@article{HibarAdamsJahanshadetal.2017, author = {Hibar, Derrek P. and Adams, Hieab H.H. and Jahanshad, Neda and Chauhan, Ganesh and Stein, Jason L and Hofer, Edith and Renteria, Miguel E. and Bis, Joshua C. and Arias-Vasquez, Alejandro and Ikram, M. Kamran and Desrivi{\`e}res, Sylvane and Vernooij, Meike W. and Abramovic, Lucija and Alhusaini, Saud and Amin, Najaf and Andersson, Micael and Arfanakis, Konstantinos and Aribisala, Benjamin S. and Armstrong, Nicola J. and Athanasiu, Lavinia and Axelsson, Tomas and Beecham, Ashley H. and Beiser, Alexa and Bernard, Manon and Blanton, Susan H. and Bohlken, Marc M. and Boks, Marco P. and Bralten, Janita and Brickman, Adam M. and Carmichael, Owen}, title = {Novel genetic loci associated with hippocampal volume}, series = {Nature Communications}, volume = {8}, journal = {Nature Communications}, doi = {10.1038/ncomms13624}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-182115}, pages = {12}, year = {2017}, abstract = {The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r\(_g\)=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.}, language = {en} } @phdthesis{Nguyen2023, author = {Nguyen, Tu Anh Thi}, title = {Neural coding of different visual cues in the monarch butterfly sun compass}, doi = {10.25972/OPUS-30380}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303807}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Monarch butterflies are famous for their annual long-distance migration. Decreasing temperatures and reduced daylight induce the migratory state in the autumn generation of monarch butterflies. Not only are they in a reproductive diapause, they also produce fat deposits to be prepared for the upcoming journey: Driven by their instinct to migrate, they depart from their eclosion grounds in the northern regions of the North American continent and start their southern journey to their hibernation spots in Central Mexico. The butterflies cover a distance of up to 4000 km across the United States. In the next spring, the same butterflies invert their preferred heading direction due to seasonal changes and start their northward spring migration. The spring migration is continued by three consecutive butterfly generations, until the animals repopulate the northern regions in North America as non-migratory monarch butterflies. The monarch butterflies' migratory state is genetically and epigenetically regulated, including the directed flight behavior. Therefore, the insect's internal compass system does not only have to encode the butterflies preferred, but also its current heading direction. However, the butterfly's internal heading representation has to be matched to external cues, to avoid departing from its initial flight path and increasing its risk of missing its desired destination. During the migratory flight, visual cues provide the butterflies with reliable orientation information. The butterflies refer to the sun as their main orientation cue. In addition to the sun, the butterflies likely use the polarization pattern of the sky for orientation. The sky compass signals are processed within a region in the brain, termed the central complex (CX). Previous research on the CX neural circuitry of the monarch butterflies demonstrated that tangential central complex neurons (TL) carry the visual input information into the CX and respond to a simulated sun and polarized light. However, whether these cells process additional visual cues like the panoramic skyline is still unknown. Furthermore, little is known about how the migratory state affects visual cue processing. In addition to this, most experiments studying the monarch butterfly CX focused on how neurons process single visual cues. However, how combined visual stimuli are processed in the CX is still unknown. This thesis is investigating the following questions: 1) How does the migratory state affect visual cue processing in the TL cells within the monarch butterfly brain? 2) How are multiple visual cues integrated in the TL cells? 3) How is compass information modulated in the CX? To study these questions, TL neurons from both animal groups (migratory and non-migratory) were electrophysiologically characterized using intracellular recordings while presenting different simulated celestial cues and visual sceneries. I showed that the TL neurons of migratory butterflies are more narrowly tuned to the sun, possibly helping them in keeping a directed flight course during migration. Furthermore, I found that TL cells encode a panoramic skyline, suggesting that the CX network combines celestial and terrestrial information. Experiments with combined celestial stimuli revealed that the TL cells combine both cue information linearly. However, if exposing the animals to a simulated visual scenery containing a panoramic skyline and a simulated sun, the single visual cues are weighted differently. These results indicate that the CX's input region can flexibly adapt to different visual cue conditions. Furthermore, I characterize a previously unknown neuron in the monarch butterfly CX which responds to celestial stimuli and connects the CX with other brain neuropiles. How this cell type affects heading direction encoding has yet to be determined.}, subject = {Monarchfalter}, language = {en} } @article{FeldheimWendLaueretal.2022, author = {Feldheim, Jonas and Wend, David and Lauer, Mara J. and Monoranu, Camelia M. and Glas, Martin and Kleinschnitz, Christoph and Ernestus, Ralf-Ingo and Braunger, Barbara M. and Meybohm, Patrick and Hagemann, Carsten and Burek, Malgorzata}, title = {Protocadherin Gamma C3 (PCDHGC3) is strongly expressed in glioblastoma and its high expression is associated with longer progression-free survival of patients}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {15}, issn = {1422-0067}, doi = {10.3390/ijms23158101}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284433}, year = {2022}, abstract = {Protocadherins (PCDHs) belong to the cadherin superfamily and represent the largest subgroup of calcium-dependent adhesion molecules. In the genome, most PCDHs are arranged in three clusters, α, β, and γ on chromosome 5q31. PCDHs are highly expressed in the central nervous system (CNS). Several PCDHs have tumor suppressor functions, but their individual role in primary brain tumors has not yet been elucidated. Here, we examined the mRNA expression of PCDHGC3, a member of the PCDHγ cluster, in non-cancerous brain tissue and in gliomas of different World Health Organization (WHO) grades and correlated it with the clinical data of the patients. We generated a PCDHGC3 knockout U343 cell line and examined its growth rate and migration in a wound healing assay. We showed that PCDHGC3 mRNA and protein were significantly overexpressed in glioma tissue compared to a non-cancerous brain specimen. This could be confirmed in glioma cell lines. High PCDHGC3 mRNA expression correlated with longer progression-free survival (PFS) in glioma patients. PCDHGC3 knockout in U343 resulted in a slower growth rate but a significantly faster migration rate in the wound healing assay and decreased the expression of several genes involved in WNT signaling. PCDHGC3 expression should therefore be further investigated as a PFS-marker in gliomas. However, more studies are needed to elucidate the molecular mechanisms underlying the PCDHGC3 effects.}, language = {en} } @article{SchadtIsraelBeezetal.2023, author = {Schadt, Fabian and Israel, Ina and Beez, Alexandra and Alushi, Kastriot and Weiland, Judith and Ernestus, Ralf-Ingo and Westermaier, Thomas and Samnick, Samuel and Lilla, Nadine}, title = {Analysis of cerebral glucose metabolism following experimental subarachnoid hemorrhage over 7 days}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-022-26183-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300725}, year = {2023}, abstract = {Little is known about changes in brain metabolism following SAH, possibly leading towards secondary brain damage. Despite sustained progress in the last decade, analysis of in vivo acquired data still remains challenging. The present interdisciplinary study uses a semi-automated data analysis tool analyzing imaging data independently from the administrated radiotracer. The uptake of 2-[18F]Fluoro-2-deoxy-glucose ([\(^{18}\)F]FDG) was evaluated in different brain regions in 14 male Sprague-Dawley rats, randomized into two groups: (1) SAH induced by the endovascular filament model and (2) sham operated controls. Serial [\(^{18}\)F]FDG-PET measurements were carried out. Quantitative image analysis was performed by uptake ratio using a self-developed MRI-template based data analysis tool. SAH animals showed significantly higher [\(^{18}\)F]FDG accumulation in gray matter, neocortex and olfactory system as compared to animals of the sham group, while white matter and basal forebrain region showed significant reduced tracer accumulation in SAH animals. All significant metabolic changes were visualized from 3 h, over 24 h (day 1), day 4 and day 7 following SAH/sham operation. This [\(^{18}\)F]FDG-PET study provides important insights into glucose metabolism alterations following SAH—for the first time in different brain regions and up to day 7 during course of disease.}, language = {en} } @article{ThoelkenThammErbacheretal.2019, author = {Th{\"o}lken, Clemens and Thamm, Markus and Erbacher, Christoph and Lechner, Marcus}, title = {Sequence and structural properties of circular RNAs in the brain of nurse and forager honeybees (Apis mellifera)}, series = {BMC Genomics}, volume = {20}, journal = {BMC Genomics}, doi = {10.1186/s12864-018-5402-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241302}, year = {2019}, abstract = {Background The honeybee (Apis mellifera) represents a model organism for social insects displaying behavioral plasticity. This is reflected by an age-dependent task allocation. The most protruding tasks are performed by young nurse bees and older forager bees that take care of the brood inside the hive and collect food from outside the hive, respectively. The molecular mechanism leading to the transition from nurse bees to foragers is currently under intense research. Circular RNAs, however, were not considered in this context so far. As of today, this group of non-coding RNAs was only known to exist in two other insects, Drosophila melanogaster and Bombyx mori. Here we complement the state of circular RNA research with the first characterization in a social insect. Results We identified numerous circular RNAs in the brain of A. mellifera nurse bees and forager bees using RNA-Seq with exonuclease enrichment. Presence and circularity were verified for the most abundant representatives. Back-splicing in honeybee occurs further towards the end of transcripts and in transcripts with a high number of exons. The occurrence of circularized exons is correlated with length and CpG-content of their flanking introns. The latter coincides with increased DNA-methylation in the respective loci. For two prominent circular RNAs the abundance in worker bee brains was quantified in TaqMan assays. In line with previous findings of circular RNAs in Drosophila, circAmrsmep2 accumulates with increasing age of the insect. In contrast, the levels of circAmrad appear age-independent and correlate with the bee's task. Its parental gene is related to amnesia-resistant memory. Conclusions We provide the first characterization of circRNAs in a social insect. Many of the RNAs identified here show homologies to circular RNAs found in Drosophila and Bombyx, indicating that circular RNAs are a common feature among insects. We find that exon circularization is correlated to DNA-methylation at the flanking introns. The levels of circAmrad suggest a task-dependent abundance that is decoupled from age. Moreover, a GO term analysis shows an enrichment of task-related functions. We conclude that circular RNAs could be relevant for task allocation in honeybee and should be investigated further in this context.}, language = {en} } @article{HabensteinSchmittLiessemetal.2021, author = {Habenstein, Jens and Schmitt, Franziska and Liessem, Sander and Ly, Alice and Trede, Dennis and Wegener, Christian and Predel, Reinhard and R{\"o}ssler, Wolfgang and Neupert, Susanne}, title = {Transcriptomic, peptidomic, and mass spectrometry imaging analysis of the brain in the ant Cataglyphis nodus}, series = {Journal of Neurochemistry}, volume = {158}, journal = {Journal of Neurochemistry}, number = {2}, doi = {10.1111/jnc.15346}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239917}, pages = {391 -- 412}, year = {2021}, abstract = {Behavioral flexibility is an important cornerstone for the ecological success of animals. Social Cataglyphis nodus ants with their age-related polyethism characterized by age-related behavioral phenotypes represent a prime example for behavioral flexibility. We propose neuropeptides as powerful candidates for the flexible modulation of age-related behavioral transitions in individual ants. As the neuropeptidome of C. nodus was unknown, we collected a comprehensive peptidomic data set obtained by transcriptome analysis of the ants' central nervous system combined with brain extract analysis by Q-Exactive Orbitrap mass spectrometry (MS) and direct tissue profiling of different regions of the brain by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS. In total, we identified 71 peptides with likely bioactive function, encoded on 49 neuropeptide-, neuropeptide-like, and protein hormone prepropeptide genes, including a novel neuropeptide-like gene (fliktin). We next characterized the spatial distribution of a subset of peptides encoded on 16 precursor proteins with high resolution by MALDI MS imaging (MALDI MSI) on 14 µm brain sections. The accuracy of our MSI data were confirmed by matching the immunostaining patterns for tachykinins with MSI ion images from consecutive brain sections. Our data provide a solid framework for future research into spatially resolved qualitative and quantitative peptidomic changes associated with stage-specific behavioral transitions and the functional role of neuropeptides in Cataglyphis ants.}, language = {en} } @article{Koepsell2020, author = {Koepsell, Hermann}, title = {Glucose transporters in brain in health and disease}, series = {Pfl{\"u}gers Archiv - European Journal of Physiology}, volume = {472}, journal = {Pfl{\"u}gers Archiv - European Journal of Physiology}, issn = {0031-6768}, doi = {10.1007/s00424-020-02441-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232746}, pages = {1299-1343}, year = {2020}, abstract = {Energy demand of neurons in brain that is covered by glucose supply from the blood is ensured by glucose transporters incapillaries and brain cells. In brain, the facilitative diffusion glucose transporters GLUT1-6 and GLUT8, and the Na+-D-glucosecotransporters SGLT1 are expressed. The glucose transporters mediate uptake of D-glucose across the blood-brain barrier anddelivery of D-glucose to astrocytes and neurons. They are critically involved in regulatory adaptations to varying energy demandsin response to differing neuronal activities and glucose supply. In this review, a comprehensive overview about verified andproposed roles of cerebral glucose transporters during health and diseases is presented. Our current knowledge is mainly based onexperiments performed in rodents. First, the functional properties of human glucose transporters expressed in brain and theircerebral locations are described. Thereafter, proposed physiological functions of GLUT1, GLUT2, GLUT3, GLUT4, andSGLT1 for energy supply to neurons, glucose sensing, central regulation of glucohomeostasis, and feeding behavior are compiled, and their roles in learning and memory formation are discussed. In addition, diseases are described in which functionalchanges of cerebral glucose transporters are relevant. These are GLUT1 deficiency syndrome (GLUT1-SD), diabetes mellitus, Alzheimer's disease (AD), stroke, and traumatic brain injury (TBI). GLUT1-SD is caused by defect mutations in GLUT1. Diabetes and AD are associated with changed expression of glucose transporters in brain, and transporter-related energy defi-ciency of neurons may contribute to pathogenesis of AD. Stroke and TBI are associated with changes of glucose transporter expression that influence clinical outcome}, language = {en} } @article{BrumbergSchroeterBlazhenetsetal.2020, author = {Brumberg, Joachim and Schr{\"o}ter, Nils and Blazhenets, Ganna and Frings, Lars and Volkmann, Jens and Lapa, Constantin and Jost, Wolfgang H. and Isaias, Ioannis U. and Meyer, Philipp T.}, title = {Differential diagnosis of parkinsonism: a head-to-head comparison of FDG PET and MIBG scintigraphy}, series = {NPJ Parkinsons Disease}, volume = {6}, journal = {NPJ Parkinsons Disease}, doi = {10.1038/s41531-020-00141-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230675}, year = {2020}, abstract = {[\(^{18}\)F]fluorodeoxyglucose (FDG) PET and [\(^{123}\)I]metaiodobenzylguanidine (MIBG) scintigraphy may contribute to the differential diagnosis of neurodegenerative parkinsonism. To identify the superior method, we retrospectively evaluated 54 patients with suspected neurodegenerative parkinsonism, who were referred for FDG PET and MIBG scintigraphy. Two investigators visually assessed FDG PET scans using an ordinal 6-step score for disease-specific patterns of Lewy body diseases (LBD) or atypical parkinsonism (APS) and assigned the latter to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome. Regions-of-interest analysis on anterior planar MIBG images served to calculate the heart-to-mediastinum ratio. Movement disorder specialists blinded to imaging results established clinical follow-up diagnosis by means of guideline-derived case vignettes. Clinical follow-up (1.7 +/- 2.3 years) revealed the following diagnoses: n = 19 LBD (n = 17 Parkinson's disease [PD], n = 1 PD dementia, and n = 1 dementia with Lewy bodies), n = 31 APS (n = 28 MSA, n = 3 PSP), n = 3 non-neurodegenerative parkinsonism; n = 1 patient could not be diagnosed and was excluded. Receiver operating characteristic analyses for discriminating LBD vs. non-LBD revealed a larger area under the curve for FDG PET than for MIBG scintigraphy at statistical trend level for consensus rating (0.82 vs. 0.69, p = 0.06; significant for investigator \#1: 0.83 vs. 0.69, p = 0.04). The analysis of PD vs. MSA showed a similar difference (0.82 vs. 0.69, p = 0.11; rater \#1: 0.83 vs. 0.69, p = 0.07). Albeit the notable differences in diagnostic performance did not attain statistical significance, the authors consider this finding clinically relevant and suggest that FDG PET, which also allows for subgrouping of APS, should be preferred.}, language = {en} } @article{UeceylerBuchholzKewenigetal.2020, author = {{\"U}{\c{c}}eyler, Nurcan and Buchholz, Hans-Georg and Kewenig, Susanne and Ament, Stephan-Johann and Birklein, Frank and Schreckenberger, Mathias and Sommer, Claudia}, title = {Cortical Binding Potential of Opioid Receptors in Patients With Fibromyalgia Syndrome and Reduced Systemic Interleukin-4 Levels - A Pilot Study}, series = {Frontiers in Neuroscience}, volume = {14}, journal = {Frontiers in Neuroscience}, issn = {1662-453X}, doi = {10.3389/fnins.2020.00512}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204457}, year = {2020}, abstract = {Objective: We investigated cerebral opioid receptor binding potential in patients with fibromyalgia syndrome (FMS) using positron-emission-tomography (PET) and correlated our results with patients' systemic interleukin-4 (IL-4) gene expression. Methods: In this pilot study, seven FMS patients (1 man, 6 women) agreed to participate in experimental PET scans. All patients underwent neurological examination, were investigated with questionnaires for pain, depression, and FMS symptoms. Additionally, blood for IL-4 gene expression analysis was withdrawn at two time points with a median latency of 1.3 years. Patients were investigated in a PET scanner using the opioid receptor ligand F-18-fluoro-ethyl-diprenorphine ([18F]FEDPN) and results were compared with laboratory normative values. Results: Neurological examination was normal in all FMS patients. Reduced opioid receptor binding was found in mid cingulate cortex compared to healthy controls (p < 0.005). Interestingly, three patients with high systemic IL-4 gene expression had increased opioid receptor binding in the fronto-basal cortex compared to those with low IL-4 gene expression (p < 0.005). Conclusion: Our data give further evidence for a reduction in cortical opioid receptor availability in FMS patients as another potential central nervous system contributor to pain in FMS.}, language = {en} } @article{FeldheimKesslerSchmittetal.2020, author = {Feldheim, Jonas and Kessler, Almuth F. and Schmitt, Dominik and Salvador, Ellaine and Monoranu, Camelia M. and Feldheim, Julia J. and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten}, title = {Ribosomal Protein S27/Metallopanstimulin-1 (RPS27) in Glioma — A New Disease Biomarker?}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {5}, issn = {2072-6694}, doi = {10.3390/cancers12051085}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203648}, year = {2020}, abstract = {Despite its significant overexpression in several malignant neoplasms, the expression of RPS27 in the central nervous system (CNS) is widely unknown. We identified the cell types expressing RPS27 in the CNS under normal and disease conditions. We acquired specimens of healthy brain (NB), adult pilocytic astrocytoma (PA) World Health Organization (WHO) grade I, anaplastic PA WHO grade III, gliomas WHO grade II/III with or without isocitrate dehydrogenase (IDH) mutation, and glioblastoma multiforme (GBM). RPS27 protein expression was examined by immunohistochemistry and double-fluorescence staining and its mRNA expression quantified by RT-PCR. Patients' clinical and tumor characteristics were collected retrospectively. RPS27 protein was specifically expressed in tumor cells and neurons, but not in healthy astrocytes. In tumor tissue, most macrophages were positive, while this was rarely the case in inflamed tissue. Compared to NB, RPS27 mRNA was in mean 6.2- and 8.8-fold enhanced in gliomas WHO grade II/III with (p < 0.01) and without IDH mutation (p = 0.01), respectively. GBM displayed a 4.6-fold increased mean expression (p = 0.02). Although RPS27 expression levels did not affect the patients' survival, their association with tumor cells and tumor-associated macrophages provides a rationale for a future investigation of a potential function during gliomagenesis and tumor immune response.}, language = {en} } @article{RoesslerSpaetheGroh2017, author = {R{\"o}ssler, Wolfgang and Spaethe, Johannes and Groh, Claudia}, title = {Pitfalls of using confocal-microscopy based automated quantification of synaptic complexes in honeybee mushroom bodies (response to Peng and Yang 2016)}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {9786}, doi = {10.1038/s41598-017-09967-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170451}, year = {2017}, abstract = {A recent study by Peng and Yang in Scientific Reports using confocal-microscopy based automated quantification of anti-synapsin labeled microglomeruli in the mushroom bodies of honeybee brains reports potentially incorrect numbers of microglomerular densities. Whereas several previous studies using visually supervised or automated counts from confocal images and analyses of serial 3D electron-microscopy data reported consistent numbers of synaptic complexes per volume, Peng and Yang revealed extremely low numbers differing by a factor of 18 or more from those obtained in visually supervised counts, and by a factor 22-180 from numbers in two other studies using automated counts. This extreme discrepancy is especially disturbing as close comparison of raw confocal images of anti-synapsin labeled whole-mount brain preparations are highly similar across these studies. We conclude that these discrepancies may reside in potential misapplication of confocal imaging followed by erroneous use of automated image analysis software. Consequently, the reported microglomerular densities during maturation and after manipulation by insecticides require validation by application of appropriate confocal imaging methods and analyses tools that rely on skilled observers. We suggest several improvements towards more reliable or standardized automated or semi-automated synapse counts in whole mount preparations of insect brains.}, language = {en} } @article{WilleSchuemannKreutzeretal.2015, author = {Wille, Michael and Sch{\"u}mann, Antje and Kreutzer, Michael and Glocker, Michael O and Wree, Andreas and Mutzbauer, Grit and Schmitt, Oliver}, title = {The proteome profiles of the olfactory bulb of juvenile, adult and aged rats - an ontogenetic study}, series = {Proteome Science}, volume = {13}, journal = {Proteome Science}, number = {8}, doi = {10.1186/s12953-014-0058-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144073}, year = {2015}, abstract = {Background: In this study, we searched for proteins that change their expression in the olfactory bulb (oB) of rats during ontogenesis. Up to now, protein expression differences in the developing animal are not fully understood. Our investigation focused on the question whether specific proteins exist which are only expressed during different development stages. This might lead to a better characterization of the microenvironment and to a better determination of factors and candidates that influence the differentiation of neuronal progenitor cells. Results: After analyzing the samples by two-dimensional polyacrylamide gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), it could be shown that the number of expressed proteins differs depending on the developmental stages. Especially members of the functional classes, like proteins of biosynthesis, regulatory proteins and structural proteins, show the highest differential expression in the stages of development analyzed. Conclusion: In this study, quantitative changes in the expression of proteins in the oB at different developmental stages (postnatal days (P) 7, 90 and 637) could be observed. Furthermore, the expression of many proteins was found at specific developmental stages. It was possible to identify these proteins which are involved in processes like support of cell migration and differentiation.}, language = {en} } @article{WilleSchuemannWreeetal.2015, author = {Wille, Michael and Sch{\"u}mann, Antje and Wree, Andreas and Kreutzer, Michael and Glocker, Michael O. and Mutzbauer, Grit and Schmitt, Oliver}, title = {The Proteome Profiles of the Cerebellum of Juvenile, Adult and Aged Rats-An Ontogenetic Study}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms160921454}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151347}, pages = {21454 -- 21485}, year = {2015}, abstract = {In this study, we searched for proteins that change their expression in the cerebellum (Ce) of rats during ontogenesis. This study focuses on the question of whether specific proteins exist which are differentially expressed with regard to postnatal stages of development. A better characterization of the microenvironment and its development may result from these study findings. A differential two-dimensional polyacrylamide gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis of the samples revealed that the number of proteins of the functional classes differed depending on the developmental stages. Especially members of the functional classes of biosynthesis, regulatory proteins, chaperones and structural proteins show the highest differential expression within the analyzed stages of development. Therefore, members of these functional protein groups seem to be involved in the development and differentiation of the Ce within the analyzed development stages. In this study, changes in the expression of proteins in the Ce at different postnatal developmental stages (postnatal days (P) 7, 90, and 637) could be observed. At the same time, an identification of proteins which are involved in cell migration and differentiation was possible. Especially proteins involved in processes of the biosynthesis and regulation, the dynamic organization of the cytoskeleton as well as chaperones showed a high amount of differentially expressed proteins between the analyzed dates.}, language = {en} } @article{GrussWieserSchweinbergeretal.2012, author = {Gruss, L. Forest and Wieser, Matthias J. and Schweinberger, Stefan R. and Keil, Andreas}, title = {Face-evoked steady-state visual potentials: effects of presentation rate and face inversion}, series = {Frontiers in Human Neuroscience}, volume = {6}, journal = {Frontiers in Human Neuroscience}, number = {316}, doi = {10.3389/fnhum.2012.00316}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134399}, year = {2012}, abstract = {Face processing can be explored using electrophysiological methods. Research with event-related potentials has demonstrated the so-called face inversion effect, in which the N170 component is enhanced in amplitude and latency to inverted, compared to upright, faces. The present study explored the extent to which repetitive lower-level visual cortical engagement, reflected in flicker steady-state visual evoked potentials (ssVEPs), shows similar amplitude enhancement to face inversion. We also asked if inversion-related ssVEP modulation would be dependent on the stimulation rate at which upright and inverted faces were flickered. To this end, multiple tagging frequencies were used (5, 10, 15, and 20 Hz) across two studies (n=21, n=18). Results showed that amplitude enhancement of the ssVEP for inverted faces was found solely at higher stimulation frequencies (15 and 20 Hz). By contrast, lower frequency ssVEPs did not show this inversion effect. These findings suggest that stimulation frequency affects the sensitivity of ssVEPs to face inversion.}, language = {en} } @article{ReuterSparwasserHuenigetal.2012, author = {Reuter, Dajana and Sparwasser, Tim and H{\"u}nig, Thomas and Schneider-Schaulies, J{\"u}rgen}, title = {Foxp3\(^+\) Regulatory T Cells Control Persistence of Viral CNS Infection}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {3}, doi = {10.1371/journal.pone.0033989}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134248}, pages = {e33989}, year = {2012}, abstract = {We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified) mice and recombinant measles virus (MV). Using this model infection we investigated the role of regulatory T cells (Tregs) as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4\(^+\) CD25\(^+\) Foxp3\(^+\) Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8\(^+\) T cells predominantly recognising the H-2D(b)-presented viral hemagglutinin epitope MV-H22-30 (RIVINREHL) were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p.) application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT) in DEREG (depletion of regulatory T cells)-mice induced an increase of virus-specific CD8\(^+\) effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.}, language = {en} } @article{BrandtZimmermannKaufholdetal.2012, author = {Brandt, Alexander U. and Zimmermann, Hanna and Kaufhold, Falko and Promesberger, Julia and Schippling, Sven and Finis, David and Aktas, Orhan and Geis, Christian and Ringelstein, Marius and Ringelstein, E. Bernd and Hartung, Hans-Peter and Paul, Friedemann and Kleffner, Ilka and D{\"o}rr, Jan}, title = {Patterns of Retinal Damage Facilitate Differential Diagnosis between Susac Syndrome and MS}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {6}, doi = {10.1371/journal.pone.0038741}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134013}, pages = {e38741}, year = {2012}, abstract = {Susac syndrome, a rare but probably underdiagnosed combination of encephalopathy, hearing loss, and visual deficits due to branch retinal artery occlusion of unknown aetiology has to be considered as differential diagnosis in various conditions. Particularly, differentiation from multiple sclerosis is often challenging since both clinical presentation and diagnostic findings may overlap. Optical coherence tomography is a powerful and easy to perform diagnostic tool to analyse the morphological integrity of retinal structures and is increasingly established to depict characteristic patterns of retinal pathology in multiple sclerosis. Against this background we hypothesised that differential patterns of retinal pathology facilitate a reliable differentiation between Susac syndrome and multiple sclerosis. In this multicenter cross-sectional observational study optical coherence tomography was performed in nine patients with a definite diagnosis of Susac syndrome. Data were compared with age-, sex-, and disease duration-matched relapsing remitting multiple sclerosis patients with and without a history of optic neuritis, and with healthy controls. Using generalised estimating equation models, Susac patients showed a significant reduction in either or both retinal nerve fibre layer thickness and total macular volume in comparison to both healthy controls and relapsing remitting multiple sclerosis patients. However, in contrast to the multiple sclerosis patients this reduction was not distributed over the entire scanning area but showed a distinct sectorial loss especially in the macular measurements. We therefore conclude that patients with Susac syndrome show distinct abnormalities in optical coherence tomography in comparison to multiple sclerosis patients. These findings recommend optical coherence tomography as a promising tool for differentiating Susac syndrome from MS.}, language = {en} } @article{ElKeredySchleyerKoenigetal.2012, author = {El-Keredy, Amira and Schleyer, Michael and K{\"o}nig, Christian and Ekim, Aslihan and Gerber, Bertram}, title = {Behavioural Analyses of Quinine Processing in Choice, Feeding and Learning of Larval Drosophila}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {7}, doi = {10.1371/journal.pone.0040525}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130811}, pages = {e40525}, year = {2012}, abstract = {Gustatory stimuli can support both immediate reflexive behaviour, such as choice and feeding, and can drive internal reinforcement in associative learning. For larval Drosophila, we here provide a first systematic behavioural analysis of these functions with respect to quinine as a study case of a substance which humans report as "tasting bitter". We describe the dose-effect functions for these different kinds of behaviour and find that a half-maximal effect of quinine to suppress feeding needs substantially higher quinine concentrations (2.0 mM) than is the case for internal reinforcement (0.6 mM). Interestingly, in previous studies (Niewalda et al. 2008, Schipanski et al 2008) we had found the reverse for sodium chloride and fructose/sucrose, such that dose-effect functions for those tastants were shifted towards lower concentrations for feeding as compared to reinforcement, arguing that the differences in dose-effect function between these behaviours do not reflect artefacts of the types of assay used. The current results regarding quinine thus provide a starting point to investigate how the gustatory system is organized on the cellular and/or molecular level to result in different behavioural tuning curves towards a bitter tastant.}, language = {en} } @article{BugaScholzKumaretal.2012, author = {Buga, Ana-Maria and Scholz, Claus J{\"u}rgen and Kumar, Senthil and Herndon, James G. and Alexandru, Dragos and Cojocaru, Gabriel Radu and Dandekar, Thomas and Popa-Wagner, Aurel}, title = {Identification of New Therapeutic Targets by Genome-Wide Analysis of Gene Expression in the Ipsilateral Cortex of Aged Rats after Stroke}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {12}, doi = {10.1371/journal.pone.0050985}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130657}, pages = {e50985}, year = {2012}, abstract = {Background: Because most human stroke victims are elderly, studies of experimental stroke in the aged rather than the young rat model may be optimal for identifying clinically relevant cellular responses, as well for pinpointing beneficial interventions. Methodology/Principal Findings: We employed the Affymetrix platform to analyze the whole-gene transcriptome following temporary ligation of the middle cerebral artery in aged and young rats. The correspondence, heat map, and dendrogram analyses independently suggest a differential, age-group-specific behaviour of major gene clusters after stroke. Overall, the pattern of gene expression strongly suggests that the response of the aged rat brain is qualitatively rather than quantitatively different from the young, i.e. the total number of regulated genes is comparable in the two age groups, but the aged rats had great difficulty in mounting a timely response to stroke. Our study indicates that four genes related to neuropathic syndrome, stress, anxiety disorders and depression (Acvr1c, Cort, Htr2b and Pnoc) may have impaired response to stroke in aged rats. New therapeutic options in aged rats may also include Calcrl, Cyp11b1, Prcp, Cebpa, Cfd, Gpnmb, Fcgr2b, Fcgr3a, Tnfrsf26, Adam 17 and Mmp14. An unexpected target is the enzyme 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 in aged rats, a key enzyme in the cholesterol synthesis pathway. Post-stroke axonal growth was compromised in both age groups. Conclusion/Significance: We suggest that a multi-stage, multimodal treatment in aged animals may be more likely to produce positive results. Such a therapeutic approach should be focused on tissue restoration but should also address other aspects of patient post-stroke therapy such as neuropathic syndrome, stress, anxiety disorders, depression, neurotransmission and blood pressure.}, language = {en} } @article{AmmarThahoulyHanaueretal.2015, author = {Ammar, Mohamed Raafet and Thahouly, Tamou and Hanauer, Andr{\´e} and Stegner, David and Nieswandt, Bernhard and Vitale, Nicolas}, title = {PLD1 participates in BDNF-induced signalling in cortical neurons}, series = {Scientific Reports}, volume = {5}, journal = {Scientific Reports}, number = {14778}, doi = {10.1038/srep14778}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139962}, year = {2015}, abstract = {The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1\(^{-/-}\) neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons.}, language = {en} } @article{LudwigSaemannAlexanderetal.2013, author = {Ludwig, K. U. and S{\"a}mann, P. and Alexander, M. and Becker, J. and Bruder, J. and Moll, K. and Spieler, D. and Czisch, M. and Warnke, A. and Docherty, S. J. and Davis, O. S. P. and Plomin, R. and N{\"o}then, M. M. and Landerl, K. and M{\"u}ller-Myhsok, B. and Hoffmann, P. and Schumacher, J. and Schulte-K{\"o}rne, G. and Czamara, D.}, title = {A common variant in Myosin-18B contributes to mathematical abilities in children with dyslexia and intraparietal sulcus variability in adults}, series = {Translational Psychiatry}, volume = {3}, journal = {Translational Psychiatry}, number = {e229}, doi = {10.1038/tp.2012.148}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131513}, year = {2013}, abstract = {The ability to perform mathematical tasks is required in everyday life. Although heritability estimates suggest a genetic contribution, no previous study has conclusively identified a genetic risk variant for mathematical performance. Research has shown that the prevalence of mathematical disabilities is increased in children with dyslexia. We therefore correlated genome-wide data of 200 German children with spelling disability, with available quantitative data on mathematic ability. Replication of the top findings in additional dyslexia samples revealed that rs133885 was a genome-wide significant marker for mathematical abilities\((P_{comb}=7.71 x 10^{-10}, n=699)\), with an effect size of 4.87\%. This association was also found in a sample from the general population (P=0.048, n=1080), albeit with a lower effect size. The identified variant encodes an amino-acid substitution in MYO18B, a protein with as yet unknown functions in the brain. As areas of the parietal cortex, in particular the intraparietal sulcus (IPS), are involved in numerical processing in humans, we investigated whether rs133885 was associated with IPS morphology using structural magnetic resonance imaging data from 79 neuropsychiatrically healthy adults. Carriers of the MYO18B risk-genotype displayed a significantly lower depth of the right IPS. This validates the identified association between rs133885 and mathematical disability at the level of a specific intermediate phenotype.}, language = {en} } @article{HahnDreslerPykaetal.2013, author = {Hahn, Tim and Dresler, Thomas and Pyka, Martin and Notebaert, Karolien and Fallgatter, Andreas J.}, title = {Local Synchronization of Resting-State Dynamics Encodes Gray's Trait Anxiety}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0058336}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131057}, pages = {e58336}, year = {2013}, abstract = {The Behavioral Inhibition System (BIS) as defined within the Reinforcement Sensitivity Theory (RST) modulates reactions to stimuli indicating aversive events. Gray's trait Anxiety determines the extent to which stimuli activate the BIS. While studies have identified the amygdala-septo-hippocampal circuit as the key-neural substrate of this system in recent years and measures of resting-state dynamics such as randomness and local synchronization of spontaneous BOLD fluctuations have recently been linked to personality traits, the relation between resting-state dynamics and the BIS remains unexplored. In the present study, we thus examined the local synchronization of spontaneous fMRI BOLD fluctuations as measured by Regional Homogeneity (ReHo) in the hippocampus and the amygdala in twenty-seven healthy subjects. Correlation analyses showed that Gray's trait Anxiety was significantly associated with mean ReHo in both the amygdala and the hippocampus. Specifically, Gray's trait Anxiety explained 23\% and 17\% of resting-state ReHo variance in the left amygdala and the left hippocampus, respectively. In summary, we found individual differences in Gray's trait Anxiety to be associated with ReHo in areas previously associated with BIS functioning. Specifically, higher ReHo in resting-state neural dynamics corresponded to lower sensitivity to punishment scores both in the amygdala and the hippocampus. These findings corroborate and extend recent findings relating resting-state dynamics and personality while providing first evidence linking properties of resting-state fluctuations to Gray's BIS.}, language = {en} } @article{HenningsKohliCzamaraetal.2013, author = {Hennings, Johannes M. and Kohli, Martin A. and Czamara, Darina and Giese, Maria and Eckert, Anne and Wolf, Christiane and Heck, Angela and Domschke, Katharina and Arolt, Volker and Baune, Bernhard T. and Horstmann, Sonja and Br{\"u}ckl, Tanja and Klengel, Torsten and Menke, Andreas and M{\"u}ller-Myhsok, Bertram and Ising, Marcus and Uhr, Manfred and Lucae, Susanne}, title = {Possible Associations of NTRK2 Polymorphisms with Antidepressant Treatment Outcome: Findings from an Extended Tag SNP Approach}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0065636}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130924}, pages = {e64947}, year = {2013}, abstract = {Background: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment. Methods: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples. Results: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (\(P_{corr}\) = .018, \(P_{corr}\) = .015 and \(P_{corr}\) = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients. Conclusions/Limitations: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies.}, language = {en} } @article{DavisYuKeenanetal.2013, author = {Davis, Lea K. and Yu, Dongmei and Keenan, Clare L. and Gamazon, Eric R. and Konkashbaev, Anuar I. and Derks, Eske M. and Neale, Benjamin M. and Yang, Jian and Lee, S. Hong and Evans, Patrick and Barr, Cathy L. and Bellodi, Laura and Benarroch, Fortu and Berrio, Gabriel Bedoya and Bienvenu, Oscar J. and Bloch, Michael H. and Blom, Rianne M. and Bruun, Ruth D. and Budman, Cathy L. and Camarena, Beatriz and Campbell, Desmond and Cappi, Carolina and Cardona Silgado, Julio C. and Cath, Danielle C. and Cavallini, Maria C. and Chavira, Denise A. and Chouinard, Sylvian and Conti, David V. and Cook, Edwin H. and Coric, Vladimir and Cullen, Bernadette A. and Deforce, Dieter and Delorme, Richard and Dion, Yves and Edlund, Christopher K. and Egberts, Karin and Falkai, Peter and Fernandez, Thomas V. and Gallagher, Patience J. and Garrido, Helena and Geller, Daniel and Girard, Simon L. and Grabe, Hans J. and Grados, Marco A. and Greenberg, Benjamin D. and Gross-Tsur, Varda and Haddad, Stephen and Heiman, Gary A. and Hemmings, Sian M. J. and Hounie, Ana G. and Illmann, Cornelia and Jankovic, Joseph and Jenike, Micheal A. and Kennedy, James L. and King, Robert A. and Kremeyer, Barbara and Kurlan, Roger and Lanzagorta, Nuria and Leboyer, Marion and Leckman, James F. and Lennertz, Leonhard and Liu, Chunyu and Lochner, Christine and Lowe, Thomas L. and Macciardi, Fabio and McCracken, James T. and McGrath, Lauren M. and Restrepo, Sandra C. Mesa and Moessner, Rainald and Morgan, Jubel and Muller, Heike and Murphy, Dennis L. and Naarden, Allan L. and Ochoa, William Cornejo and Ophoff, Roel A. and Osiecki, Lisa and Pakstis, Andrew J. and Pato, Michele T. and Pato, Carlos N. and Piacentini, John and Pittenger, Christopher and Pollak, Yehunda and Rauch, Scott L. and Renner, Tobias J. and Reus, Victor I. and Richter, Margaret A. and Riddle, Mark A. and Robertson, Mary M. and Romero, Roxana and Ros{\`a}rio, Maria C. and Rosenberg, David and Rouleau, Guy A. and Ruhrmann, Stephan and Ruiz-Linares, Andreas and Sampaio, Aline S. and Samuels, Jack and Sandor, Paul and Sheppard, Broke and Singer, Harvey S. and Smit, Jan H. and Stein, Dan J. and Strengman, E. and Tischfield, Jay A. and Valencia Duarte, Ana V. and Vallada, Homero and Van Nieuwerburgh, Flip and Veenstra-VanderWeele, Jeremy and Walitza, Susanne and Wang, Ying and Wendland, Jens R. and Westenberg, Herman G. M. and Shugart, Yin Yao and Miguel, Euripedes C. and McMahon, William and Wagner, Michael and Nicolini, Humberto and Posthuma, Danielle and Hanna, Gregory L. and Heutink, Peter and Denys, Damiaan and Arnold, Paul D. and Oostra, Ben A. and Nestadt, Gerald and Freimer, Nelson B. and Pauls, David L. and Wray, Naomi R. and Stewart, S. Evelyn and Mathews, Carol A. and Knowles, James A. and Cox, Nancy J. and Scharf, Jeremiah M.}, title = {Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture}, series = {PLoS Genetics}, volume = {9}, journal = {PLoS Genetics}, number = {10}, issn = {1553-7390}, doi = {10.1371/journal.pgen.1003864}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127377}, pages = {e1003864}, year = {2013}, abstract = {The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5\% accounted for 21\% of the TS heritability and 0\% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.}, language = {en} } @article{MeuleKueblerBlechert2013, author = {Meule, Adrian and K{\"u}bler, Andrea and Blechert, Jens}, title = {Time course of electrocortical food-cue responses during cognitive regulation of craving}, series = {Frontiers in Psychology}, volume = {4}, journal = {Frontiers in Psychology}, number = {669}, issn = {1664-1078}, doi = {10.3389/fpsyg.2013.00669}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122566}, year = {2013}, abstract = {In our current obesogenic environment, exposure to visual food-cues can easily lead to craving and overeating because short-term, pleasurable effects of food intake dominate over the anticipated long-term adverse effects such as weight gain and associated health problems. Here we contrasted these two conditions during food-cue presentation while acquiring event-related potentials (ERPs) and subjective craving ratings. Female participants (n = 25) were presented with either high-calorie (HC) or low-calorie (LC) food images under instructions to imagine either immediate (NOW) or long-term effects (LATER) of consumption. On subjective ratings for HC foods, the LATER perspective reduced cravings as compared to the NOW perspective. For LC foods, by contrast, craving increased under the LATER perspective. Early ERPs (occipital N1, 150-200 ms) were sensitive to food type but not to perspective. Late ERPs (late positive potential, LPP, 350-550 ms) were larger in the HC-LATER condition than in all other conditions, possibly indicating that a cognitive focus on negative long-term consequences induced negative arousal. This enhancement for HC-LATER attenuated to the level of the LC conditions during the later slow wave (550-3000 ms), but amplitude in the HC-NOW condition was larger than in all other conditions, possibly due to a delayed appetitive response. Across all conditions, LPP amplitudes were positively correlated with self-reported emotional eating. In sum, results reveal that regulation effects are secondary to an early attentional analysis of food type and dynamically evolve over time. Adopting a long-term perspective on eating might promote a healthier food choice across a range of food types.}, language = {en} } @article{DempfleHerpertzDahlmannTimmesfeldetal.2013, author = {Dempfle, Astrid and Herpertz-Dahlmann, Beate and Timmesfeld, Nina and Schwarte, Reinhild and Egberts, Karin M. and Pfeiffer, Ernst and Fleischhaker, Christian and Wewetzer, Christoph and B{\"u}hren, Katharina}, title = {Predictors of the resumption of menses in adolescent anorexia nervosa}, series = {BMC Psychiatry}, volume = {13}, journal = {BMC Psychiatry}, number = {308}, doi = {10.1186/1471-244X-13-308}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122106}, year = {2013}, abstract = {Background: The resumption of menses is an important indicator of recovery in anorexia nervosa (AN). Patients with early-onset AN are at particularly great risk of suffering from the long-term physical and psychological consequences of persistent gonadal dysfunction. However, the clinical variables that predict the recovery of menstrual function during weight gain in AN remain poorly understood. The aim of this study was to investigate the impact of several clinical parameters on the resumption of menses in first-onset adolescent AN in a large, well-characterized, homogenous sample that was followed-up for 12 months. Methods: A total of 172 female adolescent patients with first-onset AN according to DSM-IV criteria were recruited for inclusion in a randomized, multi-center, German clinical trial. Menstrual status and clinical variables (i.e., premorbid body mass index (BMI), age at onset, duration of illness, duration of hospital treatment, achievement of target weight at discharge, and BMI) were assessed at the time of admission to or discharge from hospital treatment and at a 12-month follow-up. Based on German reference data, we calculated the percentage of expected body weight (\%EBW), BMI percentile, and BMI standard deviation score (BMI-SDS) for all time points to investigate the relationship between different weight measurements and resumption of menses. Results: Forty-seven percent of the patients spontaneously began menstruating during the follow-up period. \%EBW at the 12-month follow-up was strongly correlated with the resumption of menses. The absence of menarche before admission, a higher premorbid BMI, discharge below target weight, and a longer duration of hospital treatment were the most relevant prognostic factors for continued amenorrhea. Conclusions: The recovery of menstrual function in adolescent patients with AN should be a major treatment goal to prevent severe long-term physical and psychological sequelae. Patients with premenarchal onset of AN are at particular risk for protracted amenorrhea despite weight rehabilitation. Reaching and maintaining a target weight between the 15th and 20th BMI percentile is favorable for the resumption of menses within 12 months. Whether patients with a higher premorbid BMI may benefit from a higher target weight needs to be investigated in further studies.}, language = {en} } @article{BurekSalvadorFoerster2012, author = {Burek, Malgorzata and Salvador, Ellaine and F{\"o}rster, Carola Y.}, title = {Generation of an Immortalized Murine Brain Microvascular Endothelial Cell Line as an In Vitro Blood Brain Barrier Model}, series = {Journal of Visualized Experiments}, volume = {66}, journal = {Journal of Visualized Experiments}, number = {e4022}, doi = {10.3791/4022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126702}, year = {2012}, abstract = {Epithelial and endothelial cells (EC) are building paracellular barriers which protect the tissue from the external and internal environment. The blood-brain barrier (BBB) consisting of EC, astrocyte end-feet, pericytes and the basal membrane is responsible for the protection and homeostasis of the brain parenchyma. In vitro BBB models are common tools to study the structure and function of the BBB at the cellular level. A considerable number of different in vitro BBB models have been established for research in different laboratories to date. Usually, the cells are obtained from bovine, porcine, rat or mouse brain tissue (discussed in detail in the review by Wilhelm et al. 1). Human tissue samples are available only in a restricted number of laboratories or companies 2,3. While primary cell preparations are time consuming and the EC cultures can differ from batch to batch, the establishment of immortalized EC lines is the focus of scientific interest. Here, we present a method for establishing an immortalized brain microvascular EC line from neonatal mouse brain. We describe the procedure step-by-step listing the reagents and solutions used. The method established by our lab allows the isolation of a homogenous immortalized endothelial cell line within four to five weeks. The brain microvascular endothelial cell lines termed cEND 4 (from cerebral cortex) and cerebEND 5 (from cerebellar cortex), were isolated according to this procedure in the F{\"o}rster laboratory and have been effectively used for explanation of different physiological and pathological processes at the BBB. Using cEND and cerebEND we have demonstrated that these cells respond to glucocorticoid- 4,6-9 and estrogen-treatment 10 as well as to pro-infammatory mediators, such as TNFalpha 5,8. Moreover, we have studied the pathology of multiple sclerosis 11 and hypoxia 12,13 on the EC-level. The cEND and cerebEND lines can be considered as a good tool for studying the structure and function of the BBB, cellular responses of ECs to different stimuli or interaction of the EC with lymphocytes or cancer cells.}, language = {en} } @article{SchecklmannGianiTupaketal.2014, author = {Schecklmann, Martin and Giani, Anette and Tupak, Sara and Langguth, Berthold and Raab, Vincent and Polak, Thomas and Varallyay, Csanad and Harnisch, Wilma and Herrmann, Martin J. and Fallgatter, Andreas J.}, title = {Functional Near-Infrared Spectroscopy to Probe State- and Trait-Like Conditions in Chronic Tinnitus: A Proof-of-Principle Study}, series = {Neural Plasticity}, journal = {Neural Plasticity}, number = {894203}, issn = {1687-5443}, doi = {10.1155/2014/894203}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117801}, pages = {8}, year = {2014}, abstract = {Objective. Several neuroscience tools showed the involvement of auditory cortex in chronic tinnitus. In this proof-of-principle study we probed the capability of functional near-infrared spectroscopy (fNIRS) for the measurement of brain oxygenation in auditory cortex in dependence from chronic tinnitus and from intervention with transcranial magnetic stimulation. Methods. Twenty-three patients received continuous theta burst stimulation over the left primary auditory cortex in a randomized sham-controlled neuronavigated trial (verum = 12; placebo = 11). Before and after treatment, sound-evoked brain oxygenation in temporal areas was measured with fNIRS. Brain oxygenation was measured once in healthy controls (n = 12). Results. Sound-evoked activity in right temporal areas was increased in the patients in contrast to healthy controls. Left-sided temporal activity under the stimulated area changed over the course of the trial; high baseline oxygenation was reduced and vice versa. Conclusions. By demonstrating that rTMS interacts with auditory evoked brain activity, our results confirm earlier electrophysiological findings and indicate the sensitivity of fNIRS for detecting rTMS induced changes in brain activity. Moreover, our findings of trait-and state-related oxygenation changes indicate the potential of fNIRS for the investigation of tinnitus pathophysiology and treatment response.}, language = {en} } @article{PfeifferGuglielmiDombertJablonkaetal.2014, author = {Pfeiffer-Guglielmi, Brigitte and Dombert, Benjamin and Jablonka, Sibylle and Hausherr, Vanessa and van Thriel, Christoph and Schobel, Nicole and Jansen, Ralf-Peter}, title = {Axonal and dendritic localization of mRNAs for glycogen-metabolizing enzymes in cultured rodent neurons}, series = {BMC Neuroscience}, volume = {15}, journal = {BMC Neuroscience}, number = {70}, issn = {1471-2202}, doi = {10.1186/1471-2202-15-70}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116049}, year = {2014}, abstract = {Background: Localization of mRNAs encoding cytoskeletal or signaling proteins to neuronal processes is known to contribute to axon growth, synaptic differentiation and plasticity. In addition, a still increasing spectrum of mRNAs has been demonstrated to be localized under different conditions and developing stages thus reflecting a highly regulated mechanism and a role of mRNA localization in a broad range of cellular processes. Results: Applying fluorescence in-situ-hybridization with specific riboprobes on cultured neurons and nervous tissue sections, we investigated whether the mRNAs for two metabolic enzymes, namely glycogen synthase (GS) and glycogen phosphorylase (GP), the key enzymes of glycogen metabolism, may also be targeted to neuronal processes. If it were so, this might contribute to clarify the so far enigmatic role of neuronal glycogen. We found that the mRNAs for both enzymes are localized to axonal and dendritic processes in cultured lumbar spinal motoneurons, but not in cultured trigeminal neurons. In cultured cortical neurons which do not store glycogen but nevertheless express glycogen synthase, the GS mRNA is also subject to axonal and dendritic localization. In spinal motoneurons and trigeminal neurons in situ, however, the mRNAs could only be demonstrated in the neuronal somata but not in the nerves. Conclusions: We could demonstrate that the mRNAs for major enzymes of neural energy metabolism can be localized to neuronal processes. The heterogeneous pattern of mRNA localization in different culture types and developmental stages stresses that mRNA localization is a versatile mechanism for the fine-tuning of cellular events. Our findings suggest that mRNA localization for enzymes of glycogen metabolism could allow adaptation to spatial and temporal energy demands in neuronal events like growth, repair and synaptic transmission.}, language = {en} } @article{BlechertMeuleBuschetal.2014, author = {Blechert, Jens and Meule, Adrian and Busch, Niko A. and Ohla, Kathrin}, title = {Food-pics: an image database for experimental research on eating and appetite}, series = {Frontiers in Psychology}, volume = {5}, journal = {Frontiers in Psychology}, issn = {1664-1078}, doi = {10.3389/fpsyg.2014.00617}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115987}, pages = {617}, year = {2014}, abstract = {Our current environment is characterized by the omnipresence of food cues. The sight and smell of real foods, but also graphically depictions of appetizing foods, can guide our eating behavior, for example, by eliciting food craving and influencing food choice. The relevance of visual food cues on human information processing has been demonstrated by a growing body of studies employing food images across the disciplines of psychology, medicine, and neuroscience. However, currently used food image sets vary considerably across laboratories and image characteristics (contrast, brightness, etc.) and food composition (calories, macronutrients, etc.) are often unspecified. These factors might have contributed to some of the inconsistencies of this research. To remedy this, we developed food-pics, a picture database comprising 568 food images and 315 non-food images along with detailed meta-data. A total of N = 1988 individuals with large variance in age and weight from German speaking countries and North America provided normative ratings of valence, arousal, palatability, desire to eat, recognizability and visual complexity. Furthermore, data on macronutrients (g), energy density (kcal), and physical image characteristics (color composition, contrast, brightness, size, complexity) are provided. The food-pics image database is freely available under the creative commons license with the hope that the set will facilitate standardization and comparability across studies and advance experimental research on the determinants of eating behavior. Read F}, language = {en} } @article{StellamannsUppaluriHochstetteretal.2014, author = {Stellamanns, Eric and Uppaluri, Sravanti and Hochstetter, Axel and Heddergott, Niko and Engstler, Markus and Pfohl, Thomas}, title = {Optical trapping reveals propulsion forces, power generation and motility efficiency of the unicellular parasites Trypanosoma brucei brucei}, series = {Scientific Reports}, volume = {4}, journal = {Scientific Reports}, number = {6515}, issn = {2045-2322}, doi = {10.1038/srep06515}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115348}, year = {2014}, abstract = {Unicellular parasites have developed sophisticated swimming mechanisms to survive in a wide range of environments. Cell motility of African trypanosomes, parasites responsible for fatal illness in humans and animals, is crucial both in the insect vector and the mammalian host. Using millisecond-scale imaging in a microfluidics platform along with a custom made optical trap, we are able to confine single cells to study trypanosome motility. From the trapping characteristics of the cells, we determine the propulsion force generated by cells with a single flagellum as well as of dividing trypanosomes with two fully developed flagella. Estimates of the dissipative energy and the power generation of single cells obtained from the motility patterns of the trypanosomes within the optical trap indicate that specific motility characteristics, in addition to locomotion, may be required for antibody clearance. Introducing a steerable second optical trap we could further measure the force, which is generated at the flagellar tip. Differences in the cellular structure of the trypanosomes are correlated with the trapping and motility characteristics and in consequence with their propulsion force, dissipative energy and power generation.}, language = {en} } @article{YongJacobowitzBaroneetal.1994, author = {Yong, Liu and Jacobowitz, David M. and Barone, Frank and McCarron, Richard and Spatz, Maria and Feuerstein, Giora and Hallenbeck, John M. and Sir{\´e}n, Anna-Leena}, title = {Quantitation of perivascular monocyte / macrophages around cerebral blood vessels of hypertensive and aged rats}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86800}, year = {1994}, abstract = {The numbers of monocytes and macrophages in the walls of cerebral blood vessels were counted on perfusion-fixed frozen brain sections (16 JLffi) of spontaneously hypertensive rats (SHR), stroke-prone SHR (SHR-SP), normotensive Wistar-Kyoto (WKY) rats, and young (16-week-old) and old (2-year-old) normotensive Sprague-Dawley rats (SD-l6w and SD-2y, respectively) using monoclonal antiborlies against rat macrophages (ED2). The staining was visualized with fluoresceinlabeled second antiborlies. The ED2-specific staining in brain sections was restricted to macrophages in a perivascular location. The number of perivascular cells per square millimeter of high-power field was significantly greater in SHR-SP (8.6 ± 2.1; n = 4) and SHR (6. 7 ± 0.9; n = 6) than in normotensive WKY (4.0 ± 0.5; n = 6; p <0.01). The number of perivascular macrophages was also greater in SD-2y (7.5 ± 2.7; n = 9) than in SD-l6w (2.9 ± 1.8; n = 8; p < 0.01). No ED2 staining was found in the resident microglia or in the endothelial cells, which were identified by double staining with rhodamine-labeled anti-factor VIII-related antigen antiborlies. The results suggest that the stroke risk factors hypertension and advanced age are associated with increased subendothelial accumulation of monocytes and macrophages. This accumulation could increase the tendency for the endothelium to convert from an anticoagulant to a procoagulant surface in response to mediators released from these subendothelial cells.}, subject = {Willebrand-Faktor}, language = {en} } @phdthesis{Elfeber2005, author = {Elfeber, Katrin}, title = {Immunologischer Nachweis des Natrium-Glukose-Kotransporters SGLT1 im mikrovaskul{\"a}ren System des Gehirns, des Herzens und des Skelettmuskels}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-19221}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {Glukose ist einer der Hauptenergielieferanten der S{\"a}ugetierzellen. Aus diesem Grund wird die Glukoseaufnahme durch erleichterte Diffusion durch die GLUT (SLC2) Familie, sowie durch die Familie der sekund{\"a}r aktiven Transporter SGLT (SLC5A) gesichert. In dieser Arbeit wurde ein polyklonaler Antik{\"o}rper gegen SGLT1 aus Kaninchen hergestellt. Dieser Antik{\"o}rper wurde f{\"u}r die Innunhistologie sowie f{\"u}r Western blots eingesetzt. Man sah eine Anf{\"a}rbung von B{\"u}rstensaummembranen an D{\"u}nndarm- und Nierentubulusepithelzellen, aber in diesen Geweben nicht an Mikrogef{\"a}ßen. Dar{\"u}berhinaus konnten wir SGLT1 an der basolateralen Membran von Speicheldr{\"u}senazini sehen, auch hier konnten wir SGLT1 in den Kapillaren nicht sehen. {\"U}berraschenderweise konnte SGLT1 in der Blut-Hirn-Schranke nachgewiesen werden. Auch konnte man die Lokalisation von SGLT1 in den Kapillaren des Herzens und des Skelettmuskels zeigen. Die physiologische und pathophysiologische Bedeutung dieser Lokalisationen liegt noch im Unklaren.}, language = {de} } @phdthesis{Mai2005, author = {Mai, Marion}, title = {Mutationsanalyse der Gene Connexin 36 (CX36) und Tyrosinkinase 3 (TYRO3) als Kandidatengene f{\"u}r periodische Katatonie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-18046}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {Das humane Chromosom 15 wurde bereits im Zusammenhang mit anderen Erkrankungen wie dem Marfan Syndrom und der Tay Sachs Erkrankung erw{\"a}hnt. F{\"u}r deren Genese wurden auf dem Chromosom gelegene Gene verantwortlich gemacht (Richard et al. 1994). Aufbauend auf den Vorarbeiten der W{\"u}rzburger Arbeitsgruppe (St{\"o}ber et al. 2000, 2002; Meyer et al. 2002) wurden auf Chromosom 15 anhand der Lokalisation, der Funktion und dem Vorhandensein im Zentralnervensystem die Gene Cx36 und TYRO3 f{\"u}r die Mutationsanalyse ausgew{\"a}hlt, um sie nach der Methode von Sanger (Sanger et al. 1977) zu sequenzieren. Sowohl Cx36 als auch TYRO3 spielen eine zentrale Rolle in der Entwicklung und Zellinteraktion im ZNS. Es w{\"a}re denkbar, daß ein Defekt w{\"a}hrend der Synaptogenese im ZNS an der Krankheitsentstehung beteiligt ist, ebenso wie eine unzureichende Ausbildung von Gap junctions, an denen Cx36 maßgeblich beteiligt ist. Die Patienten-DNA wurde aus Blutproben von Probanden mit periodischer Katatonie gewonnen. Diese wurden aus der Familie 11 der bereits erw{\"a}hnten Studie rekrutiert, die in drei Generationen von der Erkrankung betroffen ist und zehn gesunde, sowie 7 kranke Mitglieder z{\"a}hlt. Die Proben wurden zusammen mit solchen von gesunden Kontrollpersonen vergleichend sequenziert und auf {\"U}bereinstimmung mit den Eintr{\"a}gen der GenBank {\"u}berpr{\"u}ft mit dem Ziel, Mutationen zu finden, die zu einem Defekt im Protein f{\"u}hren und zur Auspr{\"a}gung der Krankheit beitragen, bzw. die Gene als Kandidaten auszuschließen.}, language = {de} } @phdthesis{Grimm2003, author = {Grimm, Oliver}, title = {Mutationsanalyse des Gens f{\"u}r das Zelladh{\"a}sionsmolek{\"u}l CELSR1bei famili{\"a}rer katatoner Schizophrenie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-9207}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2003}, abstract = {In einer k{\"u}rzlich durchgef{\"u}hrten Kopplungsanalyse der periodischen Katatonie wurden zwei Genlo­ci auf Chromosom 15 und auf Chromosom 22 identifiziert. F{\"u}r den Genlocus auf Chro­mosom 22p13.3 wurde ein LOD-Score von 1,85 (p=0,0018) ermittelt. Bei einer Durchsicht der in der fragli­chen Region auf Chromosom 22 lokalisierten Gene unter Ber{\"u}cksichtigung ihrer Funkti­on, erschien CELSR1 als eines der vielversprechendsten Gene, nicht zuletzt, da es relativ selektiv im Nervensys­tem exprimiert wird. CELSR1 ist ein zur Gruppe der Cadherine geh{\"o}rendes Zellad­h{\"a}sionsmolek{\"u}l. Cadherine spielen eine wichtige Rolle bei der Entwicklung des Gehirns, da sie eine Art Zell­sortiermechanismus darstellen, der die Bildung spezifischer Hirnnuclei durch Zella­greggation erm{\"o}glicht. Dar{\"u}ber hinaus sind sie an der synaptischen Plastizit{\"a}t, wie sie bei neuro­nalen Lernvor­g{\"a}ngen vorkommt, beteiligt [Huntley, (2002); Skaper, (2001)]. CELSR1 bildet in­nerhalb der Cadhe­rine eine eigene Subgruppe. Seine Funktion scheint zum einen in der fr{\"u}hen Embryonalentwicklung zu liegen, zum anderen ist das Drosophila-Ortholog Flamingo einer der wichtigsten Modulatoren des Dendritenwachstums. Dementsprechend erscheint CELSR1 als in­teressanter Kandidat f{\"u}r Schizo­phrenien, bei denen sowohl St{\"o}rungen in der Embryogenese des Gehirns, als auch eine Dysregulati­on der synaptischen Plastizit{\"a}t diskutiert wird. CELSR1 wurde in einer mutmaßlichen Promotorregion, dem Exonbereich, Exon/Intron-{\"U}ber­g{\"a}ngen und einem polymorphen Intron auf Mutationen untersucht. DNA-Proben von zwei der erkrankten Familienmitgliedern und drei Kontrollen wurden sequenziert und die so erhaltene Se­quenz mittels eines Online-Analyseprogramms verifiziert. Dabei wurden 18 Allelvarianten, 12 stumme Transi­tionen, f{\"u}nf missense-Mutationen und eine Insertion entdeckt, die aber in keiner der Patienten­proben exklusiv auftrat. Mit grosser Wahrscheinlichkeit enth{\"a}lt CELSR1 keine krank­heitsverursachende Mutation Die gefundenen Polymorphismen stellen eine interessante Ausgangsbasis f{\"u}r Assoziationsstudien dar.}, language = {de} }