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Tay, N., Macare, C., Liu, Y., Ruggeri, B., Jia, T., Chu, C., . . . Schumann, G. (2019). Allele-Specific Methylation of SPDEF: A Novel Moderator of Psychosocial Stress and Substance Abuse. American Journal of Psychiatry, 176(2), 146-155
Open this publication in new window or tab >>Allele-Specific Methylation of SPDEF: A Novel Moderator of Psychosocial Stress and Substance Abuse
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2019 (English)In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 176, no 2, p. 146-155Article in journal (Refereed) Published
Abstract [en]

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.

Methods: A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study.

Results: Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use.

Conclusions: Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.

Place, publisher, year, edition, pages
AMER PSYCHIATRIC PUBLISHING, INC, 2019
National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-381924 (URN)10.1176/appi.ajp.2018.17121360 (DOI)000462846000011 ()30525907 (PubMedID)
Funder
EU, Horizon 2020, 695313EU, FP7, Seventh Framework Programme, 602450EU, FP7, Seventh Framework Programme, 603016Swedish Research Council FormasGerman Research Foundation (DFG), SM 80/7-1German Research Foundation (DFG), SM 80/7-2German Research Foundation (DFG), SFB 940/1
Available from: 2019-04-18 Created: 2019-04-18 Last updated: 2019-04-18Bibliographically approved
Duarte, J., Fernandes, E. C., Kononenko, O., Sarkisyan, D., Luz, L. L., Bakalkin, G. & Safronov, B. V. (2019). Differential suppression of the ipsi- and contralateral nociceptive reflexes in the neonatal rat spinal cord by agonists of μ-, δ- and κ-opioid receptors. Brain Research, 1717, 182-189
Open this publication in new window or tab >>Differential suppression of the ipsi- and contralateral nociceptive reflexes in the neonatal rat spinal cord by agonists of μ-, δ- and κ-opioid receptors
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2019 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1717, p. 182-189Article in journal (Refereed) Published
Abstract [en]

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. Here we investigated whether three major types of opioid receptors are involved in the bilateral control of the spinal nociceptive sensorimotor processing. Effects of the μ-, δ- and κ-opioid receptor agonists on the ipsi- and contralateral nociceptive reflexes were studied by recording slow ventral root potentials in an isolated spinal cord preparation of the new-born rat. Absolute levels of expression of the opioid genes were analyzed by the droplet digital PCR. Ipsi- and contralateral slow ventral root potentials were most strongly suppressed by the μ-opioid receptor agonist DAMGO, by 63% and 85%, followed by the κ-opioid receptor agonist U-50488H, by 44% and 73%, and δ-opioid receptor agonist leucine-enkephalin, by 27% and 49%, respectively. All these agonists suppressed stronger contra- than ipsilateral responses. Naloxone prevented effects of the agonists indicating that they act through opioid receptors, which, as we show, are expressed in the neonatal spinal cord at the levels similar to those in adults. Thus, opioid receptor agonists suppress the segmental nociceptive reflexes. Stronger contralateral effects suggest that the endogenous opioid system regulates sensorimotor processing in the spinal commissural pathways. These effects of opioids may be relevant for treatment of symmetric clinical pain symptoms caused by unilateral tissue injury.

Keywords
Spinal segmental reflexes, Nociception, Opioids, Primary afferents, Motoneurons
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-388750 (URN)10.1016/j.brainres.2019.04.026 (DOI)000470799000020 ()31028728 (PubMedID)
Funder
EU, Horizon 2020Swedish Research CouncilSwedish Institute
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2019-08-15 Created: 2019-08-15 Last updated: 2020-02-17Bibliographically approved
Jia, T., Chu, C., Liu, Y., van Dongen, J., Papastergios, E., Armstrong, N. J., . . . Desrivières, S. (2019). Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.. Molecular Psychiatry
Open this publication in new window or tab >>Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.
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2019 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article in journal (Refereed) Epub ahead of print
Abstract [en]

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. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-399989 (URN)10.1038/s41380-019-0605-z (DOI)31811260 (PubMedID)
Available from: 2019-12-17 Created: 2019-12-17 Last updated: 2020-02-17Bibliographically approved
Meng, W., Sjöholm, L. K., Kononenko, O., Tay, N., Zhang, D., Sarkisyan, D., . . . Liu, Y. (2019). Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence.. Molecular Psychiatry
Open this publication in new window or tab >>Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence.
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2019 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article in journal (Refereed) Epub ahead of print
Abstract [en]

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. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-399982 (URN)10.1038/s41380-019-0588-9 (DOI)31745236 (PubMedID)
Available from: 2019-12-17 Created: 2019-12-17 Last updated: 2020-02-17Bibliographically approved
Watanabe, H., Zhang, M., Sarkisyan, D., Kononenko, O., Clausen, F., Iakovleva, T., . . . Bakalkin, G. (2018). Asymmetric Hindlimb Motor Response To Focal Traumatic Brain Injury Is Controlled By Side-Specific Opioid Mechanism. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A79-A79
Open this publication in new window or tab >>Asymmetric Hindlimb Motor Response To Focal Traumatic Brain Injury Is Controlled By Side-Specific Opioid Mechanism
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A79-A79Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Therapeutics / Drug Discovery, Rehabilitation, Receptor Mediated / Signaling, Neuropathology
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-363881 (URN)000441527400221 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Zhang, M., Watanabe, H., Sarkisyan, D., Thelin, J., Schouenborg, J. & Bakalkin, G. (2018). ASYMMETRIC HINDLIMB POSTURE AND WITHDRAW REFLEXES INDUCED BY UNILATERAL BRAIN INJURY ARE ENCODED IN SPINAL CORD. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A208-A208
Open this publication in new window or tab >>ASYMMETRIC HINDLIMB POSTURE AND WITHDRAW REFLEXES INDUCED BY UNILATERAL BRAIN INJURY ARE ENCODED IN SPINAL CORD
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A208-A208Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Rehabilitation, Electophysiology, Neuropathology
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-363882 (URN)000441527400561 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Lukoyanov, N., Carvalho, L., Watanabe, H., Zhang, M., Sarkisyan, D., Kononenko, O., . . . Bakalkin, G. (2018). Contralesional Hindlimb Motor Response Induced By Unilateral Brain Injury: Evidence For Extra Spinal Mechanism. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A201-A201
Open this publication in new window or tab >>Contralesional Hindlimb Motor Response Induced By Unilateral Brain Injury: Evidence For Extra Spinal Mechanism
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A201-A201Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Gene Expression, Neurotransmitter, Rehabilitation, Electophysiology, Endocrine
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-363878 (URN)000441527400543 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2018-11-14Bibliographically approved
Kononenko, O., Mityakina, I., Galatenko, V., Watanabe, H., Bazov, I., Gerashchenko, A., . . . Bakalkin, G. (2018). Differential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord. Brain Research, 1695, 78-83
Open this publication in new window or tab >>Differential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord
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2018 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1695, p. 78-83Article in journal (Refereed) Published
Abstract [en]

The endogenous opioid system (EOS) controls the processing of nociceptive stimuli and is a pharmacological target for opioids. Alterations in expression of the EOS genes under neuropathic pain condition may account for low efficacy of opioid drugs. We here examined whether EOS expression patterns are altered in the lumbar spinal cord of the rats with spinal nerve ligation (SNL) as a neuropathic pain model. Effects of the left- and right-side SNL on expression of EOS genes in the ipsi- and contralateral spinal domains were analysed. The SNL-induced changes were complex and different between the genes; between the dorsal and ventral spinal domains; and between the left and right sides of the spinal cord. Prodynorphin (Pdyn) expression was upregulated in the ipsilateral dorsal domains by each the left and right-side SNL, while changes in expression mu-opioid receptor (Oprm I) and proenkephalin (Penk) genes were dependent on the SNL side. Changes in expression of the Pdyn and kappa-opioid receptor (Oprk1) genes were coordinated between the ipsi- and contralateral sides. Withdrawal response thresholds, indicators of mechanical allodynia correlated negatively with Pdyn expression in the right ventral domain after right side SNL. These findings suggest multiple roles of the EOS gene products in spinal sensitization and changes in motor reflexes, which may differ between the left and right sides. (C) 2018 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Rat model, Neuropathic pain, Gene expression, Opioid system, Lumbar spinal cord, Lateralization
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-364899 (URN)10.1016/j.brainres.2018.05.043 (DOI)000440390700009 ()29852138 (PubMedID)
Funder
Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and WelfareSwedish Research Council FormasSwedish Institute
Available from: 2018-11-09 Created: 2018-11-09 Last updated: 2018-11-09Bibliographically approved
Bazov, I., Sarkisyan, D., Kononenko, O., Watanabe, H., Karpyak, V. M., Yakovleva, T. & Bakalkin, G. (2018). Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics. Translational Psychiatry, 8, Article ID 122.
Open this publication in new window or tab >>Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics
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2018 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, article id 122Article in journal (Refereed) Published
Abstract [en]

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. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Neurosciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-358683 (URN)10.1038/s41398-017-0075-5 (DOI)000437025300001 ()29925858 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2009-1709Forte, Swedish Research Council for Health, Working Life and Welfare, 259-2012-23Swedish Research Council, K2014-62X-12190-19-5
Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-17Bibliographically approved
Bazov, I., Sarkisyan, D., Kononenko, O., Watanabe, H., Yakovleva, T., Hansson, A. C., . . . Bakalkin, G. (2018). Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.. Molecular Neurobiology, 55(8), 7049-7061
Open this publication in new window or tab >>Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.
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2018 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 8, p. 7049-7061Article in journal (Refereed) Published
Abstract [en]

Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/κ-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2-containing pathways which may lead to the negative affective state in human alcoholics.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Alcohol addiction, Co-expression of gene clusters, D1-pathway, D2-pathway, Dynorphin, Dysphoria, Nucleus accumbens, Post-mortem human brain tissue, Reward system, κ-opioid receptor
National Category
Biochemistry and Molecular Biology Neurology
Identifiers
urn:nbn:se:uu:diva-343195 (URN)10.1007/s12035-017-0844-4 (DOI)000439758300057 ()29383684 (PubMedID)
Funder
Swedish Research Council, K2014-62X-12190-19-5Forte, Swedish Research Council for Health, Working Life and Welfare, 2009-1709 259-2012-23
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-10-17Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2451-4386

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