@article{SchaeferVogelVillmann2012,
  author    = {Schaefer, Natscha and Vogel, Nicolas and Villmann, Carmen},
  title     = {Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?},
  series = {Frontiers in Molecular Neuroscience},
  volume    = {5},
  journal   = {Frontiers in Molecular Neuroscience},
  number    = {98},
  doi       = {10.3389/fnmol.2012.00098},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123839},
  year      = {2012},
  abstract  = {Defects in glycinergic inhibition result in a complex neuromotor disorder in humans known as hyperekplexia (OMIM 149400) with similar phenotypes in rodents characterized by an exaggerated startle reflex and hypertonia. Analogous to genetic defects in humans single point mutations, microdeletions, or insertions in the Glra1 gene but also in the Glrb gene underlie the pathology in mice. The mutations either localized in the (spasmodic, oscillator, cincinnati, Nmf11) or the (spastic) subunit of the glycine receptor (GlyR) are much less tolerated in mice than in humans, leaving the question for the existence of different regulatory elements of the pathomechanisms in humans and rodents. In addition to the spontaneous mutations, new insights into understanding of the regulatory pathways in hyperekplexia or glycine encephalopathy arose from the constantly increasing number of knock-out as well as knock-in mutants of GlyRs. Over the last five years, various efforts using in vivo whole cell recordings provided a detailed analysis of the kinetic parameters underlying glycinergic dysfunction. Presynaptic compensation as well as postsynaptic compensatory mechanisms in these mice by other GlyR subunits or GABA(A) receptors, and the role of extra-synaptic GlyRs is still a matter of debate. A recent study on the mouse mutant oscillator displayed a novel aspect for compensation of functionality by complementation of receptor domains that fold independently. This review focuses on defects in glycinergic neurotransmission in mice discussed with the background of human hyperekplexia en route to strategies of compensation.},
  language  = {en}
}
@phdthesis{Rebhan2010,
  author    = {Rebhan, Benjamin},
  title     = {Untersuchung des Blutdrucks und der Endothelfunktion ETB-Rezeptor-defizienter M{\"a}use unter Salz-angereicherter Di{\"a}t},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-51972},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {ETB-Rezeptoren nehmen innerhalb der endothelialen Regulationsprozesse eine zentrale Rolle ein. In der vorliegenden Arbeit wurde der Frage nachgegangen, welchen Einfluss eine Salzbelastung auf den Blutdruck und die vaskul{\"a}re Funktion von ETB-Rezeptor-Knockout-M{\"a}usen hat. In diesem Zusammenhang wurden m{\"a}nnliche ETB-Rezeptor-Knockout-M{\"a}use parallel mit Wildtyp-Kontroll-M{\"a}usen 15 Tage lang mit Standard- bzw. salzreichem Futter gehalten. Der systolische Blutdruck wurde ebenfalls dokumentiert. Nach 15 Tagen wurde den narkotisierten Tieren die Aorta descendens entnommen. An isolierten Aortenringen wurden in der Organkammer die Endothel-abh{\"a}ngige und -unabh{\"a}ngige vaskul{\"a}re Funktion untersucht. Die ETB-Rezeptor defizienten M{\"a}use bleiben - unter einer Haltung mit Standardfutter - normotensiv. Eine Hypertonie entwickeln die Tiere erst bei Verabreichung von salzreichem Futter. Die Endothel-abh{\"a}ngige Gef{\"a}ßfunktion ist jedoch nicht nur bei den hypertensiven Tieren ver{\"a}ndert, sondern bei allen ETB-Rezeptor defizienten M{\"a}usen - unabh{\"a}ngig von Salzgehalt der Nahrung und Blutdruck.},
  subject      = {Hypertonie},
  language  = {de}
}
@phdthesis{Nordbeck2005,
  author    = {Nordbeck, Peter Johann},
  title     = {Untersuchungen an Kreatinkinase-Knockout-M{\"a}usen mittels MR-Tomographie : Kardialer Ph{\"a}notyp und Remodeling nach Myokardinfarkt bei Kreatinkinase-Mangel},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-18075},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {Transgene Tiermodelle erm{\"o}glichen seit einigen Jahren eine gezielte Untersuchung des Einflusses einzelner Gene, und damit auch ihrer entsprechenden Produkte und deren Substrate, auf die Integrit{\"a}t des Organismus. In der vorliegenden Arbeit wurde die Bedeutung der verschiedenen Isoenzyme der Kreatinkinase im Herzen untersucht, indem die kardiale Morphologie und Funktion dreier verschiedener St{\"a}mme von Kreatinkinase-Knockout-M{\"a}usen mit der von Wildtyp-M{\"a}usen verglichen wurde. Der Kreatinkinase wird eine wichtige Rolle im intrazellul{\"a}ren System zur Aufrechterhaltung der Energiehom{\"o}ostase zugeschrieben, beim Menschen gehen verschiedene kardiale Erkrankungen mit Ver{\"a}nderungen des Kreatinkinase-Systems einher. Neben der Bestimmung verschiedener kardialer Parameter von M{\"a}usen mit Knockout der kardialen Isoenzyme der Kreatinkinase wurde gepr{\"u}ft, inwieweit sich ein durch permanente Koronarligatur induzierter chronischer Myokardinfarkt auf die Morphologie und Funktion des Herzens bei Kreatinkinase-Knockout auswirkt. Als Methode kam hierzu die Cine-Fast Low Angle Shot (FLASH)-Magnetresonanzbildgebung zur Anwendung, die eine nicht invasive, pr{\"a}zise Erfassung verschiedener kardialer Parameter in vivo erm{\"o}glicht. Myokardmasse, links- und rechtsventrikul{\"a}re Volumina, Ejektionsfraktion, Herzzeitvolumina, Wanddicken sowie die Infarktgr{\"o}ße bei den infarzierten Kreatinkinase-Knockout-M{\"a}usen konnten erstmalig in vivo bestimmt und mit Wildtyp-M{\"a}usen verglichen werden. Es konnte gezeigt werden, dass im Alter von durchschnittlich 41 Wochen ein Knockout des mitochondrialen Isoenzyms der Kreatinkinase eine deutliche linksventrikul{\"a}re Hypertrophie sowie leichtgradige biventrikul{\"a}re Dilatation verursacht. Bei Knockout der M-Untereinheit der zytosolischen Isoenzyme und dadurch bedingtem Fehlen von CK-MM und CK-MB resultiert lediglich eine geringgradige konzentrische linksventrikul{\"a}re Hypertrophie. Der rechte Ventrikel zeigte bei allen Knockout-M{\"a}usen lediglich geringe Ver{\"a}nderungen im Vergleich mit den Wildtypen. Die Herzfunktion war bei allen Tieren unter Normalbedingungen voll erhalten, Zeichen einer Herzinsuffizienz fanden sich nicht. Vier Wochen nach Infarzierung zeigten sich bei Knockout- und Wildtyp-M{\"a}usen keine signifikanten Unterschiede in Herzmorphologie und Funktion. Die Mortalit{\"a}t nach Infarkt war in beiden Gruppen identisch. Die aus einem Fehlen der mitochondrialen Kreatinkinase resultierenden Defizite des Herzens k{\"o}nnen somit durch Ausbildung einer Hypertrophie kompensiert werden. Im Vergleich mit der mitochondrialen Form kommt den zytosolischen Isoenzymen der Kreatinkinase eine geringere Bedeutung bei der Aufrechterhaltung des Metabolismus und damit auch der Funktion des Herzens zu. Ein kombinierter Knockout sowohl der M-Untereinheit der zytosolischen CK als auch der mitochondrialen CK f{\"u}hrt bez{\"u}glich der Morphologie und Funktion des Herzens zu keiner st{\"a}rkeren Pathologie als bei selektiv mitochondrialem Knockout.},
  language  = {de}
}
@article{KlokeSchreiberBoddenetal.2014,
  author    = {Kloke, Vanessa and Schreiber, Rebecca S. and Bodden, Carina and M{\"o}llers, Julian and Ruhmann, Hanna and Kaiser, Sylvia and Lesch, Klaus-Peter and Sachser, Norbert and Lewejohann, Lars},
  title     = {Hope for the Best or Prepare for the Worst? Towards a Spatial Cognitive Bias Test for Mice},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {8},
  doi       = {10.1371/journal.pone.0105431},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115569},
  pages     = {e105431},
  year      = {2014},
  abstract  = {Cognitive bias, the altered information processing resulting from the background emotional state of an individual, has been suggested as a promising new indicator of animal emotion. Comparable to anxious or depressed humans, animals in a putatively negative emotional state are more likely to judge an ambiguous stimulus as if it predicts a negative event, than those in positive states. The present study aimed to establish a cognitive bias test for mice based on a spatial judgment task and to apply it in a pilot study to serotonin transporter (5-HTT) knockout mice, a well-established mouse model for the study of anxiety- and depression-related behavior. In a first step, we validated that our setup can assess different expectations about the outcome of an ambiguous stimulus: mice having learned to expect something positive within a maze differed significantly in their behavior towards an unfamiliar location than animals having learned to expect something negative. In a second step, the use of spatial location as a discriminatory stimulus was confirmed by showing that mice interpret an ambiguous stimulus depending on its spatial location, with a position exactly midway between a positive and a negative reference point provoking the highest level of ambiguity. Finally, the anxiety- and depression-like phenotype of the 5-HTT knockout mouse model manifested - comparable to human conditions - in a trend for a negatively distorted interpretation of ambiguous information, albeit this effect was not statistically significant. The results suggest that the present cognitive bias test provides a useful basis to study the emotional state in mice, which may not only increase the translational value of animal models in the study of human affective disorders, but which is also a central objective of animal welfare research.},
  language  = {en}
}
@article{HohoffGorjiKaiseretal.2013,
  author    = {Hohoff, Christa and Gorji, Ali and Kaiser, Sylvia and Willscher, Edith and Korsching, Eberhard and Ambr{\´e}e, Oliver and Arolt, Volker and Lesch, Klaus-Peter and Sachser, Norbert and Deckert, J{\"u}rgen and Lewejohann, Lars},
  title     = {Effect of Acute Stressor and Serotonin Transporter Genotype on Amygdala First Wave Transcriptome in Mice},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0058880},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131040},
  pages     = {e58880},
  year      = {2013},
  abstract  = {The most prominent brain region evaluating the significance of external stimuli immediately after their onset is the amygdala. Stimuli evaluated as being stressful actuate a number of physiological processes as an immediate stress response. Variation in the serotonin transporter gene has been associated with increased anxiety- and depression-like behavior, altered stress reactivity and adaptation, and pathophysiology of stress-related disorders. In this study the instant reactions to an acute stressor were measured in a serotonin transporter knockout mouse model. Mice lacking the serotonin transporter were verified to be more anxious than their wild-type conspecifics. Genome-wide gene expression changes in the amygdala were measured after the mice were subjected to control condition or to an acute stressor of one minute exposure to water. The dissection of amygdalae and stabilization of RNA was conducted within nine minutes after the onset of the stressor. This extremely short protocol allowed for analysis of first wave primary response genes, typically induced within five to ten minutes of stimulation, and was performed using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays. RNA profiling revealed a largely new set of differentially expressed primary response genes between the conditions acute stress and control that differed distinctly between wild-type and knockout mice. Consequently, functional categorization and pathway analysis indicated genes related to neuroplasticity and adaptation in wild-types whereas knockouts were characterized by impaired plasticity and genes more related to chronic stress and pathophysiology. Our study therefore disclosed different coping styles dependent on serotonin transporter genotype even directly after the onset of stress and accentuates the role of the serotonergic system in processing stressors and threat in the amygdala. Moreover, several of the first wave primary response genes that we found might provide promising targets for future therapeutic interventions of stress-related disorders also in humans.},
  language  = {en}
}
@phdthesis{Bundschu2005,
  author    = {Bundschu, Karin},
  title     = {Generation and characterization of spred-2 knockout mice},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-14333},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {Spreds are a new Sprouty-related family of membrane-associated proteins inhibiting the MAPK signaling pathway by interacting with Ras and Raf-1. Different studies have already demonstrated the inhibitory function of Spreds in cell culture systems, but the in vivo function of Spreds in the whole organism was still unclear. Therefore, Spred-2 knockout mice were generated using a gene trap approach. The Spred-2 deficiency was verified on RNA and protein levels and the lack of functional Spred-2 protein in mice caused a dwarf phenotype similar to achondroplasia, the most common form of human dwarfism. Spred-2-/- mice showed reduced growth and body weight, they had a shorter tibia length and showed narrower growth plates as compared to wildtype mice. Spred-2 promoter activity and protein expression were detected in chondrocytes, suggesting an important function of Spred-2 in chondrocytes and bone development. Furthermore, stimulation of chondrocytes with different FGF concentrations showed earlier and augmented ERK phosphorylation in Spred-2-/- chondrocytes as compared to Spred-2+/+ chondrocytes. These observations suggest a model, in which loss of Spred-2 inhibits bone growth by inhibiting chondrocyte differentiation through upregulation of the MAPK signaling pathway. An additional observation of Spred-2-/- mice was an increased bleeding phenotype after injuries, whereas the bleeding volume was extremely enlarged and the bleeding time was significantly prolonged. So far, hypertension as cause could be excluded, but to discover the physiological reasons for this phenotype, the different steps of the clotting cascade have to be investigated further. As the Spred-2 promoter activity studies demonstrated a high and specific Spred-2 expression in vascular smooth muscle cells and previous studies showed an interaction of Spreds with RhoA, a key regulator of vascular smooth muscle contraction, the regulation of smooth muscle contractility seems to be a good candidate of this phenomenon. Moreover, Spred-1 and Spred-2 specific antibodies were generated as important tools to study the protein expression patterns in mice. Furthermore, nothing was known about the Spred-2 promoter region and its regulation. Here, a detailed in situ analysis of the physiological promoter activity profile in the gene trapped Spred-2-deficient mouse strain was shown. In these mice, the beta-galactosidase and neomycin fusion gene (\&\#946;-geo) of the gene trap vector was brought under control of the endogenous Spred-2 promoter, giving the opportunity to monitor Spred-2 promoter activity in practically every organ and their corresponding sub-compartments. X-Gal staining of sections of newborn and adult mice revealed 1) a very high Spred-2 promoter activity in neural tissues and different glands; 2) a high activity in intestinal and uterine smooth muscle cells, and kidney; 3) a low activity in heart, testis, lung, and liver; 4) an almost lacking activity in skeletal muscle and spleen, and 5) very interestingly, a very distinct and strong activity in vascular smooth muscle cells. Moreover, comparison of newborn and adult mouse organs revealed a nearly congruent Spred-2 promoter activity. These detailed data provide valuable information for further studies of the physiological functions of Spred-2 in organs showing strong Spred-2 promoter activity, which are in most of these organs still unclear. Finally, gene targeting vectors for Spred-1 and Spred-2 were cloned, to generate ES cells with a floxed exon 2 of the Spred-1 and Spred-2 gene, respectively. Now, these ES cells are valuable tools to establish conditional knockout mice. This is of major interest to investigate the physiological tissue specific functions of Spred-1 and Spred-2, especially if the double knockout mice are not viable.},
  subject      = {Spred Protein},
  language  = {en}
}
@article{BoddenRichterSchreiberetal.2015,
  author    = {Bodden, Carina and Richter, S. Helene and Schreiber, Rebecca S. and Kloke, Vanessa and Gerß, Joachim and Palme, Rupert and Lesch, Klaus-Peter and Lewejohann, Lars and Kaiser, Sylvia and Sachser, Norbert},
  title     = {Benefits of adversity?! How life history affects the behavioral profile of mice varying in serotonin transporter genotype},
  series = {Frontiers in Behavioral Neuroscience},
  volume    = {9},
  journal   = {Frontiers in Behavioral Neuroscience},
  number    = {47},
  doi       = {10.3389/fnbeh.2015.00047},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143723},
  year      = {2015},
  abstract  = {Behavioral profiles are influenced by both positive and negative experiences as well as the genetic disposition. Traditionally, accumulating adversity over lifetime is considered to predict increased anxiety like behavior ("allostatic load"). The alternative "mismatch hypothesis" suggests increased levels of anxiety if the early environment differs from the later-life environment. Thus, there is a need for a whole-life history approach to gain a deeper understanding of how behavioral profiles are shaped. The aim of this study was to elucidate the effects of life history on the behavioral profile of mice varying in serotonin transporter (5-HIT) genotype, an established mouse model of increased anxiety-like behavior. For this purpose, mice grew up under either adverse or beneficial conditions during early phases of life. In adulthood, they were further subdivided so as to face a situation that either matched or mismatched the condition experienced so far, resulting in four different life histories. Subsequently, mice were tested for their anxiety-like and exploratory behavior. The main results were: (1) Life history profoundly modulated the behavioral profile. Surprisingly, mice that experienced early beneficial and later escapable adverse conditions showed less anxiety-like and more exploratory behavior compared to mice of other life histories. (2) Genotype significantly influenced the behavioral profile, with homozygous 5-HTT knockout mice displaying highest levels of anxiety-like and lowest levels of exploratory behavior. Our findings concerning life history indicate that the absence of adversity does not necessarily cause lower levels of anxiety than accumulating adversity. Rather, some adversity may be beneficial, particularly when following positive events. Altogether, we conclude that for an understanding of behavioral profiles, it is not sufficient to look at experiences during single phases of life, but the whole life history has to be considered.},
  language  = {en}
}