Application of miRNA-seq in neuropsychiatry: A methodological perspective

MiRNAs are emerging as key molecules to study neuropsychiatric diseases. However, despite the large number of methodologies and software for miRNA-seq analyses, there is little supporting literature for researchers in this area. This review focuses on evaluating how miRNA-seq has been used to study neuropsychiatric diseases to date, analyzing both the main findings discovered and the bioinformatics workflows and tools used from a methodological perspective. The objective of this review is two-fold: first, to evaluate current miRNA-seq procedures used in neuropsychiatry; and second, to offer comprehensive information that can serve as a guide to new researchers in bioinformatics. After conducting a systematic search (from 2016 to June 30, 2020) of articles using miRNA-seq in neuropsychiatry, we have seen that it has already been used for different types of studies in three main categories: diagnosis, prognosis, and mechanism. We carefully analyzed the bioinformatics workflows of each study, observing a high degree of variability with respect to the tools and methods used and several methodological complexities that are identified and discussed in this reviewInstituto de Salud Carlos III | Ref. PI18/01311Ministerio de Economía y Competitividad | Ref. RYC2014-15246Xunta de Galicia | Ref. ED431C2018/55-GR

Epigenetic management of major psychosis

Epigenetic mechanisms are thought to play a major role in the pathogenesis of the major psychoses (schizophrenia and bipolar disorder), and they may be the link between the environment and the genome in the pathogenesis of these disorders. This paper discusses the role of epigenetics in the management of major psychosis: (1) the role of epigenetic drugs in treating these disorders. At present, there are three categories of epigenetic drugs that are being actively investigated for their ability to treat psychosis: drugs inhibiting histone deacetylation; drugs decreasing DNA methylation; and drugs targeting microRNAs; and (2) the role of epigenetic mechanisms in electroconvulsive therapy in these disorders

Molecular targets of alcohol action: translational research for pharmacotherapy development and screening.

Alcohol abuse and dependence are multifaceted disorders with neurobiological, psychological, and environmental components. Research on other complex neuropsychiatric diseases suggests that genetically influenced intermediate characteristics affect the risk for heavy alcohol consumption and its consequences. Diverse therapeutic interventions can be developed through identification of reliable biomarkers for this disorder and new pharmacological targets for its treatment. Advances in the fields of genomics and proteomics offer a number of possible targets for the development of new therapeutic approaches. This brain-focused review highlights studies identifying neurobiological systems associated with these targets and possible pharmacotherapies, summarizing evidence from clinically relevant animal and human studies, as well as sketching improvements and challenges facing the fields of proteomics and genomics. Concluding thoughts on using results from these profiling technologies for medication development are also presented

Epigenetic effects of stress and corticosteroids in the brain

Stress is a common life event with potentially long lasting effects on health and behavior. Stress, and the corticosteroid hormones that mediate many of its effects, are well known for their ability to alter brain function and plasticity. While genetic susceptibility may influence the impact of stress on the brain, it does not provide us with a complete understanding of the capacity of stress to produce long lasting perturbations on the brain and behavior. The growing science of epigenetics, however, shows great promise of deepening our understanding of the persistent impacts of stress and corticosteroids on health and disease. Epigenetics, broadly defined, refers to influences on phenotype operating above the level of the genetic code itself. At the molecular level, epigenetic events belong to three major classes: DNA methylation, covalent histone modification and non-coding RNA. This review will examine the bi-directional interactions between stress and corticosteroids and epigenetic mechanisms in the brain and how the novel insights, gleaned from recent research in neuro-epigenetics, change our understanding of mammalian brain function and human disease states

Acetaldehyde as a drug of abuse: Involvement of endocannabinoid- and dopamine neurotransmission

Acetaldehyde (ACD), the first metabolite of ethanol, directly enhances dopamine neurotransmission (1) and has rewarding and motivational properties in paradigms tailored for studying addictive-like behaviours (2, 3). The endocannabinoid system affects distinct drug-related behaviours, since it may in turn fine-tune dopamine cell activity (4, 5). In light of this, the present study aimed at investigating the effects of a direct manipulation of the DAergic synapse, and the contribution of the endocannabinoid system on oral ACD self-administration in rats. ACD drinking-behaviour was evaluated in an operant paradigm consisting of acquisition and maintenance; extinction; deprivation and relapse; conflict. D2-receptor agonists, quinpirole (0.03 mg/Kg, i.p.) and ropinirole (0.03 mg/Kg, i.p.), and CB1-receptor antagonist, AM281 (1 mg/Kg, i.p.), were administered during different phases of the experiment. Our results show that oral ACD readily induced the acquisition and maintenance of an operant drinking-behaviour, even during reinstatement and conflict. Quinpirole decreased lever presses for ACD during extinction (p<0.05) and relapse (p<0.01; p<0.001) Ropinirole, administered during abstinence, reduced ACD intake during reinstatement (p<0.001). AM281 significantly decreased lever presses for ACD during extinction (p<0.001), relapse (p<0.001) and conflict (p<0.001). These data suggest that whereas the direct modulation of the dopaminergic synapse influences drug-seeking and relapse behaviour, the endocannabinoid system may also play a role in shock-paired compulsive ACD intake. These findings highlight the mandatory need for further investigation on the therapeutical potential played by the endocannabinoid system taking into account its crucial role in alcohol, and ACD neuropharmacology

Epigenetics and Drug Abuse

Gene expression and inheritance are not only a function of the DNA code, but also epigenetic mechanisms that regulate DNA accessibility, transcription, and translation of the genetic code into a functional protein. Epigenetic mechanisms are invoked by life experiences, including stress and exposure to drugs of abuse, and the resulting changes in gene expression can be inherited by future generations. This chapter highlights recent research demonstrating epigenetic changes in response to drug exposure with a focus on three different mechanisms: DNA methylation, histone modification, and noncoding RNAs. We briefly describe each of these mechanisms and then provide key examples of drug-induced changes involving these mechanisms, as well as epigenetic manipulations that alter effects of drugs. We then review cutting-edge technologies, including viral-mediated gene transfer and gene editing, that are being used to manipulate epigenetic processes with temporal and cell-type specificity. We also describe and provide examples of intergenerational epigenetic modifications, a topic that has interesting implications for how addiction-related traits may be passed down across generations. Finally, we discuss how this research provides a greater understanding of drug addiction and may lead to novel molecular targets for preventions and interventions for drug abuse

Adolescent alcohol exposure modifies adult anxiety-like behavior and amygdala sensitivity to alcohol in rats: Increased c-Fos activity and sex-dependent microRNA-182 expression

Adolescent binge alcohol drinking is a serious health concern contributing to adult alcohol abuse often associated with anxiety disorders. We have used adolescent intermittent ethanol (AIE) administration as a model of binge drinking in rats in order to explore its long-term effect on the basolateral amygdala (BLA) responsiveness to alcohol and anxiety-like behavior. AIE increased the number of BLA c-Fos positive cells in adult Wistar rats and anxiety-like behavior assessed by the open field test (OFT). Additionally, in adult female rats receiving AIE BLA over expression of miR-182 was found. Therefore, our results indicate that alcohol consumption during adolescence can lead to enduring changes in anxiety-like behavior and BLA susceptibility to alcohol that may be mediated by sex-dependent epigenetic changes. These results contribute to understanding the mechanisms involved in the development of alcohol use disorders (AUD) and anxiety-related disorders.This study was funded by the research projects PID2020-114269GB-I00 funded by MCIN/AEI/10.13039/501100011033 (MICIU, Spain), BSEJ.514.UGR20 (FEDER, Junta de Andalucía, Spain) and a pre-doctoral fellowship FPU18/05012 to AV-Á (MIU, Spain)

Adolescent alcohol exposure modifies adult anxiety-like behavior and amygdala sensitivity to alcohol in rats: Increased c-Fos activity and sex-dependent microRNA-182 expression

Adolescent binge alcohol drinking is a serious health concern contributing to adult alcohol abuse often associated with anxiety disorders. We have used adolescent intermittent ethanol (AIE) administration as a model of binge drinking in rats in order to explore its long-term effect on the basolateral amygdala (BLA) responsiveness to alcohol and anxiety-like behavior. AIE increased the number of BLA c-Fos positive cells in adult Wistar rats and anxiety-like behavior assessed by the open field test (OFT). Additionally, in adult female rats receiving AIE BLA over expression of miR-182 was found. Therefore, our results indicate that alcohol consumption during adolescence can lead to enduring changes in anxiety-like behavior and BLA susceptibility to alcohol that may be mediated by sex-dependent epigenetic changes. These results contribute to understanding the mechanisms involved in the development of alcohol use disorders (AUD) and anxiety-related disorders.Project PID2020-114269GBI00 funded by MCIN/AEI/10.13039/501100011033 (MICIU, Spain)Project BSEJ.514.UGR20 (FEDER, Junta de Andalucía, Spain)Predoctoral fellowship FPU18/05012 to AV-Á (MIU, Spain)Funding for open access charge: Universidad de Granada/CBUA