Opioid precursor protein isoform is targeted to the cell nuclei in the human brain

Background: Neuropeptide precursors are traditionally viewed as proteins giving rise to small neuropeptide molecules. Prodynorphin (PDYN) is the precursor protein to dynorphins, endogenous ligands for the kappa-opioid receptor. Alternative mRNA splicing of neuropeptide genes may regulate cell- and tissue-specific neuropeptide expression and produce novel protein isoforms. We here searched for novel PDYN mRNA and their protein product in the human brain. Methods: Novel PDYN transcripts were identified using nested PCR amplification of oligo(dT) selected full-length capped mRNA. Gene expression was analyzed by qRT-PCR, PDYN protein by western blotting and confocal imaging, dynorphin peptides by radioimmunoassay. Neuronal nuclei were isolated using fluorescence activated nuclei sorting (FANS) from postmortem human striatal tissue. lmmunofluorescence staining and con focal microscopy was performed for human caudate nucleus. Results: Two novel human PDYN mRNA splicing variants were identified. Expression of one of them was confined to the striatum where its levels constituted up to 30% of total PDYN mRNA. This transcript may be translated into ASP-PDYN protein lacking 13 N-terminal amino acids, a fragment of signal peptide (SP). Delta SP-PDYN was not processed to mature dynorphins and surprisingly, was targeted to the cell nuclei in a model cellular system. The endogenous PDYN protein was identified in the cell nuclei in human striatum by western blotting of isolated neuronal nuclei, and by confocal imaging. Conclusions and general significance: High levels of alternatively spliced Delta SP-PDYN mRNA and nuclear localization of PDYN protein suggests a nuclear function for this isoform of the opioid peptide precursor in human striatum. (C) 2016 Elsevier B.V. All rights reserved

Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression

Background: This report provides histopathological evidence to support prior neuroimaging findings of decreased volume and altered metabolism in the frontal cortex in major depressive disorder. Methods: Computer-assisted three-dimensional cell counting was used to reveal abnormal cytoarchitecture in left rostral and caudal orbitofrontal and dorsolateral prefrontal cortical regions in subjects with major depression as compared to psychiatrically normal controls. Results: Depressed subjects had decreases in cortical thickness, neuronal sizes, and neuronal and glial densities in the upper (II–IV) cortical layers of the rostral orbitofrontal region. In the caudal orbitofrontal cortex in depressed subjects, there were prominent reductions in glial densities in the lower (V–VI) cortical layers that were accompanied by small but significant decreases in neuronal sizes. In the dorsolateral prefrontal cortex of depressed subjects marked reductions in the density and size of neurons and glial cells were found in both supra- and infragranular layers. Conclusions: These results reveal that major depression can be distinguished by specific histopathology of both neurons and glial cells in the prefrontal cortex. Our data will contribute to the interpretation of neuroimaging findings and identification of dysfunctional neuronal circuits in major depression

Human orbital and anterior medial prefrontal cortex:Intrinsic connectivity parcellation and functional organization

The orbital and medial prefrontal cortex (OMPFC) has been implicated in decision-making, reward and emotion processing, and psychopathology, such as depression and obsessive-compulsive disorder. Human and monkey anatomical studies indicate the presence of various cortical subdivisions and suggest that these are organized in two extended networks, a medial and an orbital one. Attempts have been made to replicate these neuroanatomical findings in vivo using MRI techniques for imaging connectivity. These revealed several consistencies, but also many inconsistencies between reported results. Here, we use fMRI resting-state functional connectivity (FC) and data-driven modularity optimization to parcellate the OMPFC to investigate replicability of in vivo parcellation more systematically. By collecting two resting-state data sets per participant, we were able to quantify the reliability of the observed modules and their boundaries. Results show that there was significantly more than chance overlap in modules and their boundaries at the level of individual data sets. Moreover, some of these consistent boundaries significantly co-localized across participants. Hierarchical clustering showed that the whole-brain FC profiles of the OMPFC subregions separate them in two networks, a medial and orbital one, which overlap with the organization proposed by Barbas and Pandya (J Comp Neurol 286:353-375, 1989) and Ongür and Price (Cereb Cortex 10:206-219, 2000). We conclude that in vivo resting-state FC can delineate reliable and neuroanatomically plausible subdivisions that agree with established cytoarchitectonic trends and connectivity patterns, while other subdivisions do not show the same consistency across data sets and studies

Glyceraldehyde-3-Phosphate Dehydrogenase–Monoamine Oxidase B-Mediated Cell Death-Induced by Ethanol is Prevented by Rasagiline and 1-R-Aminoindan

KlimafolgenSturmfluten in den Ästuaren von Elbe, Jade-Weser und Ems können bereits heute sowohl große Schäden verursachen als auch das Leben der Bewohner dieser Küstengebiete gefährden. Zur Entwicklung geeigneter Anpassungsstrategien an die Folgen des Klimawandels ist es nötig, sowohl die heutige Situation zu verstehen, als auch mögliche Zukünfte unter Klimaänderungsbedingungen zu analysieren. Sturmfluten in den Ästuaren werden sowohl durch die Gezeitendynamik und den Windstau in der Deutschen Bucht als auch durch die Topographie des Ästuares, den Oberwasserzufluss in das Ästuar oder den Wind über dem Ästuar geprägt. In einer vorausgehenden Sensitivitätsstudie werden Szenarien untersucht, die zentrale Elemente einer möglichen Zukunft wie z. B. ein Meeresspiegelanstieg in der Nordsee oder eine Zunahme des Oberwasserzuflusses in die Ästuare berücksichtigen und deren Einfluss auf den Sturmflutscheitelwasserstand analysieren. Der Einsatz hydrodynamisch - numerischer Modelle ermöglicht es, den Einfluss der genannten Prozesse auf den Wasserstandsverlauf bei Sturmflut jeweils einzeln zu untersuchen. Auf der Grundlage dieser Sensitivitätsstudie können durch Sturmfluten gefährdete Gebiete entlang der Ästuare identifiziert und Anpassungsoptionen entwickelt werden. In der vorliegenden Studie wird die Wirksamkeit von Anpassungsoptionen betrachtet. So wird z. B. die Schutzfunktion von Einengungsmaßnahmen oder Sturmflutsperrwerken in den Mündungsgebieten der Ästuare bei durch den Klimawandel veränderten Wasserständen der Nordsee oder den veränderten Abflüssen aus dem Binnenbereich untersucht. Die Ergebnisse dieser Untersuchung ermöglichen es, die Vor- und Nachteile der Anpassungsoptionen für z. B. die Metropolregion Hamburg oder die Wasserstraßen in den Ästuaren von Elbe, Jade-Weser und Ems abzuwägen und Anpassungsstrategien zu entwickeln, die den durch einen Klimawandel entstehenden Problemen entgegenwirken

Transcriptome analysis of post-mortem brain tissue reveals up-regulation of the complement cascade in a subgroup of schizophrenia patients

Schizophrenia is a genetically complex neuropsychiatric disorder with largely unresolved mechanisms of pathology. Identification of genes and pathways associated with schizophrenia is important for understanding the development, progression and treatment of schizophrenia. In this study, pathways associated with schizophrenia were explored at the level of gene expression. The study included post-mortem brain tissue samples from 68 schizophrenia patients and 44 age and sex-matched control subjects. Whole transcriptome poly-A selected paired-end RNA sequencing was performed on tissue from the prefrontal cortex and orbitofrontal cortex. RNA expression differences were detected between case and control individuals, focusing both on single genes and pathways. The results were validated with RT-qPCR. Significant differential expression between patient and controls groups was found for 71 genes. Gene ontology analysis of differentially expressed genes revealed an up-regulation of multiple genes in immune response among the patients (corrected p-value = 0.004). Several genes in the category belong to the complement system, including C1R, C1S, C7, FCN3, SERPING1, C4A and CFI. The increased complement expression is primarily driven by a subgroup of patients with increased expression of immune/inflammatory response genes, pointing to important differences in disease etiology within the patient group. Weighted gene co-expression network analysis highlighted networks associated with both synaptic transmission and activation of the immune response. Our results demonstrate the importance of immune-related pathways in schizophrenia and provide evidence for elevated expression of the complement cascade as an important pathway in schizophrenia pathology.