| 1. |
- Bazov, Igor, 1973-, et al.
(författare)
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Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain
- 2018
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 28:9, s. 3129-3142
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Tidskriftsartikel (refereegranskat)abstract
- Molecular mechanisms that define patterns of neuropeptide expression are essential for the formation and rewiring of neural circuits. The prodynorphin gene (PDYN) gives rise to dynorphin opioid peptides mediating depression and substance dependence. We here demonstrated that PDYN is expressed in neurons in human dorsolateral prefrontal cortex (dlPFC), and identified neuronal differentially methylated region in PDYN locus framed by CCCTC-binding factor binding sites. A short, nucleosome size human-specific promoter CpG island (CGI), a core of this region may serve as a regulatory module, which is hypomethylated in neurons, enriched in 5-hydroxymethylcytosine, and targeted by USF2, a methylation-sensitive E-box transcription factor (TF). USF2 activates PDYN transcription in model systems, and binds to nonmethylated CGI in dlPFC. USF2 and PDYN expression is correlated, and USF2 and PDYN proteins are co-localized in dlPFC. Segregation of activatory TF and repressive CGI methylation may ensure contrasting PDYN expression in neurons and glia in human brain.
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| 2. |
- Mueller, Christian P., et al.
(författare)
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The Cortical Neuroimmune Regulator TANK Affects Emotional Processing and Enhances Alcohol Drinking : A Translational Study
- 2019
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Ingår i: Cerebral Cortex. - : OXFORD UNIV PRESS INC. - 1047-3211 .- 1460-2199. ; 29:4, s. 1736-1751
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Watanabe, Hiroyuki, et al.
(författare)
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Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate : a Putative Molecular Basis for Lateralization of Emotions and Pain
- 2015
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Ingår i: Cerebral Cortex. - United kingdom : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 25:1, s. 97-108
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Tidskriftsartikel (refereegranskat)abstract
- Lateralization of processing of positive and negative emotions and pain suggests an asymmetric distribution of the neurotransmitter systems regulating these functions between the left and right brain hemispheres. By virtue of their ability to selectively mediate euphoria, dysphoria and pain, the m-, d- and k-opioid receptors and their endogenous ligands may subserve these lateralized functions. We addressed this hypothesis by comparing the levels of the opioid receptors and peptides in the left and right anterior cingulate cortex (ACC), a key area for emotion and pain processing. Opioid mRNAs and peptides and five “classical” neurotransmitters were analyzed in postmortem tissues from 20 human subjects. Leu-enkephalin-Arg and Met-enkephalin-Arg-Phe, preferential d-/m- and k-/m-opioid agonists demonstrated marked lateralization to the left and right ACC, respectively. Dynorphin B strongly correlated with Leu-enkephalin-Arg in the left but not right ACC suggesting different mechanisms of conversion of this k-opioid agonist to d-/m-opioid ligand in the two hemispheres; in the right ACC dynorphin B may be cleaved by PACE4, a proprotein convertase regulating left-right asymmetry formation. These findings suggest that region-specific lateralization of neuronal networks expressing opioid peptides underlyes in part lateralization of higher functions including positive and negative emotions and pain in the human brain.
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