Associated Members

Our research focus is to investigate how specific, goal-directed behaviors are determined at the level of single neurons and neural circuits in the vertebrate visual system. The aim is to obtain a quantitative understanding of how sensory information is encoded in the visual system downstream of the retina, and how brain areas between the eye and the motor system process sensory signals and compute command signals that allow the animal to orient and steer in response to sensory cues. The group uses the zebrafish as a model organism, which has the essential features of the vertebrate nervous system and precise, visually guided behaviors. Optophysiological methods are developed to monitor the distribution of neuronal signals in the intact larval brain during processing of visual stimuli. In addition, activity of single neurons is probed with electrophysiology in vivo to understand how salient features of a complex stimulus are encoded in single neuron activity at the level of individual spikes and synaptic potentials. Complementarily, the repertoire of motor behaviors in response to specific visual stimuli is analyzed using video- and high-speed video recordings.
In recent work, we could show that in the developing retino-tectal projection of young Xenopus tadpoles, visually driven Ca²⁺ signals are topographically organized at the sub-cellular, dendritic scale. Functional in vivo Ca²⁺ imaging revealed that the sensitivity of dendritic Ca²⁺ signals to stimulus location in visual space is correlated with their anatomical position within the dendritic tree of individual neurons. This topographic distribution of local dendritic Ca²⁺ signals may both impact the elaboration of neural connectivity and control dendrite-specific synaptic plasticity.

Die Forschungsgruppe „Neural Circuits and Behavior" untersucht die neuronalen Grundlagen zielgerichteter Verhaltensweisen im visuellen System des Wirbeltieres. Insbesondere sollen Mechanismen der Informationsverarbeitung in spezifischen neuronalen Schaltkreisen im Zentralnervensystem des Zebrabärblings aufgeklärt werden. Visuelle Reize werden durch die Retina und nachgeschaltete visuelle Zentren im Mittel- und Rautenhirn der Larve verarbeitet, die daraufhin Motorbefehle an Schaltkreise im Rückenmark der Larve ausgeben, die wiederum die Rekrutierung der Schwanzmuskulatur steuern. Die Kodierung von visuellen Reizen erfolgt in Form elektrischer Aktivität und molekularer Signaturen in bestimmten Neuronen-Gruppen, die vermutlich für die Klassifizierung und Interpretation der Reizumgebung verantwortlich sind und letztlich die Entscheidung über das auszuführende Bewegungsmuster treffen.
Wir nutzen elektro- und optophysiologische Messtechniken, um die Verteilung und Ausbreitung elektrischer Signale in Zellverbänden im ZNS der Larve zu untersuchen. Die Kombination von patch-clamp und extrazellulärer Ableitungen in Verbindung mit Zweiphotonen-Fluoreszenzmikroskopie erlaubt es, die Funktion einzelner Neurone als Elemente eines weitverzweigten Nervenzellnetzwerkes zu studieren. Darüberhinaus werden visuell gesteuerte Bewegungsmuster der Larve mit Video- und Hochgeschwindigkeitskameras aufgezeichnet, um die grundlegenden Komponenten der Schwimmbewegung im Verhältnis zu vorgeschalteter neuronaler Aktivität analysieren zu können.

Bollmann, J. H. and Engert. F. (2009). Sub-cellular topography of visually driven dendritic activity in the vertebrate visual system. Neuron. 61 (6): 895-905.

Orger, M.B., Kampff, A.R., Severi, K.E., Bollmann, J.H. and Engert, F. (2008). Control of visually guided behavior by distinct populations of spinal projection neurons. Nat. Neurosci. 11 (3):327-333.

Bollmann, J. H. and Sakmann, B. (2005). Control of synaptic strength and timing by the release-site Ca2+ signal. Nat. Neurosci. 8: 426-434.

Sätzler, K., Söhl, L. F., Bollmann, J. H., Borst, J. G. G., Frotscher, M., Sakmann, B. and Lübke, J. H. (2002). Three-dimensional reconstruction of a calyx of Held and its postsynaptic principal neuron in the medial nucleus of the trapezoid body. J. Neurosci. 22:10567-10579.
Bollmann, J. H., Sakmann, B. and Borst, J. G. G. (2000). Calcium sensitivity of glutamate release in a calyx-type terminal. Science. 289:953-957

Johann Bollmann

Research Group Neural Circuits and Behavior
Max-Planck-Institute for Medical Research
Jahnstrasse 29
69120 Heidelberg
Germany

Phone.: +49-6221-486-282
Fax.: +49-6221-486-325
Email: johann.bollmann(at)mpimf-heidelberg.mpg.de

The mechanisms controlling the generation of cell diversity in the nervous system belong to the major unsolved problems in developmental biology. In Drosophila, neurons are arranged in stereotyped patterns with remarkable differences between segments, which makes the fruit fly an attractive model to examine the mechanisms of nervous system diversification at the tissue, cell and molecular level. In order to understand how regional differences are generated during nervous system development, it is necessary to elucidate the underlying regulatory circuits. Hox proteins represent one important class of transcriptional regulators involved in the diversification of neurons along the anterior-posterior (A/P) axis. Despite of this fact, it is still largely unknown how Hox proteins execute their neuronal functions on a cellular and molecular level. We have identified a large number of neuronal Hox downstream genes by microarray experiments and have used computational tools to identify neuronal Hox response elements. Using these valuable datasets, we plan on addressing the role of Hox proteins during diversification of the nervous system on a mechanistic level.

Die Mechanismen, die der Erzeugung von Zelldiversität im Nervensystem dienen, gehören zu einem der ungelösten Probleme in der Entwicklungsbiologie. In dem Modellorganismsus Drosophila sind individuelle Neuronen in einem stereotypen, aber segmental teilweise stark unterschiedlichen Muster angeordnet, was die Fruchtfliege zu einem attraktiven System macht, die Mechanismen der Nervensystem-Differenzierung auf der Ebene individueller Zellen zu untersuchen. Um die Entstehung dieser Unterschiede zu verstehen, ist es notwendig, die regulatorischen Netzwerke der zugrundeliegenden Musterbildungsprozesse während der Nervensystem-Entwicklung aufzuklären. Hox-Gene repräsentieren eine wichtige Klasse von Schlüssel-Regulatoren für die Diversifizierung des Nervensystems entlang der anterior-posterioren (A/P) Körperachse. Trotz dieses Wissens ist es immer noch größtenteils unklar, wie Hox-Gene ihre Funktion im Nervensystem auf zellulärer und molekularer Ebene ausüben. Wir haben nun eine große Anzahl an neuronalen Hox Zielgenen mittels eines Microarray Experiments und viele neuronale Hox regulatorische Elemente mittels einer bioinformatischen Vorhersage identifiziert, was uns nun erlaubt, die Funktion von Hox-Genen während der Diversifizierung des Nervensystems aufzuklären.

Fuchs, A. L., Hunczek, A., Bezdan, D., Schaefer, M. and Lohmann I. Dfd-dependent function and regulation of the robo gene leak in Drosophila. (in preparation)
Bezdan, D., Schaefer, M., Henz, R. S. and Lohmann I. Combinatorial logic of Hox target gene regulation in Drosophila. (in preparation)
Stöbe, P., Stein, M. S., Habring-Müller, A., Fuchs, A. L., Hueber, S. D., Wu, H. and Lohmann I. Combinatorial regulation of the Drosophila Hox target gene reaper. (in submission process)
Lohmann, I. (2006) Hox genes: realising the importance of realisators. Curr Biol 16: R988-R989.
Lohmann, I. (2003) Dissecting the regulation of the Drosophila cell death activator reaper. Gene Expr Patterns 3: 159-163.
Lohmann, I., McGinnis, N., Bodmer, M. and McGinnis, W. (2002) The Drosophila Hox gene Deformed sculpts head morphology via direct regulation of the apoptosis activator reaper. Cell 23: 457-466.
Lohmann, I. and McGinnis, W. (2002) Hox genes: it's all a matter of context. Curr Biol 12: R514-R516.

Ingrid Lohmann

Heidelberg Institute of Zoology
Im Neuenheimer Feld 230
69120 Heidelberg

Phone: +49-6221-54-51312
Fax: +49-6221-54-51485
Email: ilohmann(at)flydev.org

The goal of this proposed study is to investigate the factors that specify neural lineages using the Zebrafish retina. The best way to understand how extrinsic and intrinsic cues influence the lineage of retinal neurons is to follow the process while it is happening in real time. Following up on our previous studies, we will combine functional studies and in vivo imaging approaches to look at factors that potentially affect the lineage of retinal progenitors (RPs) expressing the transcription factor Ath5. Ath5 is known to be essential for the formation of retinal ganglion cells (RGCs). However, not all Ath5 expressing RPs turn into RGCs. Indeed, our previous in vivo lineage analysis revealed that Ath5-expressing progenitors always divide once, generating one RGC and another retinal cell type. This finding raises the intriguing questions on how Ath5-expressing RPs always generate two post-mitotic daughters that become different from each other, and what factors might affect the fate of the non-RGC daughter cell. We have accumulated evidence pointing to the role of another intrinsic factor, the homeobox transcription factor, BarhL2, which potentially interacts with Ath5 in regulating cell-fate decision of RGC progenitors. We plan to apply gain and loss of function approaches to investigate how BarhL2 affects the fate of retinal cells. Functional studies will be combined with 3D in vivo time-lapse movies of transgenic retinas expressing reporter genes under the control of the ath5 and barhL2 promoters. In particular, using a double transgenic line expressing both transgenes, we will establish the lineage of BarhL2-expressing progenitors with respect to the Ath5-expressing progenitors, and we will analyse how these lineages change when we alter Ath5 and BarhL2 function.

Die Retina im Fisch eignet sich vorzüglich, um Faktoren zu analysieren, die Spezifizierung von Zelltypen beeinflussen. Zwei zellinterne Faktoren in der Retina, Ath5 und Barhl2, wurden in früheren Studien als Zelltyp beeinflussend identifiziert. Ein primäres Ziel unserer Studie ist herauszufinden, welche Rolle Barhl2 in diesem Prozess in lebenden Embryonen insbesondere im Zusammenspiel mit Ath5 in der Retina spielt. Zu diesem Zweck werden vornehmlich in vivo timelapse Analysen der retinalen Entwicklung unter Benutzung (doppelt) transgener Fische, die fluoreszent markierte Ath5 und Barhl2 expremierende Zellen aufweisen, vorgenommen. Diese Studien werden sowohl in unbehandelten als auch in manipulierten Embryonen ausgeführt.

Cayouette, M., Poggi, L., and Harris, W. A. (2006) Lineage in the vertebrate retina. Trends Neurosci 29: 563-570
Zolessi, F. R., Poggi, L., Wilkinson, C. J., Chien, C. B., and Harris, W. A. (2006) Polarization and orientation of retinal ganglion cells in vivo. Neural Develop 1: 2
Poggi, L., Carl, M., Vignali, R., Barsacchi, G., and Wittbrodt, J. (2002) Expression of a medaka (Oryzias latipes) Bar homologue in the differentiating central nervous system and retina. Mech Dev 114: 193-196
Poggi, L., Vitorino, M., Masai, I., and Harris, W. A. (2005) Influences on neural lineage and mode of division in the zebrafish retina in vivo. J Cell Biol 171: 991-999
Poggi, L., Vottari, T., Barsacchi, G., Wittbrodt, J., and Vignali, R. (2004) The homeobox gene Xbh1 cooperates with proneural genes to specify ganglion cell fate within the Xenopus neural retina. Development 131: 2305-2315

Lucia Poggi

Heidelberg Institute of Zoology
University of Heidelberg
Im Neuenheimer Feld 230
69120 Heidelberg

Phone:+49-6221-546494
Fax: +49-6221-545639
Email: Lucia.Poggi(at)zoo.uni-heidelberg.de

The hypothalamus is an evolutionarily ancient integrative center, which orchestrates complex adaptive behaviors that regulate numerous physiological functions including stress responses, food intake, thermoregulation, fluid homeostasis and reproductive behavior. Reflecting the complexity of its function, the hypothalamus is composed of multiple nuclei, each composed of several distinct neuronal cell types that form connections with many parts of the nervous system. Despite their physiological importance, mechanisms that regulate the differentiation of neuronal subtypes in hypothalamus is poorly understood. The zebrafish offers an excellent experimental system to dissect the development of hypothalamus since it shares conserved developmental mechanisms with mammals, yet contains much fewer neurons making it easier to analyze and manipulate these neurons. Using forward genetics approach in zebrafish, we have previously identified a transcription factor, Orthopedia, to be a key regulator of hypothalamic dopaminergic neuronal development (Ryu et al., 2007, Curr. Biol. 17, 873-880). We are continuing to investigate the role of Orthopedia in hypothalamic neuronal development. Furthermore, we are employing forward genetics approach as well as various genomic approaches to identify novel regulators important for the development of several additional hypothalamic neuronal subtypes. We use biochemical analysis, in vivo imaging and embryological manipulation to probe at multiple levels, functions of the identified molecules. Our ultimate aim is a comprehensive mechanistic description of the molecular regulatory network responsible for the generation of distinct hypothalamic neuronal subtypes.

Der Hypothalamus spielt eine Schlüsselrolle für Überleben und Fortpflanzung eines Organismus - komplexe Verhaltensmuster wie Essensaufnahme, Schlaf, Fortpflanzung oder die Stressantwort werden durch hypothalamische Netzwerke koordiniert und reguliert. Trotz seiner zentralen Bedeutung ist die Entwicklung des Hypothalamus kaum verstanden. Ziel des hier vorgestellten Projektes ist es daher, die Abstammungslinien hypothalamischer Neurone zu untersuchen und zentrale regulatorische Mechanismen zu beschreiben, die die Identität einzelner Zellen bedingen.

Publications since 2005

Loehr, H. B., Ryu, S., and Driever, W. (2008) Zebrafish diencephalic A11 related dopaminergic neurons share a conserved transcriptional network including Arnt2, Sim1 and Otp with neuroendocrine cell lineages. Development. 136(6):1007-17.

Meng, S., Ryu, S., Zhao, B., Zhang, D.Q., Driever, W., McMahon, D.G. (2008) Targeting retinal dopaminergic neurons in tyrosine hydroxylase-driven green fluorescent protein transgenic zebrafish. Mol Vis.14:2475-83.

Filippi, A., Duerr, K., Ryu, S. Willaredt, M., Holzschuh, J., Driever, W. (2007)
Expression and function of nr4a2, lmx1b, and pitx3 in zebrafish dopaminergic andnoradrenergic neuronal development. BMC Dev Biol. 7:135

Ryu, S., Mahler, J., Acampora, D., Holzschuh, J. Erhardt, S., Simeone, A., and Driever,
W. (2007) Orthopedia homeodomain protein is essential for diencephalic dopaminergic neuron development. Current Biology. 17 (10): 873-80.

Brochschmidt, A., Todt, U., Ryu, S., Hoischen, A., Landwehr, C., Birnbaum, S.,
Frenck, W., Radlwimmer, B., Lichter, P., Engels, H., Driever, W., Kubisch, C., Weber
R. G. (2007) Severe mental retardation with breathing abnormalities (Pitt-Hopkins
syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Hum. Mol. Genet. 15;16(12):1488-94.

Ryu, S., Holzschuh, J. Mahler, J. and Driever, W. (2006) Genetic analysis of
Dopaminergic system development in zebrafish. J. Neural. Transm. Suppl. 70: 61-66. Review.

Ryu, S., and Driever, W. (2006) Minichromosome maintenance proteins as markers forproliferation zones during embryogenesis. Cell Cycle. 11:1140-1142. Review.

Chapouton, P., Adolf, B., Leucht, C., Tannhauser, B., Ryu, S., Driever, W., and Bally-
Cuif, L. (2006) her5 expression reveals a pool of neural stem cells in the adult zebrafish midbrain. Development. 133:4293-4303.

Durr, K., Holzschuh, J., Filippi, A., Ettl, A.K., Ryu, S., Shepherd, I.T., and Driever,
W. (2006) Differential roles of transcriptional mediator complex subunits
Crsp34/Med27, Crsp150/Med14, and Trap100/Med24 during zebrafish retinal development. Genetics. 174:693-705.

Ryu, S., Holzschuh, J., Erhardt, S., Ettl, A.K., and Driever, W. (2005) Depletion of
minichromosome maintenance protein 5 in zebrafish retina causes cell-cycle defect and
apoptosis. Proc. Natl. Acad. Sci. USA. 102: 18467-18472.

Soojin Ryu

Max-Planck- Institut für Medizinische Forschung
Jahnstraße 29
69120 Heidelberg

Phone: +49-6221-486210
Fax: +49-6221-486459
Email: soojin.ryu(at)mpimf-heidelberg.mpg.de