DNA methylation at DLGAP2 and risk for relapse in alcohol dependence during acamprosate treatment.

Background: Alcohol use disorders are prevalent mental disorders with significant health implications. Epigenetic alterations may play a role in their pathogenesis, as DNA methylation at several genes has been associated with these disorders. We have previously shown that methylation in the DLGAP2 gene, coding for a synaptic density protein, is associated with alcohol dependence.

The left-right side-specific endocrine signaling in the effects of brain lesions: questioning of the neurological dogma.

Each cerebral hemisphere is functionally connected to the contralateral side of the body through the decussating neural tracts. The crossed neural pathways set a basis for contralateral effects of brain injury such hemiparesis and hemiplegia as it has been already noted by Hippocrates. Recent studies demonstrated that, in addition to neural mechanisms, the contralateral effects of brain lesions are mediated through the humoral pathway by neurohormones that produce either the left or right side-specific effects.

Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum.

Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD.

Left-right side-specific endocrine signaling complements neural pathways to mediate acute asymmetric effects of brain injury.

Brain injuries can interrupt descending neural pathways that convey motor commands from the cortex to spinal motoneurons. Here, we demonstrate that a unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic spinal cord produces hindlimb postural asymmetry with contralateral flexion and asymmetric hindlimb withdrawal reflexes within 3 hr, as well as asymmetry in gene expression patterns in the lumbar spinal cord. The injury-induced postural effects were abolished by hypophysectomy and were mimicked by transfusion of serum from animals with brain injury.

Epigenetic and Transcriptional Control of the Opioid Prodynorphine Gene: In-Depth Analysis in the Human Brain.

Neuropeptides serve as neurohormones and local paracrine regulators that control neural networks regulating behavior, endocrine system and sensorimotor functions. Their expression is characterized by exceptionally restricted profiles. Circuit-specific and adaptive expression of neuropeptide genes may be defined by transcriptional and epigenetic mechanisms controlled by cell type and subtype sequence-specific transcription factors, insulators and silencers.

Effect of the Expression of and Genes on the Metastatic Potential of Breast Cancer Cells.

Breast cancer (BC) is the leading cause of death from malignant neoplasms among women worldwide, and metastatic BC presents the biggest problems for treatment. Previously, it was shown that lower expression of and genes is associated with a higher risk of the formation of distant metastases in BC. In this work, we studied the change in phenotypical traits, as well as in the transcriptomic and proteomic profiles of BC cells as a result of the stable knockdown of and genes.

Coordinated expression of the renin-angiotensin genes in the lumbar spinal cord: Lateralization and effects of unilateral brain injury.

In spite of its apparent symmetry, the spinal cord is asymmetric in its reflexes and gene expression patterns including leftward expression bias of the opioid and glutamate genes. To examine whether this is a general phenomenon for neurotransmitter and neurohormonal genes, we here characterized expression and co-expression (transcriptionally coordinated) patterns of genes of the renin-angiotensin system (RAS) that is involved in neuroprotection and pathological neuroplasticity in the left and right lumbar spinal cord. We also tested whether the RAS expression patterns were affected by unilateral brain injury (UBI) that rewired lumbar spinal neurocircuits.

Unilateral traumatic brain injury of the left and right hemisphere produces the left hindlimb response in rats.

Traumatic brain injury and stroke result in hemiplegia, hemiparesis, and asymmetry in posture. The effects are mostly contralateral; however, ipsilesional deficits may also develop. We here examined whether ablation brain injury and controlled cortical impact (CCI), a rat model of clinical focal traumatic brain injury, both centered over the left or right sensorimotor cortex, induced hindlimb postural asymmetry (HL-PA) with contralesional or ipsilesional limb flexion.

Left-Right Side-Specific Neuropeptide Mechanism Mediates Contralateral Responses to a Unilateral Brain Injury.

Neuropeptides are implicated in control of lateralized processes in the brain. A unilateral brain injury (UBI) causes the contralesional sensorimotor deficits. To examine whether opioid neuropeptides mediate UBI induced asymmetric processes we compared effects of opioid antagonists on the contralesional and ipsilesional hindlimb responses to the left-sided and right-sided injury in rats.

Unilateral brain injury to pregnant rats induces asymmetric neurological deficits in the offspring.

Effects of environmental factors may be transmitted to the following generation, and cause neuropsychiatric disorders including depression, anxiety, and posttraumatic stress disorder in the offspring. Enhanced synaptic plasticity induced by environmental enrichment may be also transmitted. We here test the hypothesis that the effects of brain injury in pregnant animals may produce neurological deficits in the offspring.

Ipsilesional contralesional postural deficits induced by unilateral brain trauma: a side reversal by opioid mechanism.

Unilateral traumatic brain injury and stroke result in asymmetric postural and motor deficits including contralateral hemiplegia and hemiparesis. In animals, a localized unilateral brain injury recapitulates the human upper motor neuron syndrome in the formation of hindlimb postural asymmetry with contralesional limb flexion and the asymmetry of hindlimb nociceptive withdrawal reflexes. The current view is that these effects are developed due to aberrant activity of motor pathways that descend from the brain into the spinal cord.

Differential DNA Methylation of the Genes for Amyloid Precursor Protein, Tau, and Neurofilaments in Human Traumatic Brain Injury.

Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI.

Hindlimb motor responses to unilateral brain injury: spinal cord encoding and left-right asymmetry.

Mechanisms of motor deficits (e.g. hemiparesis and hemiplegia) secondary to stroke and traumatic brain injury remain poorly understood.

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability.

Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence.

Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence.

Differential suppression of the ipsi- and contralateral nociceptive reflexes in the neonatal rat spinal cord by agonists of µ-, δ- and κ-opioid receptors.

Nociceptive discharges caused by the unilateral tissue damage are processed in the spinal cord by both ipsi- and contralateral neuronal circuits. The mechanisms of the neurotransmitter control of this bilateral excitation spread is poorly understood. Spinally administered opiates are known to suppress nociceptive transmission and nociceptive withdrawal reflexes.

Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord.

Background/objectives: Motor impairment induced by traumatic brain injury (TBI) may be mediated through changes in spinal molecular systems regulating neuronal plasticity. We assessed whether a focal controlled cortical impact (CCI) TBI in the rat alters expression of the Tgfb1, c-Fos, Bdnf, and Gap43 neuroplasticity genes in lumbar spinal cord.Approach/Methods:Adult male Sprague-Dawley rats (n = 8) were subjected to a right-side CCI over the anterior sensorimotor hindlimb representation area or sham-injury (n = 8).

Correlations between sex-related hormones, alcohol dependence and alcohol craving.

Background: Sex-related differences in the susceptibility, progression, and treatment response in alcohol-dependent subjects have been repeatedly reported. In this study, we aimed to investigate the associations of the sex-related hormone/protein levels with alcohol dependence (AD) and alcohol craving in male and female subjects.

Methods: Plasma sex-related hormones (estradiol, estrone, total testosterone, progesterone, follicle stimulated hormone [FSH], luteinizing hormone), and sex hormone binding globulin were measured by mass spectrometry or automated immunoassays from 44 recently-abstained subjects (29 males and 15 females; mean age = 45.

The Cortical Neuroimmune Regulator TANK Affects Emotional Processing and Enhances Alcohol Drinking: A Translational Study.

Alcohol abuse is a major public health problem worldwide. Understanding the molecular mechanisms that control regular drinking may help to reduce hazards of alcohol consumption. While immunological mechanisms have been related to alcohol drinking, most studies reported changes in immune function that are secondary to alcohol use.

Allele-Specific Methylation of SPDEF: A Novel Moderator of Psychosocial Stress and Substance Abuse.

Objective: Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population.

Activation of NF-κB in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis: A Potential Contributor to Inflammatory Aspects of Disease Progression.

The aim was to assess the activation and association of the NF-κB system across synovial membrane (SM) and articular cartilage (AC) in patients with knee osteoarthritis (OA) and ascertain its potential effects on catabolic mediator expression in advanced OA. SM and AC were obtained from 40 OA patients undergoing total knee arthroplasty and from 19 postmortem control subjects. NF-κB subunit RelA in nuclear and cytosolic fractions and NF-κB1-DNA binding in nuclear extracts was assessed by ELISA, whereas , , , , and gene expression were analyzed by reverse transcriptase-quantitative PCR in tissues.

Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics.

Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models.