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ABSTRACT: Behavioral syndromes are suites of two or more behaviors that correlate across environmental contexts. The aggression-boldness syndrome links aggression, boldness, and exploratory activity in a novel environment. Although aggression-boldness has been described in many animals, the mechanism linking its behavioral components is not known. Here we show that mutation of the gene encoding fibroblast growth factor receptor 1a (fgfr1a) simultaneously increases aggression, boldness, and exploration in adult zebrafish. We demonstrate that altered Fgf signaling also results in reduced brain histamine levels in mutants. Pharmacological increase of histamine signaling is sufficient to rescue the behavioral phenotype of fgfr1a mutants. Together, we show that a single genetic locus can underlie the aggression-boldness behavioral syndrome. We also identify one of the neurotransmitter pathways that may mediate clustering of these behaviors.
Journal of Neuroscience 09/2011; 31(39):13796-807. · 7.11 Impact Factor
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ABSTRACT: The balanced proliferation and cell cycle exit of neural progenitors, by generating the appropriate amount of postmitotic progeny at the correct time and in the proper location, is required for the establishment of the highly ordered structure of the adult brain. Little is known about the extrinsic signals regulating these processes, particularly in the midbrain. Fibroblast growth factor (Fgf) 15, the mouse ortholog of FGF19 and member of an atypical Fgf subfamily, is prominently expressed in the dorsolateral midbrain of the midgestational mouse embryo. In the absence of Fgf15, dorsal midbrain neural progenitors fail to exit the cell cycle and to generate the proper amount of postmitotic neurons. We show here that this is due to the altered expression of inhibitory/neurogenic and proneural/neuronal differentiation helix-loop-helix transcription factor (TF) genes. The expression of Id1, Id3, and Hes5 was strongly increased and ectopically expanded, whereas the expression of Ascl1 (Mash1), Neurog1 (Ngn1) and Neurog2 (Ngn2) was strongly decreased and transcription of Neurod1 (NeuroD) was completely abolished in the dorsolateral midbrain of Fgf15(-/-) mice. These abnormalities were not caused by the mis-expression of cell cycle regulatory proteins such as cyclin-dependent kinase inhibitors or retinoblastoma proteins. Furthermore, human FGF19 promotes cell cycle exit of murine dorsal neural progenitors in vitro. Therefore, our data suggest that Fgf15 is a crucial signaling molecule regulating the postmitotic transition of dorsal neural progenitors and thus the initiation and proper progression of dorsal midbrain neurogenesis in the mouse, by controlling the expression of neurogenic and proneural TFs.
Developmental Biology 02/2011; 350(2):496-510. · 4.07 Impact Factor
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Prisca Chapouton,
Paulina Skupien,
Birgit Hesl,
Marion Coolen,
John C Moore,
Romain Madelaine,
Elizabeth Kremmer, Theresa Faus-Kessler,
Patrick Blader,
Nathan D Lawson,
Laure Bally-Cuif
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ABSTRACT: The limited generation of neurons during adulthood is controlled by a balance between quiescence and recruitment of neural stem cells (NSCs). We use here the germinal zone of the zebrafish adult telencephalon to examine how the frequency of NSC divisions is regulated. We show, using several in vivo techniques, that progenitors transit back and forth between the quiescent and dividing state, according to varying levels of Notch activity: Notch induction drives progenitors into quiescence, whereas blocking Notch massively reinitiates NSC division and subsequent commitment toward becoming neurons. Notch activation appears predominantly triggered by newly recruited progenitors onto their neighbors, suggesting an involvement of Notch in a self-limiting mechanism, once neurogenesis is started. These results identify for the first time a lateral inhibition-like mechanism in the context of adult neurogenesis and suggest that the equilibrium between quiescence and neurogenesis in the adult brain is controlled by fluctuations of Notch activity, thereby regulating the amount of adult-born neurons.
Journal of Neuroscience 06/2010; 30(23):7961-74. · 7.11 Impact Factor
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ABSTRACT: In early development, an excess of neurons is generated, of which later about half will be lost by cell death due to a limited supply of trophic support by their respective target areas. However, some of the neurons die when their axons have not yet reached their target, thus suggesting that additional causes of developmental cell death exist. Semaphorin 3A (Sema3A), in addition to its function as a guidance cue and mediator of timing and fasciculation of motor and sensory axon outgrowth, can also induce death of sensory neurons in vitro. However, it is unknown whether Neuropilin-1 (Npn-1), its binding receptor in axon guidance, also mediates the death-inducing activity. We show here that abolished Sema3A-Npn-1 signaling does not influence the cell death patterns of motor or sensory neurons in mouse during the developmental wave of programmed cell death. The number of motor and sensory neurons was unchanged at embryonic day 15.5 when this wave is concluded. Interestingly, the defasciculation of early motor and sensory projections that is observed in the absence of Sema3A or Npn-1 persists to postnatal stages. Thus, Sema3A-Npn-1 signaling plays an important role in the guidance and fasciculation of motor and sensory axons but does not contribute to the developmental elimination of these neurons.
European Journal of Neuroscience 03/2010; 31(7):1164-72. · 3.63 Impact Factor
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ABSTRACT: Wnt/beta-catenin signaling controls the proper development of the mid-/hindbrain region (MHR) and of midbrain dopaminergic (mDA) neurons, but the Frizzled (Fzd) receptors transducing these signals are still unknown. Fzd3 is expressed throughout the mouse anterior neural tube, whereas Fzd6 is restricted to the MHR. We show that the MHR is properly established and mDA neurons develop normally in Fzd6(-/-) mutants, but the number of mDA neurons is initially reduced and recovers at later stages in Fzd3(-/-) embryos. Fzd3(-/-); Fzd6(-/-) double mutants exhibit a severe midbrain morphogenesis defect consisting of collapsed brain ventricles, apparent thickening of the neuroepithelium, focal disruption of the ventricular basal lamina and protrusion of individual cells, and increased proliferation at later stages, despite a normal closure of the anterior neural tube and the rescue of the mDA defect in these embryos. Fzd3 and Fzd6 thus control proper midbrain morphogenesis by a yet unknown mechanism in the mouse.
Developmental Dynamics 10/2009; 239(1):246-60. · 2.54 Impact Factor
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ABSTRACT: Survival and integration of new neurons in the hippocampal circuit are rate-limiting steps in adult hippocampal neurogenesis. Neuronal network activity is a major regulator of these processes, yet little is known about the respective downstream signaling pathways. Here, we investigate the role of cAMP response element-binding protein (CREB) signaling in adult hippocampal neurogenesis. CREB is activated in new granule neurons during a distinct developmental period. Loss of CREB function in a cell-autonomous manner impairs dendritic development, decreases the expression of the neurogenic transcription factor NeuroD and of the neuronal microtubule-associated protein, doublecortin (DCX), and compromises the survival of newborn neurons. In addition, GABA-mediated excitation regulates CREB activation at early developmental stages. Importantly, developmental defects after loss of GABA-mediated excitation can be compensated by enhanced CREB signaling. These results indicate that CREB signaling is a central pathway in adult hippocampal neurogenesis, regulating the development and survival of new hippocampal neurons downstream of GABA-mediated excitation.
Journal of Neuroscience 07/2009; 29(25):7966-77. · 7.11 Impact Factor
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Magdalena Kallnik,
Ralf Elvert,
Nicole Ehrhardt,
Daniela Kissling,
Esther Mahabir,
Gerd Welzl, Theresa Faus-Kessler,
Martin Hrabé de Angelis,
Wolfgang Wurst,
Jörg Schmidt,
Sabine M Hölter
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ABSTRACT: Housing conditions are known to influence laboratory animal behavior. However, it is not known whether housing mice in individually ventilated cages (IVCs) to maintain optimal hygienic conditions alters behavioral baselines established in conventional housing. This issue is important with regard to comparability and reproducibility of data. Therefore, we investigated the impact of IVC housing on emotionality and fear learning in male C3HeB/FeJ (C3H) and C57BL/6J (B6J) mice housed singly either in conventional type II cages with wire bar lids (Conventional), or in IVCs of the same size, but with smooth, untextured lids (IVC classic), thus acoustically attenuated from external stimuli and with limited climbing facilities compared to Conventional. To evaluate the role of climbing, additional mice were kept in IVCs with lids having wire bars ("grid") added to the inner surface (IVC grid). Spontaneous behavior, sensorimotor behavior, and fear learning were measured. IVC housing reduced activity and enhanced anxiety-related behavior in both strains, whereas grooming latency was reduced in B6J only. IVC housing increased Acoustic Startle Response in C3H but not in B6J mice. The "grid" did not compensate for these IVC housing effects. In contrast, B6J mice in IVC grid performed best in fear potentiated startle while B6J mice in IVC classic performed the worst, suggesting that climbing facilities combined with IVC housing facilitate FPS performance in singly-housed B6J males. Our data show that IVC housing can affect behavioral performance and can modulate behavioral parameters in a general and a strain-specific manner, thus having an impact on mouse functional genomics.
Mammalian Genome 04/2007; 18(3):173-86. · 2.89 Impact Factor
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Ilka Schneider,
Werner S Tirsch, Theresa Faus-Kessler,
Lore Becker,
Eva Kling,
Rose-Leah Austin Busse,
Andreas Bender,
Berend Feddersen,
Johannes Tritschler,
Helmut Fuchs,
Valérie Gailus-Durner,
Karl-Hans Englmeier,
Martin Hrabé de Angelis,
Thomas Klopstock
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ABSTRACT: Neurological and psychiatric disorders are among the most common and most serious health problems in developed countries. Transgenic mouse models mimicking human neurological diseases have provided new insights into development and function of the nervous system. One of the prominent goals of the German National Genome Research Network is the understanding of the in vivo function of single genes and the pathophysiological and clinical consequences of respective mutations. The German Mouse Clinic (GMC) offers a high-throughput primary screen of genetically modified mouse models as well as an in-depth analysis in secondary and tertiary screens covering various fields of mouse physiology. Here we describe the phenotyping methods of the Neurological Screen in the GMC, exemplified in the four inbred mouse lines C57BL/6J, C3HeB/FeJ, BALB/cByJ, and 129S2/SvPas. For our primary screen, we generated "standard operating procedures" that were validated between different laboratories. The phenotyping of inbred strains already showed significant differences in various parameters, thus being a prerequisite for the examination of mutant mouse lines.
Journal of Neuroscience Methods 11/2006; 157(1):82-90. · 1.98 Impact Factor
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ABSTRACT: Since 1981, the Bavarian State Office for Environmental Protection (LfU) has been operating a bioindication network of epiphytic mosses Hypnum cupressiforme located on a regular grid with distances 16 km, in order to observe immission-derived metal accumulation in plant material. About 300 specimens are collected yearly (since 1991 every second year) at the end of the growth period, and the concentration of trace metals is determined. In order to gain insight into predominant sources of metal pollution in Bavaria, correlation patterns between Al, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, As, Cd, Sb, Hg, and Pb are analyzed by Principal Component Analysis. Detailed results are presented for the 1984 and 1995 data. At least 80% of the variance can be explained by five components. The following factors are extracted from both data sets by varimax rotation: factor 1 with similar loadings of Al, Ti, V, Cr, Fe, and As; factor 2 representing Cd and Zn; factor 3 with loadings of Sb, Pb, and Cu; factor 4 representing Mn; factor 5 being nearly identical with the Hg variable. For comparison, published region-specific correlation matrices from the 1991 moss survey performed by the German Federal Environmental Agency (UBA) – observing epigeic mosses Pleurozium schreberi – were submitted to Principal Component Analysis. With respect to the first factor, our 1991 results from Bavaria are similar to those from the Southern former GDR, but different from those from Western Germany (including Bavaria). Possible common and specific sources are discussed.
Atmospheric Environment.
