Dialogues in Clinical Neuroscience最新文献

The risk for major depression is both genetically and environmentally determined. It has been proposed that epigenetic mechanisms could mediate the lasting increases in depression risk following exposure to adverse life events and provide a mechanistic framework within which genetic and environmental factors can be integrated. Epigenetics refers to processes affecting gene expression and translation that do not involve changes in the DNA sequence and include DNA methylation (DNAm) and microRNAs (miRNAs) as well as histone modifications. Here we review evidence for a role of epigenetics in the pathogenesis of depression from studies investigating DNAm, miRNAs, and histone modifications using different tissues and various experimental designs. From these studies, a model emerges where underlying genetic and environmental risk factors, and interactions between the two, could drive aberrant epigenetic mechanisms targeting stress response pathways, neuronal plasticity, and other behaviorally relevant pathways that have been implicated in major depression.
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Psychosocial stress-especially when chronic, excessive, or occurring early in life-has been associated with accelerated aging and increased disease risk. With rapid aging of the world population, the need to elucidate the underlying mechanisms is pressing, now more so than ever. Among molecular mechanisms linking stress and aging, the present article reviews evidence on the role of epigenetics, biochemical processes that can be set into motion by stressors and in turn influence genomic function and complex phenotypes, including aging-related outcomes. The article further provides a conceptual mechanistic framework on how stress may drive epigenetic changes at susceptible genomic sites, thereby exerting systems-level effects on the aging epigenome while also regulating the expression of molecules implicated in aging-related processes. This emerging evidence, together with work examining related biological processes, begins to shed light on the epigenetic and, more broadly, molecular underpinnings of the long-hypothesized connection between stress and aging.
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Schizophrenia is a debilitating psychiatric disorder with a complex genetic architecture and limited understanding of its neuropathology, reflected by the lack of diagnostic measures and effective pharmacological treatments. Geneticists have recently identified more than 145 risk loci comprising hundreds of common variants of small effect sizes, most of which lie in noncoding genomic regions. This review will discuss how the epigenetic toolbox can be applied to contextualize genetic findings in schizophrenia. Progress in next-generation sequencing, along with increasing methodological complexity, has led to the compilation of genome-wide maps of DNA methylation, histone modifications, RNA expression, and more. Integration of chromatin conformation datasets is one of the latest efforts in deciphering schizophrenia risk, allowing the identification of genes in contact with regulatory variants across 100s of kilobases. Large-scale multiomics studies will facilitate the prioritization of putative causal risk variants and gene networks that contribute to schizophrenia etiology, informing clinical diagnostics and treatment downstream.
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Despite effective pharmacological treatments for psychotic symptoms (eg, hallucinations, delusions), functional outcomes for people with psychotic disorders are often disappointing. Although it is not included in the diagnostic criteria for psychotic disorders, cognitive impairment is one of the strongest determinants of community functioning in this clinical population, and thus it is an important target for intervention. In this review, we discuss the major areas of research regarding impaired cognition in psychotic illness. The specific topics covered include: (i) the prevalence of cognitive impairment in psychotic disorders; (ii) the profile and magnitude of cognitive impairment in psychotic disorders; (iii) the developmental course of cognitive impairment; (iv) the longitudinal stability of cognitive impairment; and (v) treatment approaches to improve cognitive performance in people with psychotic disorders.
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