call rates. Coupled with the low return on investment for common single-nucleotide polymorphisms, this has caused a significant rise in interest in correlating genome sequences with comprehensive environmental and trait data (GET). The cost of electronic health records, imaging, and microbial, immunological, and behavioral data are also dropping quickly. Sharing such integrated GET datasets and their interpretations with a diversity of researchers and research subjects highlights the need for informed-consent models capable of addressing novel privacy and other issues, as well as for flexible data-sharing resources that make materials and data available with minimum restrictions on use. This article examines the Personal Genome Project''s effort to develop a GET database as a public genomics resource broadly accessible to both researchers and research participants, while pursuing the highest standards in research ethics.     

Current research in child and adolescent bipolar disorder

Although recently more research has considered children with bipolar disorder than in the past, much controversy still surrounds the validity of the diagnosis. Furthermore, questions remain as to whether or not childhood expressions of bipolarity are continuous with adult manifestations of the illness. In order to advance current knowledge of bipolar disorders in children, researchers have begun to conduct phenomenological, longitudinal, treatment, and neuroimaging studies in youths who exhibit symptoms of bipolar illness, as well as offspring of parents with bipolar disorders. Regardless of the differences between research groups regarding how bipolar disorder in children is defined, it is agreed that pediatric bipolarity is a serious and pernicious illness. With early intervention during the period of time in which youths are exhibiting subsyndromal symptoms of pediatric bipolarity, it appears that the progression of the illness to the more malignant manifestation of the disorder may be avoided. This paper will review what is currently known and what still is left to learn about clinically salient topics that pertain to bipolar disorder in children and adolescents.