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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
Ho, A.-C. M., Geske, J. R., Bakalkin, G., Winham, S. J. & Karpyak, V. M. (2019). Correlations between sex-related hormones, alcohol dependence and alcohol craving. Drug And Alcohol Dependence, 197, 183-190
Open this publication in new window or tab >>Correlations between sex-related hormones, alcohol dependence and alcohol craving
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2019 (English)In: Drug And Alcohol Dependence, ISSN 0376-8716, E-ISSN 1879-0046, Vol. 197, p. 183-190Article in journal (Refereed) Published
Abstract [en]

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 = 45.9 ± 15.6) meeting DSM-IV-TR criteria for AD and 44 age-, sex- and race-matched non-AD controls. Conditional logistic regression was conducted to examine the association of sex-related hormone and protein levels with AD risk, accounting for matching variables. Their associations with alcohol craving scales (Penn Alcohol Craving Scale and Inventory of Drug-Taking Situations) were assessed in AD subjects.

Results: Plasma FSH level was significantly higher in AD males (10.3 ± 9.8 IU/L) than control males (8.0 ± 15.9 IU/L; p = 0.005, pcorrected = 0.035). We also found a significant inverse correlation of FSH level with propensity to drink in negative emotional situations (Spearman’s rho=-.540; p = 0.021) and positive correlations between progesterone level and craving intensity (Spearman’s rho=.464; p = 0.020) and between total testosterone level and propensity to drink under temptations (adjusted for no-drinking days; β=6.496; p = 0.041) in AD males.

Conclusions: These results suggest that FSH, progesterone, and testosterone levels may be associated with AD and alcohol craving in AD males. Future research is needed to replicate these findings and investigate the underlying biological mechanisms.

Keywords
Alcohol use disorders, Alcohol dependence, Craving, Sex differences, Sex hormones
National Category
Substance Abuse
Identifiers
urn:nbn:se:uu:diva-382988 (URN)10.1016/j.drugalcdep.2019.01.029 (DOI)000464479000027 ()30840924 (PubMedID)
Available from: 2019-05-13 Created: 2019-05-13 Last updated: 2019-05-13Bibliographically 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
Kononenko, O., Watanabe, H., Stålhandske, L., Zarelius, A., Clausen, F., Yakovleva, T., . . . Marklund, N. (2019). Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord. Restorative Neurology and Neuroscience, 37(2), 87-96
Open this publication in new window or tab >>Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord
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2019 (English)In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 37, no 2, p. 87-96Article in journal (Refereed) Published
Abstract [en]

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). Absolute expression levels of Tgfb1, c-Fos, Bdnf, and Gapd43 genes were measured by droplet digital PCR in ipsi- and contralesional, dorsal and ventral quadrants of the L4 and L5 spinal cord. The neuronal activity marker c-Fos was analysed by immunohistochemistry in the dorsal L4 and L5 segments. The contra- vs. ipsilesional expression pattern was examined as the asymmetry index, AI.

Results: The Tgfb1 mRNA levels were significantly higher in the CCI vs. sham-injured rats, and in the contra- vs. ipsilesional dorsal domains in the CCI group. The number of c-Fos-positive cells was elevated in the L4 and L5 segments; and on the contralesional compared to the ipsilesional side in the CCI group. The c-Fos AI in the dorsal laminae was significantly increased by CCI.

Conclusions: The results support the hypothesis that focal TBI induces plastic alterations in the lumbar spinal cord that may contribute to either motor recovery or maladaptive motor responses.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Traumatic brain injury, Tgfb1, c-Fos, spinal cord, plasticity
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-383037 (URN)10.3233/RNN-180882 (DOI)000464944000001 ()30856132 (PubMedID)
Funder
Swedish Research CouncilSwedish Institute
Note

De tre första författarna delar förstaförfattarskapet.

de två sista författarna delar sistaförfattarskapet.

Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-05-08Bibliographically 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
Mueller, C. P., Chu, C., Qin, L., Liu, C., Xu, B., Gao, H., . . . Schumann, G. (2019). The Cortical Neuroimmune Regulator TANK Affects Emotional Processing and Enhances Alcohol Drinking: A Translational Study. Cerebral Cortex, 29(4), 1736-1751
Open this publication in new window or tab >>The Cortical Neuroimmune Regulator TANK Affects Emotional Processing and Enhances Alcohol Drinking: A Translational Study
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2019 (English)In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 29, no 4, p. 1736-1751Article in journal (Refereed) Published
Abstract [en]

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. In this report, we analyse how the gene "TRAF family member-associated NF-kappa B activator" (TANK) affects alcohol drinking behavior. Based on our recent discovery in a large GWAS dataset that suggested an association of TANK, SNP rs197273, with alcohol drinking, we report that SNP rs197273 in TANK is associated both with gene expression (P = 1.16 x 10(-19)) and regional methylation (P = 5.90 x 10(-25)). A tank knock out mouse model suggests a role of TANK in alcohol drinking, anxiety-related behavior, as well as alcohol exposure induced activation of insular cortex NF-kappa B. Functional and structural neuroimaging studies among up to 1896 adolescents reveal that TANK is involved in the control of brain activity in areas of aversive interoceptive processing, including the insular cortex, but not in areas related to reinforcement, reward processing or impulsiveness. Our findings suggest that the cortical neuroimmune regulator TANK is associated with enhanced aversive emotional processing that better protects from the establishment of alcohol drinking behavior.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2019
Keywords
alcohol, anxiety, drinking, insular cortex, NF-kappa B, TANK
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-393754 (URN)10.1093/cercor/bhy341 (DOI)000482180900035 ()30721969 (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: 2019-10-18 Created: 2019-10-18 Last updated: 2019-10-18Bibliographically approved
Ahmed, A. S., Gedin, P., Hugo, A., Bakalkin, G., Kanar, A., Hart, D. A., . . . Kosek, E. (2018). Activation of NF-kappa B in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis: A Potential Contributor to Inflammatory Aspects of Disease Progression. Journal of Immunology, 201(7), 1918-1927
Open this publication in new window or tab >>Activation of NF-kappa B in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis: A Potential Contributor to Inflammatory Aspects of Disease Progression
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2018 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 201, no 7, p. 1918-1927Article in journal (Refereed) Published
Abstract [en]

The aim was to assess the activation and association of the NF-kappa B 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-kappa B subunit RelA in nuclear and cytosolic fractions and NF-kappa B1-DNA binding in nuclear extracts was assessed by ELISA, whereas NFKB1, RELA, IL-8, IL-6, and MMP3 gene expression were analyzed by reverse transcriptase-quantitative PCR in tissues. We observed higher SM nuclear RelA protein levels and upregulated NF-kappa B1-DNA binding in OA patients compared with postmortem controls. However, in AC, lower nuclear RelA levels were observed compared with cytosolic extracts in patients. Nuclear RelA levels correlated positively with NF-kappa B1-DNA binding in SM and AC in patients. SM RELA and MMP3 mRNA levels were upregulated, whereas IL-8 and IL-6 as well as AC RELA were downregulated in patients compared with controls. In SM, nuclear RelA levels correlated positively with MMP3 gene expression in patients. A negative correlation was observed between SM nuclear RelA levels and AC NF-kappa B1-DNA binding, and SM nuclear NF-kappa B1-DNA binding correlated negatively with AC MMP3 and NFKB1 mRNA levels in patients. These findings highlight NF-kappa B-triggered cross-talk and feedback mechanisms between SM and AC in OA. Further, our findings strongly support a role for an activated NF-kappa B system in the transcriptional mechanism of inflammatory processes, especially in SM of patients with advanced OA.

Place, publisher, year, edition, pages
AMER ASSOC IMMUNOLOGISTS, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-366723 (URN)10.4049/jimmunol.1800486 (DOI)000444804300013 ()30135182 (PubMedID)
Funder
Swedish Research Council, K2013-52X-22199-01-3Swedish Research Council, 542-2013-8373Swedish Rheumatism Association
Available from: 2018-12-13 Created: 2018-12-13 Last updated: 2018-12-13Bibliographically 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
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ORCID iD: ORCID iD iconorcid.org/0000-0002-8074-9833

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