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Dive into the research topics where Manuel Zimmer is active.

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Featured researches published by Manuel Zimmer.


Nature Cell Biology | 2003

EphB–ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion

Manuel Zimmer; Amparo Palmer; Jenny Köhler; Rüdiger Klein

Eph receptors and their membrane-associated ephrin ligands mediate cell–cell repulsion to guide migrating cells and axons. Repulsion requires that the ligand–receptor complex be removed from the cell surface, for example by proteolytic processing of the ephrin ectodomain. Here we show that cell contact-induced EphB–ephrinB complexes are rapidly endocytosed during the retraction of cells and neuronal growth cones. Endocytosis occurs in a bi-directional manner that comprises of full-length receptor and ligand complexes. Endocytosis is sufficient to promote cell detachment and seems necessary for axon withdrawal during growth cone collapse. Here, we show a mechanism for the termination of adhesion and the promotion of cell repulsion after intercellular (trans) interaction between two transmembrane proteins.


Neuron | 2009

Neurons Detect Increases and Decreases in Oxygen Levels Using Distinct Guanylate Cyclases

Manuel Zimmer; Jesse M. Gray; Navin Pokala; Andrew Chang; David S. Karow; Michael A. Marletta; Martin L. Hudson; David B. Morton; Nikos Chronis; Cornelia I. Bargmann

Homeostatic sensory systems detect small deviations in temperature, water balance, pH, and energy needs to regulate adaptive behavior and physiology. In C. elegans, a homeostatic preference for intermediate oxygen (O2) levels requires cGMP signaling through soluble guanylate cyclases (sGCs), proteins that bind gases through an associated heme group. Here we use behavioral analysis, functional imaging, and genetics to show that reciprocal changes in O2 levels are encoded by sensory neurons that express alternative sets of sGCs. URX sensory neurons are activated by increases in O2 levels, and require the sGCs gcy-35 and gcy-36. BAG sensory neurons are activated by decreases in O2 levels, and require the sGCs gcy-31 and gcy-33. The sGCs are instructive O2 sensors, as forced expression of URX sGC genes causes BAG neurons to detect O2 increases. Both sGC expression and cell-intrinsic dynamics contribute to the differential roles of URX and BAG in O2-dependent behaviors.


Neuron | 2009

Quantitative Mapping of a Digenic Behavioral Trait Implicates Globin Variation in C. elegans Sensory Behaviors

Patrick T. McGrath; Matthew V. Rockman; Manuel Zimmer; Heeun Jang; Evan Z. Macosko; Cornelia I. Bargmann

Most heritable behavioral traits have a complex genetic basis, but few multigenic traits are understood at a molecular level. Here we show that the C. elegans strains N2 and CB4856 have opposite behavioral responses to simultaneous changes in environmental O(2) and CO(2). We identify two quantitative trait loci (QTL) that affect this trait and map each QTL to a single-gene polymorphism. One gene, npr-1, encodes a previously described neuropeptide receptor whose high activity in N2 promotes CO(2) avoidance. The second gene, glb-5, encodes a neuronal globin domain protein whose high activity in CB4856 modifies behavioral responses to O(2) and combined O(2)/CO(2) stimuli. glb-5 acts in O(2)-sensing neurons to increase O(2)-evoked calcium signals, implicating globins in sensory signaling. An analysis of wild C. elegans strains indicates that the N2 alleles of npr-1 and glb-5 arose recently in the same strain background, possibly as an adaptation to laboratory conditions.


Nature Methods | 2013

Brain-wide 3D imaging of neuronal activity in Caenorhabditis elegans with sculpted light

Tina Schrödel; Robert Prevedel; Karin Aumayr; Manuel Zimmer; Alipasha Vaziri

Recent efforts in neuroscience research have been aimed at obtaining detailed anatomical neuronal wiring maps as well as information on how neurons in these networks engage in dynamic activities. Although the entire connectivity map of the nervous system of Caenorhabditis elegans has been known for more than 25 years, this knowledge has not been sufficient to predict all functional connections underlying behavior. To approach this goal, we developed a two-photon technique for brain-wide calcium imaging in C. elegans, using wide-field temporal focusing (WF-TeFo). Pivotal to our results was the use of a nuclear-localized, genetically encoded calcium indicator, NLS-GCaMP5K, that permits unambiguous discrimination of individual neurons within the densely packed head ganglia of C. elegans. We demonstrate near-simultaneous recording of activity of up to 70% of all head neurons. In combination with a lab-on-a-chip device for stimulus delivery, this method provides an enabling platform for establishing functional maps of neuronal networks.


Nature Neuroscience | 2008

Serine phosphorylation of ephrinB2 regulates trafficking of synaptic AMPA receptors

Clara L. Essmann; Elsa Martinez; Julia C. Geiger; Manuel Zimmer; Matthias H. Traut; Valentin Stein; Rüdiger Klein; Amparo Acker-Palmer

Plasticity in the brain is essential for maintaining memory and learning and is associated with the dynamic membrane trafficking of AMPA receptors. EphrinB proteins, ligands for EphB receptor tyrosine kinases, are transmembrane molecules with signaling capabilities that are required for spine morphogenesis, synapse formation and synaptic plasticity. Here, we describe a molecular mechanism for ephrinB2 function in controlling synaptic transmission. EphrinB2 signaling is critical for the stabilization of AMPA receptors at the cellular membrane. Mouse hippocampal neurons from conditional ephrinB2 knockouts showed enhanced constitutive internalization of AMPA receptors and reduced synaptic transmission. Mechanistically, glutamate receptor interacting proteins bridge ephrinB ligands and AMPA receptors. Moreover, this function involved a regulatory aspect of ephrinB reverse signaling that involves the phosphorylation of a single serine residue in their cytoplasmic tails. In summary, our findings uncover a model of cooperative AMPA receptor and ephrinB reverse signaling at the synapse.


Science | 2017

A global brain state underlies C. elegans sleep behavior.

Annika L.A. Nichols; Tomáš Eichler; Richard Latham; Manuel Zimmer

Neuronal basis of lethargy in worms How does the brain switch between wakefulness and sleep? Nichols et al. studied this question using brain-wide Ca2+ imaging at single-neuron resolution in nematodes. By changing O2 concentrations, they could rapidly switch the worms between behaviorally quiescent and active states. They observed a global quiescence brain state characterized by the systemic down-regulation of neuronal network dynamics. Signaling from O2 sensory neurons rapidly evoked and maintained active network dynamics. Conversely, in the absence of such arousing cues, network dynamics converged into the quiescent mode. Science, this issue p. eaam6851 Brain imaging in nematode mutants reveals how a brain switches between alert wakefulness and sleep. INTRODUCTION Global brain states such as sleep and wakefulness involve reconfigurations of neural circuit activity across the entire nervous system. Yet it is not understood how the brain can effectively switch between and maintain different states. Do dedicated brain centers control states via top-down mechanisms? And to what extent do self-organizing principles of neuronal networks play a role? To address these questions, it would be ideal to measure the contributions of all individual neurons to a global brain state. Unfortunately, this is currently not possible in mammals or other large organisms. Every animal thoroughly studied exhibits sleeplike behaviors, implying that sleep is an essential, primordial, and common function of neural networks. In mammals, sleep is defined at the physiological level by a characteristic electroencephalography (EEG) signal. Such a definition is missing for invertebrate models, which primarily rely on behavioral definitions. RATIONALE The nematode Caenorhabditis elegans is a tractable model organism with the potential to overcome these limitations: It has a stereotypic and mapped nervous system of only 302 neurons. Sleep is developmentally timed and occurs predominantly during lethargus periods of ~2 hours at the end of each larval stage. During wakefulness, the worm brain exhibits neuronal population dynamics that involve a large fraction (~40%) of neurons. These neuronal activities are highly coordinated across the neuronal population; that is, they share common activity patterns. This feature can be quantified with computational methods and visualized in low-dimensional brain state phase plots. The resulting brain state trajectory represents the action sequence of the animals. To control sensory-evoked switching between sleep and wakefulness, we established a behavioral genetics paradigm combined with controlled changes in oxygen (O2) concentration. This method, together with whole-brain imaging at single-cell resolution, enables us to observe brainwide neuronal activity dynamics during brain state transitions. RESULTS During lethargus, wild C. elegans strains prefer to sleep in social aggregates, and local O2 concentrations are a key underlying cue. In this study, we have shown that a neuropeptide receptor (NPR-1) expressed in a hub interneuron regulates information processing of the arousal cue. We could recapitulate these switches between sleep and wakefulness in immobilized animals while recording the activity of nearly all neurons in the brain via Ca2+ imaging. We found that sleep in C. elegans is a global brain state in which about 75% of neurons displaying activity during wakefulness become inactive. However, a few specific neurons retained activity during sleep, notably γ-aminobutyric acid–producing (GABAergic) and peptidergic head neurons such as the sleep-promoting interneuron RIS. Chemosensory circuits activated by atmospheric O2 rapidly evoked transitions to wakefulness by effectively activating neuronal population dynamics. In contrast, entries into sleep occurred spontaneously in the absence of arousing cues via convergence of neuronal activities toward the global quiescent state. Here, the sleep-active neurons retained stationary high activity. CONCLUSION Using computational analysis, we have shown that sleep is an emergent property of neuronal networks. When lethargus animals are in a favorable environment such as a social aggregate, sleep can evolve spontaneously in the absence of arousing cues; these, however, can rapidly reactivate dynamical brain activity. Our analysis reveals that neuronal networks feature properties of dynamic attractors during wakefulness, whereas during sleep these dynamics converge toward a fixed point. This attractor state mechanism could be a means to effectively switch between and maintain global brain states. Sleep is a global quiescence brain state. Social aggregates of worms create a preferred milieu of low oxygen. During the lethargus developmental stage, these conditions permit sleep. Fluorescence heat maps (rectangles) show that wakefulness is associated with brainwide activity, whereas during sleep most neurons are down-regulated. The brain state cycles on a low-dimensional trajectory [as displayed by computational analysis (phase plot)], which corresponds to the pictured action command sequence. At sleep onset, these dynamics converge toward a tangle representing a fixed-point attractor state. How the brain effectively switches between and maintains global states, such as sleep and wakefulness, is not yet understood. We used brainwide functional imaging at single-cell resolution to show that during the developmental stage of lethargus, the Caenorhabditis elegans brain is predisposed to global quiescence, characterized by systemic down-regulation of neuronal activity. Only a few specific neurons are exempt from this effect. In the absence of external arousing cues, this quiescent brain state arises by the convergence of neuronal activities toward a fixed-point attractor embedded in an otherwise dynamic neural state space. We observed efficient spontaneous and sensory-evoked exits from quiescence. Our data support the hypothesis that during global states such as sleep, neuronal networks are drawn to a baseline mode and can be effectively reactivated by signaling from arousing circuits.


eLife | 2016

Regulation of two motor patterns enables the gradual adjustment of locomotion strategy in Caenorhabditis elegans

Ingrid Hums; Julia Riedl; Fanny Mende; Saul Kato; Harris S. Kaplan; Richard Latham; Michael Sonntag; Lisa Traunmüller; Manuel Zimmer

In animal locomotion a tradeoff exists between stereotypy and flexibility: fast long-distance travelling (LDT) requires coherent regular motions, while local sampling and area-restricted search (ARS) rely on flexible movements. We report here on a posture control system in C. elegans that coordinates these needs. Using quantitative posture analysis we explain worm locomotion as a composite of two modes: regular undulations versus flexible turning. Graded reciprocal regulation of both modes allows animals to flexibly adapt their locomotion strategy under sensory stimulation along a spectrum ranging from LDT to ARS. Using genetics and functional imaging of neural activity we characterize the counteracting interneurons AVK and DVA that utilize FLP-1 and NLP-12 neuropeptides to control both motor modes. Gradual regulation of behaviors via this system is required for spatial navigation during chemotaxis. This work shows how a nervous system controls simple elementary features of posture to generate complex movements for goal-directed locomotion strategies. DOI: http://dx.doi.org/10.7554/eLife.14116.001


PLOS Genetics | 2013

EGL-13/SoxD specifies distinct O2 and CO2 sensory neuron fates in Caenorhabditis elegans.

Jakob Gramstrup Petersen; Teresa Rojo Romanos; Vaida Juozaityte; Alba Redo Riveiro; Ingrid Hums; Lisa Traunmüller; Manuel Zimmer; Roger Pocock

Animals harbor specialized neuronal systems that are used for sensing and coordinating responses to changes in oxygen (O2) and carbon dioxide (CO2). In Caenorhabditis elegans, the O2/CO2 sensory system comprises functionally and morphologically distinct sensory neurons that mediate rapid behavioral responses to exquisite changes in O2 or CO2 levels via different sensory receptors. How the diversification of the O2- and CO2-sensing neurons is established is poorly understood. We show here that the molecular identity of both the BAG (O2/CO2-sensing) and the URX (O2-sensing) neurons is controlled by the phylogenetically conserved SoxD transcription factor homolog EGL-13. egl-13 mutant animals fail to fully express the distinct terminal gene batteries of the BAG and URX neurons and, as such, are unable to mount behavioral responses to changes in O2 and CO2. We found that the expression of egl-13 is regulated in the BAG and URX neurons by two conserved transcription factors—ETS-5(Ets factor) in the BAG neurons and AHR-1(bHLH factor) in the URX neurons. In addition, we found that EGL-13 acts in partially parallel pathways with both ETS-5 and AHR-1 to direct BAG and URX neuronal fate respectively. Finally, we found that EGL-13 is sufficient to induce O2- and CO2-sensing cell fates in some cellular contexts. Thus, the same core regulatory factor, egl-13, is required and sufficient to specify the distinct fates of O2- and CO2-sensing neurons in C. elegans. These findings extend our understanding of mechanisms of neuronal diversification and the regulation of molecular factors that may be conserved in higher organisms.


Proceedings of the Royal Society B: Biological Sciences | 2016

Oxygen-induced social behaviours in Pristionchus pacificus have a distinct evolutionary history and genetic regulation from Caenorhabditis elegans.

Eduardo Moreno; Angela McGaughran; Christian Rödelsperger; Manuel Zimmer; Ralf J. Sommer

Wild isolates of the nematode Caenorhabditis elegans perform social behaviours, namely clumping and bordering, to avoid hyperoxia under laboratory conditions. In contrast, the laboratory reference strain N2 has acquired a solitary behaviour in the laboratory, related to a gain-of-function variant in the neuropeptide Y-like receptor NPR-1. Here, we study the evolution and natural variation of clumping and bordering behaviours in Pristionchus pacificus nematodes in a natural context, using strains collected from 22 to 2400 metres above sea level on La Réunion Island. Through the analysis of 106 wild isolates, we show that the majority of strains display a solitary behaviour similar to C. elegans N2, whereas social behaviours are predominantly seen in strains that inhabit high-altitude locations. We show experimentally that P. pacificus social strains perform clumping and bordering to avoid hyperoxic conditions in the laboratory, suggesting that social strains may have adapted to or evolved a preference for the lower relative oxygen levels available at high altitude in nature. In contrast to C. elegans, clumping and bordering in P. pacificus do not correlate with locomotive behaviours in response to changes in oxygen conditions. Furthermore, QTL analysis indicates clumping and bordering to represent complex quantitative traits. Thus, clumping and bordering behaviours represent an example of phenotypic convergence with a different evolutionary history and distinct genetic control in both nematode species.


EMBO Reports | 2014

Cellular and molecular basis of decision‐making

Nilay Yapici; Manuel Zimmer; Ana I. Domingos

People think they are in control of their own decisions: what to eat or drink, whom to marry or pick a fight with, where to live, what to buy. Behavioural economists and neurophysiologists have long studied decision‐making behaviours. However, these behaviours have only recently been studied through the light of molecular genetics. Here, we review recent research in mice, Drosophila melanogaster and Caenorhabditis elegans, that analyses the molecular and cellular mechanisms underlying decision‐making. These studies interrogate decision‐making about food, sexual behaviour, aggression or foraging strategies, and add molecular and cell biology understanding onto the consilience of brain and decision.

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Harris S. Kaplan

Research Institute of Molecular Pathology

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Richard Latham

Research Institute of Molecular Pathology

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Susanne Skora

Research Institute of Molecular Pathology

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Cornelia I. Bargmann

Howard Hughes Medical Institute

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Fanny Mende

Research Institute of Molecular Pathology

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Ingrid Hums

Research Institute of Molecular Pathology

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Lisa Traunmüller

Research Institute of Molecular Pathology

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Saul Kato

Research Institute of Molecular Pathology

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Tina Schrödel

Research Institute of Molecular Pathology

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