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1.
Hist Philos Life Sci ; 44(4): 65, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36417009

RESUMO

What sets someone on a life trajectory? This question is at the heart of studies of 21st-century neurosciences that build on scientific models developed over the last 150 years that attempt to link psychopathology risk and human development. Historically, this research has documented persistent effects of singular, negative life experiences on people's subsequent development. More recently, studies have documented neuromolecular effects of early life adversity on life trajectories, resulting in models that frame lives as disproportionately affected by early negative experiences. This view is dominant, despite little evidence of the stability of the presumably early-developed molecular traits and their potential effects on phenotypes. We argue that in the context of gaps in knowledge and the need for scientists to reason across molecular and phenotypic scales, as well as time spans that can extend beyond an individual's life, specific interpretative frameworks shape the ways in which individual scientific findings are assessed. In the process, scientific reasoning oscillates between understandings of cellular homeostasis and organisms' homeorhesis, or life trajectory. Biologist and historian François Jacob described this framework as the "attitude" that researchers bring to bear on their "objects" of study. Through an analysis of, first, historical and contemporary scientific literature and then ethnographic research with neuroscientists, we consider how early life trauma came to be associated with specific psychological and neurobiological effects grounded in understandings of life trajectories. We conclude with a consideration of the conceptual, ontological, and ethical implications of interpreting life trajectories as the result of the persistence of long-embodied biological traits, persistent life environments, or both.


Assuntos
Conhecimento , Neurobiologia , Humanos , Antropologia Cultural , Princípios Morais , Lógica
2.
Artigo em Inglês | MEDLINE | ID: mdl-35104608

RESUMO

Next-generation sequencing now enables the rapid and affordable production of reliable biological data at multiple molecular levels, collectively referred to as "omics". To maximize the potential for discovery, computational biologists have created and adapted integrative multi-omic analytical methods. When applied to diseases with traceable pathophysiology such as cancer, these new algorithms and statistical approaches have enabled the discovery of clinically relevant molecular mechanisms and biomarkers. In contrast, these methods have been much less applied to the field of molecular psychiatry, although diagnostic and prognostic biomarkers are similarly needed. In the present review, we first briefly summarize main findings from two decades of studies that investigated single molecular processes in relation to mood disorders. Then, we conduct a systematic review of multi-omic strategies that have been proposed and used more recently. We also list databases and types of data available to researchers for future work. Finally, we present the newest methodologies that have been employed for multi-omics integration in other medical fields, and discuss their potential for molecular psychiatry studies.


Assuntos
Genômica , Transtornos do Humor , Biomarcadores , Genômica/métodos , Humanos , Transtornos do Humor/genética
3.
Psychoneuroendocrinology ; 136: 105600, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34839083

RESUMO

Childhood abuse significantly increases the lifetime risk of negative mental health outcomes. The oxytocinergic system, which plays a role in complex social and emotional behaviors, has been shown to be sensitive to early-life experiences. While previous studies have investigated the relationship between early-life adversity and oxytocin, they did so with peripheral samples. We, therefore, aimed to characterize the relationship between early-life adversity and oxytocin receptor (OXTR) expression in the brain, using post-mortem human samples, as well as a rodent model of naturally occurring variation in early-life environment. Focusing on the dorsal anterior cingulate cortex, we compared OXTR expression and epigenetic regulation between MDD suicides with (N = 26) and without history of childhood abuse (N = 24), as well as psychiatrically healthy controls (N = 23). We also compared Oxtr expression in the cingulate cortex of adult rats raised by dams displaying high (N = 13) and low levels (N = 12) of licking and grooming (LG) behavior. Overall, our results indicate that childhood abuse associates with an upregulation of OXTR expression, and that similarly, this relationship is also observed in the cingulate cortex of adult rats raised by low-LG dams. Additionally, we found an effect of rs53576 genotype on expression, showing that carriers of the A variant also show upregulated OXTR expression. The effects of early-life adversity and rs53576 genotype on OXTR expression are, however, not explained by differences in DNA methylation within and around the MT region of the OXTR gene.


Assuntos
Receptores de Ocitocina , Suicídio , Animais , Criança , Epigênese Genética/genética , Giro do Cíngulo/metabolismo , Humanos , Ocitocina/metabolismo , Polimorfismo de Nucleotídeo Único , Ratos , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo
4.
Nat Commun ; 12(1): 1132, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602921

RESUMO

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.


Assuntos
Maus-Tratos Infantis , Metilação de DNA/genética , Histonas/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Tonsila do Cerebelo/patologia , Criança , Cromatina/metabolismo , Epigenoma/genética , Perfilação da Expressão Gênica , Ontologia Genética , Genoma Humano , Código das Histonas , Humanos , Processamento de Proteína Pós-Traducional
5.
Neuropsychopharmacology ; 46(5): 920-927, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33531622

RESUMO

The mu opioid receptor (MOR) is a G protein-coupled receptor that plays an essential role in reward and hedonic processes, and that has been implicated in disorders such as depression and addiction. Over the last decade, several brain imaging studies in depressed patients have consistently found that dysregulation of MOR function occurs in particular in the anterior insular cortex, an important brain site for the perception of internal states and emotional regulation. To investigate molecular mechanisms that may underlie these effects, here we assessed genetic polymorphisms, expression, and functional G-protein coupling of MOR in a large post-mortem cohort (N = 95) composed of depressed individuals who died by suicide, and healthy controls. Results indicated that depression, but not comorbid substance use disorder or acute opiate consumption, was associated with increased MOR activity. This effect was partly explained by a specific increase in expression of the inhibitory alpha G-protein subunit GNAI2. Consistent with previous neuroimaging studies, our findings support the notion that enhanced endogenous opioidergic tone in the anterior insula may buffer negative affective states in depressed individuals, a mechanism that could potentially contribute to the antidepressant efficacy of emerging opioid-based medications.


Assuntos
Encéfalo , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/metabolismo , Receptores Opioides mu , Analgésicos Opioides , Encéfalo/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Emoções , Humanos , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo
6.
Curr Top Behav Neurosci ; 46: 197-210, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865762

RESUMO

With more than 800,000 deaths by suicide each year and 20 to 30 times more suicide attempts worldwide, suicide is a major public health problem. Current treatments of SB are mainly based on pharmacological treatments that are not specific of SB (e.g. antidepressants), and new therapeutic targets are urgently needed. Recent data strengthen the ancient conception pain (social, psychic, physical) that is at the core of the suicidal process and should be incorporated in the clinical assessment of suicide risk. Then, the mechanisms involved in the regulation of pain may open new avenues regarding therapeutic perspectives. Opiates appear to be a promising candidate in treatment of SB. Indeed, since the last two decades, growing evidences suggest an implication of the opioid system in the pathophysiology of SB, this conduct to the elaboration of randomized controlled trials (RCTs) using opiates in patients with SB. Results suggesting an anti-suicidal effect of buprenorphine and the potential opioidergic-related anti-suicidal effect of ketamine both contribute to the growing interest in opiates use in SB. In this review, we will summarize a large part of the evidence that leads researchers and clinicians to be interested in the use of opiates for SB treatment and discuss on new opioid pharmacological options for suicidal patients.


Assuntos
Buprenorfina , Alcaloides Opiáceos , Humanos , Dor , Ideação Suicida , Tentativa de Suicídio
8.
Artigo em Inglês | MEDLINE | ID: mdl-32145361

RESUMO

OBJECTIVES: Psychological pain increases the risk of suicidal ideas and acts, and represents a potential therapeutic target. However, the mechanisms of mental pain remain unclear. Here, we assessed the peripheral transcriptomic and central neural correlates of mental pain during a depressive episode. METHODS: 172 adult un-medicated depressed patients were recruited. Leucocytes were extracted for RNA quantification at baseline (T0) and after 8 weeks (T8) of an antidepressant treatment. Ninety-nine genes of the cortisol, immune, opioid, serotonergic, and kynurenine systems were a priori selected, and 41 were sufficiently expressed to be analyzed. At both T0 and T8, mean level of mental pain over the last 15 days was measured with a visual analog scale. A subset of 38 patients was additionally scanned with Magnetic Resonance Imaging at T0. Resting-state sequences of 4 networks (default-mode, basal ganglia, central executive, salience) were examined. RESULTS: Mean psychological pain scores significantly decreased between T0 and T8. At conservative p-corrected levels, T0 mental pain was significantly correlated with 11 brain clusters encompassing the prefrontal, parietal, and temporal cortices, the striatum, and the cerebellum. There was no direct association between peripheral gene expression and mean mental pain at any time points or in terms of temporal changes. However, expressions of 5HTR2B at p-corrected levels, and 5HTR3A, TPH1, and OPRL1 were correlated with the activity of several identified brain clusters at T0. Finally, while suicidal ideas and mental pain were correlated, the neural and molecular correlates of suicidal ideas were not the same. CONCLUSION: Our study suggests that the serotonergic and nociceptin systems are associated with the activity of a cortico-subcortical brain network underlying the perception of mental pain during depression. Mental pain may be a necessary but insufficient condition for the emergence of suicidal ideation during depression.


Assuntos
Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/genética , Medição da Dor/tendências , Dor/diagnóstico por imagem , Dor/genética , Ideação Suicida , Adulto , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/psicologia , Succinato de Desvenlafaxina/uso terapêutico , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/tendências , Masculino , Pessoa de Meia-Idade , Dor/psicologia , Medição da Dor/métodos , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Tentativa de Suicídio/psicologia , Tentativa de Suicídio/tendências
9.
J Neurosci Res ; 98(4): 588-600, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30051488

RESUMO

In the past decade, considerable attention has been drawn to social interactions and behaviors as sources of pleasurable (social reward) and painful (social pain) emotional states. While the role of the opioid system in the regulation of reward and pain processes has long been recognized, it has more recently been investigated and characterized in the specific context of social experiences across several mammalian species. Accordingly, the present narrative review provides a comprehensive summary of studies detailing how the opioid system controls social reward and social pain. From a translational and pathophysiological perspective, we further discuss how opioid-dependent regulation of social behaviors may contribute to depressive illness and suicidal behaviors, and ultimately provide innovative therapeutic opportunities.


Assuntos
Encéfalo/fisiopatologia , Transtorno Depressivo/fisiopatologia , Peptídeos Opioides/fisiologia , Receptores Opioides/fisiologia , Comportamento Social , Suicídio , Transtorno Depressivo/complicações , Emoções/fisiologia , Humanos , Dor/complicações , Dor/fisiopatologia , Recompensa
10.
J Neurosci Res ; 98(4): 601-615, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30561057

RESUMO

Aberrant gene expression can contribute to brain and nervous system dysfunction that causes many psychiatric illnesses. Here, we review how transcriptomic approaches have deepened our understanding of the neurobiological underpinnings of psychiatric disorders and how they have to the identification of biomarkers for these disorders, with a focus on their relevance to suicide and suicide behaviors. We begin by providing an overview of the genetic, transcriptomic, and epigenetic factors (including non-coding RNAs) implicated in suicide and their roles in the regulation of gene expression. Then, we highlight the unique benefits and limitations of using either postmortem brain or peripheral tissues in transcriptomic analyses. We examine the current shift from candidate gene to genome-wide approaches in psychiatric research, which are concurrently emerging with the increased consideration of the Research Domain Criteria (RDoC) framework for classifying mental illnesses. Furthermore, we discuss the use of transcription networks and how they can be integrated into multiomic analyses. Finally, we end by highlighting recent findings of peripheral markers of suicide risk identified through the use of transcriptomic tools. Technological advancements and increased accessibility of these technologies are drastically shaping the current research landscape. We present an overview of the significant changes currently taking place to usher in a new era of psychiatric research.


Assuntos
Encéfalo/metabolismo , Encéfalo/fisiopatologia , Perfilação da Expressão Gênica/métodos , Transtornos Mentais/genética , Transtornos Mentais/psicologia , Suicídio , Transcriptoma , Animais , Epigênese Genética , Humanos , RNA não Traduzido/genética
11.
Nat Genet ; 51(12): 1702-1713, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768071

RESUMO

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Animais , Encéfalo/patologia , Linhagem Celular Tumoral , Humanos , Lactente , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Fibras Nervosas/patologia , Fibras Nervosas/fisiologia , Prosencéfalo/citologia , Prosencéfalo/embriologia , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Análise de Célula Única
12.
Neuropsychopharmacology ; 44(12): 2099-2111, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31374562

RESUMO

Glial dysfunction is a major pathophysiological feature of mood disorders. While altered astrocyte (AS) and oligodendrocyte-lineage (OL) functions have been associated with depression, the crosstalk between these glial cell types has never been assessed in that context. AS are potent regulators of myelination, in part through gap junction (GJ) channels formed by the heterotypic coupling of AS-specific (Cx30 and Cx43) and OL-specific (Cx32 and Cx47) connexins. This study therefore aimed at addressing the integrity of AS/OL coupling in the anterior cingulate cortex (ACC) of depressed suicides. Using immunofluorescence and confocal imaging, we characterized the distribution of Cx30 and mapped its expression onto OL somas, myelinated axons, and brain vasculature in postmortem brain samples from depressed suicides (N = 48) and matched controls (N = 23). Differential gene expression of key components of the GJ nexus was also screened through RNA-sequencing previously generated by our group, and validated by quantitative real-time PCR. We show that Cx30 expression localized onto OL cells and myelinated fibers is decreased in deep cortical layers of the ACC in male-depressed suicides. This effect was associated with decreased expression of OL-specific connexins, as well as the downregulation of major connexin-interacting proteins essential for the scaffolding, trafficking, and function of GJs. These results provide a first evidence of impaired AS/OL GJ-mediated communication in the ACC of individuals with mood disorders. These changes in glial coupling are likely to have significant impact on brain function, and may contribute to the altered OL function previously reported in this brain region.


Assuntos
Astrócitos/metabolismo , Conexina 30/metabolismo , Transtorno Depressivo/metabolismo , Giro do Cíngulo/metabolismo , Oligodendroglia/metabolismo , Suicídio Consumado , Conexinas/metabolismo , Humanos , Fibras Nervosas Mielinizadas/metabolismo , Suicídio Consumado/psicologia
13.
Transl Psychiatry ; 8(1): 224, 2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30337518

RESUMO

Long non-coding RNAs (lncRNAs) are an emerging class of regulatory RNA that may be implicated in psychiatric disorders. Here we performed RNA-sequencing in the rostral anterior cingulate cortex of 26 depressed suicides and 24 matched controls. We first performed differential lncRNA expression analysis, and then conducted Weighted Gene Co-expression Network Analysis (WGCNA) to identify co-expression modules associating with depression and suicide. We identified 23 differentially expressed lncRNAs (FDR < 0.1) as well as their differentially expressed overlapping and antisense protein-coding genes. Several of these overlapping or antisense genes were associated with interferon signaling, which is a component of the innate immune response. Using WGCNA, we identified modules of highly co-expressed genes associated with depression and suicide and found protein-coding genes highly connected to differentially expressed lncRNAs within these modules. These protein-coding genes were located distal to their associated lncRNAs and were found to be part of several GO terms enriched in the significant modules, which include: cytoskeleton organization, plasma membrane, cell adhesion, nucleus, DNA-binding, and regulation of dendrite development and morphology. Altogether, we report that lncRNAs are differentially expressed in the brains of depressed individuals who died by suicide and may represent regulators of important molecular functions and biological processes.


Assuntos
Transtorno Depressivo Maior/metabolismo , Giro do Cíngulo/metabolismo , RNA Longo não Codificante/metabolismo , Suicídio , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Análise de Sequência de RNA , Transcriptoma
14.
J Neurosci ; 38(46): 9934-9954, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30249798

RESUMO

In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act. We show two distinct mechanisms by which the selective inhibitor of serotonin and noradrenaline reuptake duloxetine and the tricyclic antidepressant amitriptyline relieve neuropathic allodynia. One of these mechanisms is acute, central, and requires descending noradrenergic inhibitory controls and α2A adrenoceptors, as well as the mu and delta opioid receptors. The second mechanism is delayed, peripheral, and requires noradrenaline from peripheral sympathetic endings and ß2 adrenoceptors, as well as the delta opioid receptors. We then conducted a transcriptomic analysis in dorsal root ganglia, which suggested that the peripheral component of duloxetine action involves the inhibition of neuroimmune mechanisms accompanying nerve injury, including the downregulation of the TNF-α-NF-κB signaling pathway. Accordingly, immunotherapies against either TNF-α or Toll-like receptor 2 (TLR2) provided allodynia relief. We also compared duloxetine plasma levels in the animal model and in patients and we observed that patients' drug concentrations were compatible with those measured in animals under chronic treatment involving the peripheral mechanism. Our study highlights a peripheral neuroimmune component of antidepressant drugs that is relevant to their delayed therapeutic action against neuropathic pain.SIGNIFICANCE STATEMENT In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. However, the mechanism by which antidepressant drugs can relieve neuropathic pain remained in part elusive. Indeed, preclinical studies led to contradictions concerning the anatomical and molecular substrates of this action. In the present work, we overcame these apparent contradictions by highlighting the existence of two independent mechanisms. One is rapid and centrally mediated by descending controls from the brain to the spinal cord and the other is delayed, peripheral, and relies on the anti-neuroimmune action of chronic antidepressant treatment.


Assuntos
Amitriptilina/administração & dosagem , Antidepressivos/administração & dosagem , Cloridrato de Duloxetina/administração & dosagem , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Norepinefrina/metabolismo , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Manejo da Dor/métodos , Receptor A2A de Adenosina/metabolismo
15.
Trends Mol Med ; 24(2): 206-220, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29396147

RESUMO

Substance use disorders (SUD) and behavioral addictions are devastating conditions that impose a severe burden on all societies, and represent difficult challenges for clinicians. Therefore, biomarkers are urgently needed to help predict vulnerability, clinical course, and response to treatment. Here, we elaborate on the potential for addiction biomarker discovery of the opioid system, particularly within the emerging framework aiming to probe opioid function in peripheral tissues. Mu, delta, and kappa opioid receptors all critically regulate neurobiological and behavioral processes that define addiction, and are also targeted by major pharmacotherapies used in the management of patients with SUD. We propose that opioid biomarkers may have the potential to improve and guide diagnosis and therapeutic decisions in the addiction field.


Assuntos
Comportamento Aditivo/metabolismo , Biomarcadores/metabolismo , Receptores Opioides/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Comportamento Aditivo/diagnóstico , Comportamento Aditivo/terapia , Humanos , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/terapia
16.
J Neurosci ; 38(12): 3102-3115, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29463643

RESUMO

Pain associates both sensory and emotional aversive components, and often leads to anxiety and depression when it becomes chronic. Here, we characterized, in a mouse model, the long-term development of these sensory and aversive components as well as anxiodepressive-like consequences of neuropathic pain and determined their electrophysiological impact on the anterior cingulate cortex (ACC, cortical areas 24a/24b). We show that these symptoms of neuropathic pain evolve and recover in different time courses following nerve injury in male mice. In vivo electrophysiological recordings evidence an increased firing rate and bursting activity within the ACC when anxiodepressive-like consequences developed, and this hyperactivity persists beyond the period of mechanical hypersensitivity. Whole-cell patch-clamp recordings also support ACC hyperactivity, as shown by increased excitatory postsynaptic transmission and contribution of NMDA receptors. Optogenetic inhibition of the ACC hyperactivity was sufficient to alleviate the aversive and anxiodepressive-like consequences of neuropathic pain, indicating that these consequences are underpinned by ACC hyperactivity.SIGNIFICANCE STATEMENT Chronic pain is frequently comorbid with mood disorders, such as anxiety and depression. It has been shown that it is possible to model this comorbidity in animal models by taking into consideration the time factor. In this study, we aimed at determining the dynamic of different components and consequences of chronic pain, and correlated them with electrophysiological alterations. By combining electrophysiological, optogenetic, and behavioral analyses in a mouse model of neuropathic pain, we show that the mechanical hypersensitivity, ongoing pain, anxiodepressive consequences, and their recoveries do not necessarily exhibit temporal synchrony during chronic pain processing, and that the hyperactivity of the anterior cingulate cortex is essential for driving the emotional impact of neuropathic pain.


Assuntos
Dor Crônica/fisiopatologia , Dor Crônica/psicologia , Giro do Cíngulo/fisiopatologia , Neuralgia/fisiopatologia , Neuralgia/psicologia , Animais , Ansiedade/etiologia , Ansiedade/fisiopatologia , Depressão/etiologia , Depressão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Eur Neuropsychopharmacol ; 28(2): 334-340, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29336871

RESUMO

Preclinical and clinical studies have demonstrated that the kappa opioid receptor (KOR) regulates reward, hedonic tone and emotions. At therapeutic level, on-going clinical trials are assessing the potential of targeting the KOR for the management of depression, anxiety disorders and substance use disorders. However, genetic polymorphisms in the KOR gene that potentially contribute to its implication in these phenotypes have been poorly studied. Here we investigated an insertion-deletion in the promoter region of KOR (rs35566036), recently associated with alcohol addiction, in a cohort of depressed subjects who died by suicide, as well as psychiatrically healthy individuals. Focusing on 3 brain regions (anterior insula, anterior cingulate cortex, and mediodorsal thalamus), we characterized the functional impact of this structural variant on the expression and patterns of DNA methylation of the KOR gene, using qPCR and targeted Bisulfite-Sequencing, respectively. While there was no significant change in the expression of KOR as a function of the insertion-deletion, or as a function of disease status in any brain region, we found that this variant strongly determines DNA methylation in KOR promoter, leading to a significant decrease in methylation levels of 8 nearby CpG dinucleotides located approximately 500 base pairs upstream the transcription start site. In addition, our results suggest a possible association between the insertion-deletion and depression; however, this result should be tested in larger populations. In sum, in this study we uncovered an epigenetic mechanism potentially contributing to KOR dysfunction in carriers of the insertion-deletion.


Assuntos
Epigênese Genética , Mutação INDEL , Regiões Promotoras Genéticas , Receptores Opioides kappa/genética , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Estudos de Coortes , Ilhas de CpG , Transtorno Depressivo/genética , Transtorno Depressivo/metabolismo , Transtorno Depressivo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Opioides kappa/metabolismo , Suicídio , Tálamo/metabolismo , Tálamo/patologia
18.
J Affect Disord ; 233: 36-44, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28918100

RESUMO

BACKGROUND: Antidepressant treatment is associated with a high rate of poor response, and thus, biomarker development is warranted. METHODS: We aimed to synthesize studies investigating gene expression, small RNAs, and epigenomic biomarkers of antidepressant response. We conducted a narrative review of the literature. RESULTS: Firstly, we detailed the challenges involved, in terms of biological tissues, relevant study time frames, and mandatory statistical tools. Secondly we synthesized results obtained in gene expression studies, focusing mainly on genome-wide studies, particularly small non-coding RNA, including micro-RNA and other small RNA species. In addition, we reviewed the potential biomarkers of antidepressant response arising from studies investigating DNA methylation variation and histone modifications. LIMITATIONS: We did not conduct a meta-analysis due to the heterogeneity of the study. CONCLUSION: Although promising, the field of gene expression and epigenomic biomarkers of antidepressant response is still in its infancy, and needs further development to define useful biomarkers in clinical practice.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Epigenômica , Marcadores Genéticos , Transcriptoma/genética , Metilação de DNA , Humanos , MicroRNAs/genética
19.
Biol Psychiatry ; 84(10): 751-761, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28886759

RESUMO

BACKGROUND: Experiences of abuse and neglect during childhood are major predictors of the emergence of depressive and suicidal behaviors throughout life. The underlying biological mechanisms, however, remain poorly understood. Here, we focused on the opioid system as a potential brain substrate mediating these effects. METHODS: Postmortem samples from three brain structures regulating social bonds and emotions were analyzed. Groups were constituted of depressed individuals who died by suicide, with or without a history of severe child abuse, and of psychiatrically healthy control subjects. Expression of opioid peptides and receptors was measured using real-time polymerase chain reaction. DNA methylation, a major epigenetic mark, was investigated using targeted bisulfite sequencing and characterized at functional level using in vitro reporter assays. Finally, oxidative bisulfite sequencing was used to differentiate methylation and hydroxymethylation of DNA. RESULTS: A history of child abuse specifically associated in the anterior insula with a downregulation of the kappa opioid receptor (Kappa), as well as decreased DNA methylation in the second intron of the Kappa gene. In vitro assays further showed that this intron functions as a genomic enhancer where glucocorticoid receptor binding regulates Kappa expression, unraveling a new mechanism mediating the well-established interactions between endogenous opioids and stress. Finally, results showed that child abuse is associated in the Kappa intron with a selective reduction in levels of DNA hydroxymethylation, likely mediating the observed downregulation of the receptor. CONCLUSIONS: Altogether, our findings uncover new facets of Kappa physiology, whereby this receptor may be epigenetically regulated by stressful experiences, in particular as a function of early social life.


Assuntos
Maus-Tratos Infantis , Epigênese Genética , Regiões Promotoras Genéticas , Receptores Opioides kappa/genética , Adulto , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Criança , Metilação de DNA , Transtorno Depressivo/genética , Transtorno Depressivo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Suicídio , Tálamo/metabolismo , Tálamo/patologia
20.
Semin Cell Dev Biol ; 77: 115-132, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29017800

RESUMO

Early life adversity remains a significant risk factor for the development of a host of negative behavioural and pathological outcomes in adulthood long after the stressor is over. Recent evidence indicates that these lasting effects of ELS may occur via alterations in the epigenetic landscape. Here, we review the main findings of the effects of early life adversity on DNA methylation, histone post-translational modification, and non-coding RNAs in the context of psychiatric disease in animal models and human cohorts. We specifically explore how early life adversity alters epigenetic patterns in both a global manner, and in specific candidate genes that play a role in relevant systems such as the hypothalamic-pituitary-adrenal axis, as well as neurotransmitter and neuroendocrine signalling. We also discuss how individual factors, such as genetics, sex, and age, as well as the type, and timing of early life adversity, can create differential susceptibility and significantly moderate outcomes. Although challenges remain in deciphering the complexity of how the early environment interacts with individual factors to determine epigenetic patterns, as well as how to translate these mechanistic findings into clinically relevant populations, the reviewed literature sheds light on the potential of the field to identify effective interventions for vulnerable individuals.


Assuntos
Epigênese Genética/genética , Transtornos Mentais/etiologia , Transtornos Mentais/genética , Resiliência Psicológica , Estresse Psicológico/genética , Estresse Psicológico/psicologia , Fatores Etários , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Metilação de DNA/genética , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Camundongos , Sistema Hipófise-Suprarrenal/fisiologia , Processamento de Proteína Pós-Traducional/genética , Psicopatologia , RNA não Traduzido/genética , Ratos , Serotonina/metabolismo , Transdução de Sinais/fisiologia , Ácido gama-Aminobutírico/metabolismo
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