ERC FUNDED PROJECTS

The deep-sea floor hosts a distinct microbial biome covering 67% of the Earth’s surface, characterized by cold temperatures, permanent darkness, high pressure and food limitation. The surface sediments are dominated by bacteria, with on average a billion cells per ml. Benthic bacteria are highly relevant to the Earth’s element cycles as they remineralize most of the organic matter sinking from the productive surface ocean, and return nutrients, thereby promoting ocean primary production. What passes the bacterial filter is a relevant sink for carbon on geological time scales, influencing global oxygen and carbon budgets, and fueling the deep subsurface biosphere. Despite the relevance of deep-sea sediment bacteria to climate, geochemical cycles and ecology of the seafloor, their genetic and functional diversity, niche differentiation and biological interactions remain unknown. Our preliminary work in a global survey of deep-sea sediments enables us now to target specific genes for the quantification of abyssal bacteria. We can trace isotope-labeled elements into communities and single cells, and analyze the molecular alteration of organic matter during microbial degradation, all in context with environmental dynamics recorded at the only long-term deep-sea ecosystem observatory in the Arctic that we maintain. I propose to bridge biogeochemistry, ecology, microbiology and marine biology to develop a systematic understanding of abyssal sediment bacterial community distribution, diversity, function and interactions, by combining in situ flux studies and different visualization techniques with a wide range of molecular tools. Substantial progress is expected in understanding I) identity and function of the dominant types of indigenous benthic bacteria, II) dynamics in bacterial activity and diversity caused by variations in particle flux, III) interactions with different types and ages of organic matter, and other biological factors.

3 375 693 €

Start date: 2012-06-01, End date: 2018-05-31

Converging studies from psychophysics in humans to single-cell recordings in monkeys and rodents indicate that most important cognitive processes depend on both feed-forward and feedback information interacting in the brain. Intriguingly, feedback to early cortical processing stages appears to play a causal role in these processes. Despite the central nature of this fact to understanding brain cognition, there is still no mechanistic explanation as to how this information could be so pivotal and what events take place that might be decisive. In this research program, we will test the hypothesis that the extraordinary performance of the cortex derives from an associative mechanism built into the basic neuronal unit: the pyramidal cell. The hypothesis is based on two important facts: (1) feedback information is conveyed predominantly to layer 1 and (2) the apical tuft dendrites that are the major recipient of this feedback information are highly electrogenic. The research program is divided in to several workpackages to systematically investigate the hypothesis at every level. As a whole, we will investigate the causal link between intrinsic cellular activity and behaviour. To do this we will use eletrophysiological and optical techniques to record and influence cell the intrinsic properties of cells (in particular dendritic activity) in vivo and in vitro in rodents. In vivo experiments will have a specific focus on context driven behaviour and in vitro experiments on the impact of long-range (feedback-carrying) fibers on cell activity. The study will also focus on synaptic plasticity at the interface of feedback information and dendritic electrogenesis, namely synapses on to the tuft dendrite of pyramidal neurons. The proposed program will not only address a long-standing and important hypothesis but also provide a transformational contribution towards understanding the operation of the cerebral cortex.

2 386 304 €

Start date: 2016-01-01, End date: 2020-12-31

AMPA glutamate receptors (AMPAR) play key roles in information processing by the brain as they mediate nearly all fast excitatory synaptic transmission. Their spatio-temporal organization in the post synapse with respect to presynaptic glutamate release sites is a key determinant in synaptic transmission. The activity-dependent regulation of AMPAR organization is at the heart of synaptic plasticity processes underlying learning and memory. Dysfunction of synaptic transmission - hence AMPAR organization - is likely at the origin of a number of brain diseases. Building on discoveries made during my past ERC grant, our new ground-breaking objective is to uncover the mechanisms that link synaptic transmission with the dynamic organization of AMPAR and associated proteins. For this aim, we have assembled a team of neurobiologists, computer scientists and chemists with a track record of collaboration. We will combine physiology, cellular and molecular neurobiology with development of novel quantitative imaging and biomolecular tools to probe the molecular dynamics that regulate synaptic transmission. Live high content 3D SuperResolution Light Imaging (SRLI) combined with electron microscopy will allow unprecedented visualization of AMPAR organization in synapses at the scale of individual subunits up to the level of intact tissue. Simultaneous SRLI and electrophysiology will elucidate the intricate relations between dynamic AMPAR organization, trafficking and synaptic transmission. Novel peptide- and small protein-based probes used as protein-protein interaction reporters and modulators will be developed to image and directly interfere with synapse organization. We will identify new processes that are fundamental to activity dependent modifications of synaptic transmission. We will apply the above findings to understand the causes of early cognitive deficits in models of neurodegenerative disorders and open new avenues of research for innovative therapies.

2 491 157 €

Start date: 2014-02-01, End date: 2019-01-31

The frequency of Alzheimer's disease (AD) will dramatically increase in the ageing western society during the next decades. Currently, about 18 million people suffer worldwide from AD. Since no cure is available, this devastating disorder represents one of the most challenging socio-economical problems of our future. As onset and progression of AD is triggered by the amyloid cascade, I will put particular attention on amyloid ß-peptide (Aß). The reason for this approach is, that even though 20 years ago the Aß generating processing pathway was identified (Haass et al., Nature 1992a & b), the identity of the Aß species, which initiate the deadly cascade is still unknown. I will first tackle this challenge by investigating if a novel and so far completely overlooked proteolytic processing pathway is involved in the generation of Aß species capable to initiate spreading of pathology and neurotoxicity. I will then search for modulating proteins, which could affect generation of pathological Aß species. This includes a genome-wide screen for modifiers of gamma-secretase, one of the proteases involved in Aß generation as well as a targeted search for RNA binding proteins capable to posttranscriptionally regulate beta- and alpha-secretase. In a disease-crossing approach, RNA binding proteins, which were recently found not only to be deposited in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis but also in many AD cases, will be investigated for their potential to modulate Aß aggregation and AD pathology. Modifiers and novel antibodies specifically recognizing neurotoxic Aß assemblies will be validated for their potential not only to prevent amyloid plaque formation, but also spreading of pathology as well as neurotoxicity. In vivo validations include studies in innovative zebrafish models, which allow life imaging of neuronal cell death, as well as the establishment of microPET amyloid imaging for longitudinal studies in individual animals.

2 497 020 €

Start date: 2013-03-01, End date: 2018-02-28

"The attine fungus-growing ants are prime models for understanding phenotypic adaptations in social evolution and symbiosis. The mutualism has many hallmarks of advanced cooperation in its mating system commitments and functional complementarity between multiple symbiont partners, but potential conflicts between sexes and castes over reproductive priorities, and between hosts and symbionts over symbiont mixing have also been documented. With collaborators at BGI-Shenzhen and the Smithsonian Institution my group has obtained six reference genomes representing all genus-level branches of the higher attine ants and a lower attine outgroup. With collaborators in Denmark and Australia we have pioneered proteomic approaches to understand the preservation of sperm viability in spite of sperm competition and the enzymatic decomposition of plant substrates that the ants use to make their fungus gardens grow. Here, I propose an integrated study focusing on four major areas of attine ant biology that are particularly inviting for in depth molecular approaches: 1. The protein-level networks that secure life-time (up to 20 years) sperm storage in specialized ant-queen organs and the genetic mechanisms that shape and adjust these “sexual symbiome” networks. 2. The ant-fungal symbiome, i.e. the dynamics of fungal enzyme production for plant substrate degradation and the redistribution of these enzymes in fungus gardens through fecal deposition after they are ingested but not digested by the ants. 3. The microbial symbiome of ant guts and other tissues with obligate bacterial mutualists, of which we have identified some and will characterize a wider collection across the different branches of the attine ant phylogeny. 4. The genome-wide frequency of genomic imprinting and the significance of these imprints for the expression of caste phenotypes and the regulation of potential reproductive conflicts."

2 290 102 €

Start date: 2013-05-01, End date: 2018-04-30

In the 90s, two landmark observations brought to a paradigm shift about the role of astrocytes in brain function: 1) astrocytes respond to signals coming from other cells with transient Ca2+ elevations; 2) Ca2+ transients in astrocytes trigger release of neuroactive and vasoactive agents. Since then, many modulatory astrocytic actions and mechanisms were described, forming a complex - partly contradictory - picture, in which the exact roles and modes of astrocyte action remain ill defined. Our project wants to bring light into the “language of astrocytes”, i.e. into how they communicate with neurons and, ultimately, address their role in brain computations and cognitive behavior. To this end we will perform 4 complementary levels of analysis using highly innovative methodologies in order to obtain unprecedented results. We will study: 1) the subcellular organization of astrocytes underlying local microdomain communications by use of correlative light-electron microscopy; 2) the way individual astrocytes integrate inputs and control synaptic ensembles using 3D two-photon imaging, genetically-encoded Ca2+ indicators, optogenetics and electrophysiology; 3) the contribution of astrocyte ensembles to behavior-relevant circuit operations using miniaturized microscopes capturing neuronal/astrocytic population dynamics in freely-moving mice during memory tests; 4) the contribution of astrocytic signalling mechanisms to cognitive behavior using a set of new mouse lines with conditional, astrocyte-specific genetic modification of signalling pathways. We expect that this combination of groundbreaking ideas, innovative technologies and multilevel analysis makes our project highly attractive to the neuroscience community at large, bridging aspects of molecular, cellular, systems and behavioral neuroscience, with the goal of leading from a provocative hypothesis to the conclusive demonstration of whether and how “the language of astrocytes” participates in memory and cognition.

2 513 896 €

Start date: 2014-02-01, End date: 2019-01-31

Neurons make long-distance connections with synaptic targets via axons. These axons survive throughout the lifetime of an organism, often many years in mammals, yet how axons are maintained is not fully understood. Recently, we provided in vivo evidence that local mRNA translation in mature axons is required for their maintenance. This new finding, along with in vitro work from other groups, indicates that promoting axonal protein synthesis is a key mechanism by which trophic factors act to prevent axon degeneration. Here we propose a program of research to investigate the importance of ribosomal proteins (RPs) in axon maintenance and degeneration. The rationale for this is fourfold. First, recent genome-wide studies of axonal transcriptomes have revealed that protein synthesis (including RP mRNAs) is the highest functional category in several neuronal types. Second, some RPs have evolved extra-ribosomal functions that include signalling, such as 67LR which acts both as a cell surface receptor for laminin and as a RP. Third, mutations in different RPs in vertebrates cause unexpectedly specific defects, such as the loss of optic axons. Fourth, preliminary results show that RP mRNAs are translated in optic axons in response to trophic factors. Collectively these findings lead us to propose that locally synthesized RPs play a role in axon maintenance through either ribosomal or extra-ribosomal function. To pursue this proposal, we will perform unbiased screens and functional assays using an array of experimental approaches and animal models. By gaining an understanding of how local RP synthesis contributes to axon survival, our studies have the potential to provide novel insights into how components conventionally associated with a housekeeping role (translation) are linked to axon degeneration. Our findings could provide new directions for developing therapeutic tools for neurodegenerative disorders and may have an impact on more diverse areas of biology and disease.

2 426 573 €

Start date: 2013-03-01, End date: 2018-09-30

The discovery of deep-sea hydrothermal vents in 1977 was one of the most profound findings of the 20th century, revolutionizing our perception of energy sources fueling primary productivity on Earth. These ecosystems are based on chemosynthesis, that is the fixation of carbon dioxide into organic compounds as in photosynthesis, but using inorganic compounds such as sulfide, methane or hydrogen, as energy sources instead of sunlight. Hydrothermal vents support tremendous biomass and productivity of which the majority is generated through symbiotic microbe-animal associations. Bathymodiolus mussels are able to build extraordinarily large and productive communities at hydrothermal vents because they harbor symbiotic bacteria that use inorganic energy sources from the vent fluids to feed their hosts via carbon fixation. In addition to their beneficial symbionts, the mussels are infected by a novel bacterial parasite that exclusively invades and multiplies in their nuclei. In the work proposed here, I will use a wide array of tools that range from deep-sea in situ instruments to sophisticated molecular, 'omic' and imaging analyses to study the microbiome associated with Bathymodiolus mussels. The proposed research bridges biogeochemistry, ecological and evolutionary biology, and molecular microbiology to develop a systematic understanding of the symbiotic interactions between microbes, their hosts, and their environment in one of the most extreme and fascinating habitats on Earth, hydrothermal vents.

2 499 122 €

Start date: 2014-02-01, End date: 2019-01-31

This project addresses a key issue in fundamental research - one that has challenged ecologists ever since Darwin s time that is why some species are common, and others rare, and why, despite marked turnover at the level of individual species abundances, the structure of a community is generally conserved through time. Its aim is to examine the temporal dynamics of species abundance distributions (SADs), and to assess the capacity of these distributions to withstand change (resistance) and to recover from change (resilience). These are topical and important questions given the increasing impact that humans are having on the natural world. There are three components to the research. First, we will model SADs and predict responses to a range of events including climate change and the arrival of invasive species. A range of modeling approaches (including neutral, niche and statistical) will be adopted; by incorporating temporal turnover in hitherto static models we will advance the field. Second, we will test predictions concerning the resistance and resilience of SADs by a comparative analysis of existing data sets (that encompass communities in terrestrial, freshwater and marine environments for ecosystems extending from the poles to the tropics) and through a new field experiment that quantifies temporal turnover across a community (unicellular organisms to vertebrates) in relation to factors both natural (dispersal limitation) and anthropogenic (human disturbance) thought to shape SADs. In the final part of the project we will apply these new insights into the temporal dynamics of SADs to two important conservation challenges. These are 1) the conservation of biodiversity in a heavily utilized European landscape (Fife, Scotland) and 2) the conservation of biodiversity in Mamirauá and Amaña reserves in Amazonian flooded forest. Taken together this research will not only shed new light on the structure of ecological communities but will also aid conservation.

1 812 782 €

Start date: 2010-08-01, End date: 2016-01-31

Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.

2 489 643 €

Start date: 2009-01-01, End date: 2014-12-31

Pericytes, located at intervals along capillaries, have recently been revealed as major controllers of brain blood flow. Normally, they dilate capillaries in response to neuronal activity, increasing local blood flow and energy supply. But in pathology they have a more sinister role. After artery block causes a stroke, the brain suffers from the so-called “no-reflow” phenomenon - a failure to fully reperfuse capillaries, even after the upstream occluded artery has been reperfused successfully. The resulting long-lasting decrease of energy supply damages neurons. I have shown that a major cause of no-reflow lies in pericytes: during ischaemia they constrict and then die in rigor. This reduces capillary diameter and blood flow, and probably degrades blood-brain barrier function. However, despite their crucial role in regulating blood flow physiologically and in pathology, little is known about the mechanisms by which pericytes function. By using blood vessel imaging, patch-clamping, two-photon imaging, optogenetics, immunohistochemistry, mathematical modelling, and live human tissue obtained from neurosurgery, this programme of research will: (i) define the signalling mechanisms controlling capillary constriction and dilation in health and disease; (ii) identify the relative contributions of neurons, astrocytes and microglia to regulating pericyte tone; (iii) develop approaches to preventing brain pericyte constriction and death during ischaemia; (iv) define how pericyte constriction of capillaries and pericyte death contribute to Alzheimer’s disease; (v) extend these results from rodent brain to human brain pericytes as a prelude to developing therapies. The diseases to which pericytes contribute include stroke, spinal cord injury, diabetes and Alzheimer’s disease. These all have an enormous economic impact, as well as causing great suffering for patients and their carers. This work will provide novel therapeutic approaches for treating these diseases.

2 499 954 €

Start date: 2017-09-01, End date: 2022-08-31

Synaptic scaffolding molecules control the localization and the abundance of neurotransmitter receptors at the synapse, a key parameter to shape synaptic transfer function. Most characterized synaptic scaffolds are intracellular, yet a growing number of secreted proteins appear to organize the synapse from the outside of the cell. We recently demonstrated in C. elegans that an evolutionarily conserved protein secreted by motoneurons specifies the excitatory versus inhibitory identity of the postsynaptic domains at neuromuscular synapses. We propose to use this system as a genetically tractable paradigm to perform a comprehensive characterization of this unforeseen synaptic organization. Specifically, this project will pursue 4 complementary aims: 1) Identify and characterize a comprehensive set of genes that organize and control the formation and maintenance of these scaffolds through a series of genetic screens based on the direct visualization of fluorescent acetylcholine and GABA receptors in living animals. 2) Solve the spatial synaptic organization of these scaffolds at a nanoscale resolution using super-resolutive and correlative light and electron microscopy, and analyze their dynamic behavior in vivo by implementing Single Particle Tracking imaging in living worms. 3) Decipher the role of the synaptomatrix in the organization of synaptic extracellular scaffolds and evaluate its functional contribution at the physiological and molecular levels using a candidate gene strategy and innovative imaging. 4) Analyze the formation and decline of these scaffolds at the lifetime scale and evaluate the role of synaptic activity and aging in these processes by taking advantage of the possibility to follow identified synapses over the entire life of C. elegans. Using powerful genetics in combination with cutting-edge in vivo imaging and electrophysiology, we anticipate to identify new genes and new mechanisms at work to regulate normal and pathological synaptic function.

2 492 750 €

Start date: 2016-10-01, End date: 2021-09-30

Eusociality, in which workers sacrifice their own reproduction to rear the offspring of queens, is a major focus of interest in evolutionary biology. A key aim during recent decades has been to understand the conflicts of interest within eusocial groups. In contrast, however, little is known about the underlying genetic architecture. In this proposal, we will use a mixture of field experiments and transcriptomics to address novel questions about the evolutionary dynamics of queen-worker interactions. Borrowing concepts from the field of sexual conflict, we will investigate a new idea: that the productivity of social groups is limited because castes are constrained by inter-caste genetic correlations from simultaneously reaching their optimal (dimorphic) phenotypes. We will also quantify caste dimorphism across an environmental gradient, and investigate the plasticity of dimorphism using transplants and social manipulations. In addition, we will cross-foster individuals between nests to test for coadaptation between queens and workers. And we will test a long-standing hypothesis experimentally for the first time: that queens manipulate worker phenotype in their own interests. The proposed research will force us to look at eusociality in a completely new way. How caste dimorphism can evolve, the possibility that its evolution could be limited by genetic constraints, and the processes that could resolve those constraints, are topics that have hardly been considered. Recent research has strongly emphasized conflict between queens and workers, but the coadaptation of complementary phenotypes may be just as important. Our approach will be multidisciplinary: we will capitalize on state-of-the-art transcriptomic technology in combination with innovative field methods, and use study systems that allow exceptional sample sizes to be obtained in the wild, where natural selection operates. The overall result will be a new and exciting perspective on queen-worker coevolution.

2 424 263 €

Start date: 2017-01-01, End date: 2021-12-31

CDREG develops the major new Earth system science research hypothesis that tectonic-related variations in Earth’s atmospheric CO2 concentration ([CO2]a) drive negative ecological feedbacks on terrestrial silicate weathering rates that stabilise further [CO2]a change and regulate climate. This paradigm-changing hypothesis integrates ecological and abiotic controls on silicate weathering to understand how terrestrial ecosystems have shaped past Earth system dynamics. The proposed ecological feedbacks are mechanistically linked to the extent and activities of forested ecosystems and their symbiotic fungal partners as the primary engines of biological weathering. CDREG’s core hypothesis establishes an exciting cross-disciplinary Research Programme that offers novel opportunities for major breakthroughs implemented through four linked hypothesis-driven work packages (WPs) employing experimental, geochemical and numerical modelling approaches. WP1 quantitatively characterises [CO2]a-driven tree/grass-fungal mineral weathering by coupling metabolic profiling with advanced nanometre scale surface metrological techniques for investigating hyphal-mineral interactions. WP2 quantifies the role [CO2]a-drought interactions on savanna tree mortality and C4 grass survivorship, plus symbiotic fungal-driven mineral weathering. WP3 exploits the past 8 Ma of marine sediment archives to investigate the links between forest to savanna transition, terrestrial weathering, fire, and climate in Africa. WP4 integrates findings from WP1-3 into a new Earth system modelling framework to rigorously investigate the biogeochemical feedbacks of [CO2]a-regulated ecological weathering on [CO2]a via marine carbonate deposition and organic C burial. The ultimate goal is to provide a new synthesis in which the role of [CO2]a in regulating the ecological weathering engine across scales from root-associated microorganisms to terrestrial ecosystems is mechanistically understood and assessed.

2 271 980 €

Start date: 2013-06-01, End date: 2018-05-31

"Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."

2 375 600 €

Start date: 2013-03-01, End date: 2018-02-28

Timing is everything in ecology, and because plants provide the foundation for most land-based food webs, the timing of their activities profoundly orchestrates the majority of ecological interactions. Most photosynthetic and growth processes are under circadian control, but many additional processes--approximately 30-40% of all genes—are under circadian control, and yet the Darwinian fitness impact of being “in synch” with the environment has not been systematically studied for any organism. We have developed a toolbox for a native tobacco plant, Nicotiana attenuata, that allows us to “ask the plant” which genes, proteins or metabolites are regulated in particular plant-mediated ecological interactions; identify “the genes that matter” for a given interaction; silence or ectopically express these genes, and conduct field releases with the transformed plants at a nature preserve in the Great Basin Desert to rigorously test hypotheses of gene function. By taking advantage of both our understanding of what it takes for this plant to survive in nature, and the procedures established to disentangle the skein of subtle interactions that determine its performance, we will systematically examine the importance of synchronous entrained endogenous rhythms at all life stages: longevity in the seed bank, germination, rosette growth, elongation, flowering and senescence. Specifically, we propose to silence a key components (starting with NaTOC1) of the plant’s endogenous clock to shorten the plant’s circadian rhythm, both constitutively and with strong dexamethasone-inducible promoters, at all life stages. With a combination of real-time phenotype imaging, metabolite and transcriptome analysis, and ecological know-how, the research will reveal how plants adjust their physiologies to the ever-changing panoply of environmental stresses with which they must cope; by creating arrhythmic plants, we will understand why so many processes are under circadian control.

2 496 002 €

Start date: 2012-04-01, End date: 2017-03-31

The genetic code was established at a very early stage during the evolution of life on Earth and is nearly universal. In eukaryotic nuclear genes, the only known examples of a sense codon that underwent an evolutionary change of meaning, from one amino acid to another, occur in yeast species. The codon CUG is translated as Leu in the universal genetic code, but it has long been known to be translated as Ser in some Candida species. In recent work, we discovered that this switch is one of three parallel reassignments of CUG that occurred in three closely related clades of yeasts. CUG was reassigned once from Leu to Ala, and twice from Leu to Ser, in three separate events. The meaning of sense codons in the nuclear genetic code has otherwise remained completely stable during all of eukaryotic evolution, so why was CUG so unstable in yeasts? CODEKILLER will test a radical new hypothesis that the genetic code changes were caused by a killer toxin that specifically attacked the tRNA that translated CUG as Leu. The hypothesis implies that the reassignments of CUG were not driven by selection in favor of their effects on the proteome, as commonly assumed, but by selection against the existence of a particular tRNA. As well as searching for this killer toxin, we will study the detailed mechanism of genetic code change by engineering a reversal of a CUG-Ser species back to CUG-Leu translation, and investigate translation in some species that naturally contain both tRNA-Leu and tRNA-Ser molecules capable of decoding CUG.

2 368 356 €

Start date: 2018-10-01, End date: 2023-09-30

Our sensory systems gather stimuli as elemental physical features yet we perceive a world made up of familiar objects, not wavelengths or vibrations. Perception occurs when the neuronal representation of physical parameters is transformed into the neuronal representation of meaningful objects. How does this recoding occur? An ideal platform for the inquiry is the rat whisker sensory system: it produces fast and accurate judgments of complex stimuli, yet can be broken down into accessible neuronal mechanisms. CONCEPT will examine the process that begins with whisker motion and ends with perception of the contacted object. Understanding the general principles for the construction of perception will help explain why we experience the world as we do. The main hypothesis is that graded neuronal representations at early processing stages are “fractured” to generate discrete object representations at late processing stages. Of particular interest is the emergence of object representations as the meaning of new stimuli is acquired. We will collect multi-site single-unit and local field potential signals simultaneously with precise behavioral indices, and will interpret data through advanced computational methods. We will begin by quantifying whisker motion as rats discriminate texture, thus defining the raw material on which the brain operates. Next, we will characterize the transformation of texture along an intracortical stream from sensory areas (where we expect that neurons encode whisker kinematics) to frontal and rhinal areas (where we expect that neurons encode objects extracted from the graded physical continuum) and hippocampus (where we expect that neurons encode objects in conjunction with context). We will test candidate processing schemes by manipulating perception on single trials using optogenetic methods.

2 500 000 €

Start date: 2012-06-01, End date: 2018-05-31

CoralWarm will generate for the first time projections of temperate and subtropical coral survival by integrating sublethal temperature increase effects on metabolic and skeletal processes in Mediterranean and Red Sea key species. CoralWarm unique approach is from the nano- to the macro-scale, correlating molecular events to environmental processes. This will show new pathways to future investigations on cellular mechanisms linking environmental factors to final phenotype, potentially improving prediction powers and paleoclimatological interpretation. Biological and chemical expertise will merge, producing new interdisciplinary approaches for ecophysiology and biomineralization. Field transplantations will be combined with controlled experiments under IPCC scenarios. Corals will be grown in aquaria, exposing the Mediterranean species native to cooler waters to higher temperatures, and the Red Sea ones to gradually increasing above ambient warming seawater. Virtually all state-of-the-art methods will be used, by uniquely combining the investigators expertise. Expected results include responses of algal symbionts photosynthesis, host, symbiont and holobiont respiration, biomineralization rates and patterns, including colony architecture, and reproduction to temperature and pH gradients and combinations. Integration of molecular aspects of potential replacement of symbiont clades, changes in skeletal crystallography, with biochemical and physiological aspects of temperature response, will lead to a novel mechanistic model predicting changes in coral ecology and survival prospect. High-temperature tolerant clades and species will be revealed, allowing future bioremediation actions and establishment of coral refuges, saving corals and coral reefs for future generations.

3 332 032 €

Start date: 2010-06-01, End date: 2016-05-31

Neurons in primary visual cortex (area V1) receive feedforward inputs from thalamic afferents and lateral inputs from other cortical neurons. Little is known about how these components interact to determine the responses of a V1 neuron. One camp ascribes most responses to feedforward mechanisms. The other camp ascribes them mostly to lateral interactions. We propose that these two apparently opposed views can be simply reconciled in a single framework. We hypothesize that area V1 can operate both in a feedforward regime and in a lateral interaction regime, depending on the nature of the stimulus and on the cognitive task at hand, and that the transition from one regime to the other is governed by synaptic inhibition. We will test these hypotheses by recording from individual V1 neurons while monitoring the activity of nearby populations of cortical neurons via multiprobe electrodes. In Aim 1 we will relate the activity of V1 neurons to that of nearby populations. We will use simple measures of correlation and nonlinear models that predict individual spikes to measure how responses depend on a feedforward contribution (the receptive field ) and on a lateral contribution (the connection field ). We will test our first hypothesis, concerning the role of the stimulus in changing this dependence. In Aim 2 we will extend these results to a behaving animal. We will record from V1 of mice performing a 2-alternative forced-choice psychophysical task, and we will test our second hypothesis, concerning the role of the cognitive task in determining the operating regime of the cortex. In Aim 3 we will seek a biophysical interpretation of the functional mechanisms and effective connectivity revealed by the previous Aims. We will test our third hypothesis, concerning the role of synaptic inhibition. The tools involved will include intracellular recordings and optical stimulation in transgenic mice whose cortical neurons are sensitive to light.

2 499 921 €

Start date: 2009-04-01, End date: 2014-03-31

The neural assembly underlying the formation of functional networks in the cerebral cortex is conceivably the most complex biological system that exists. Much of this complexity arises during development through the interaction of dozens of different neuronal populations, which belong to two general classes: excitatory glutamatergic pyramidal cells and inhibitory gamma-aminobutyric containing (GABAergic) interneurons. Perhaps the most fascinating aspect of the assembly of cortical circuits is that pyramidal cells and interneurons are generated in distant germinal zones. Pyramidal cells are born locally from progenitors located in the cortical anlage, while interneurons derive from progenitors in the embryonic subpallium. Much progress has been made recently in understanding the molecular mechanisms that regulate the migration of interneurons towards the cortex, but how interneurons find their appropriate partners to build cortical networks with balanced excitation and inhibition remains an enigma. The general goal of this project is to identify the mechanisms controlling the precise allocation of different classes of interneurons into specific layers of the cortex, where they assemble into neural circuits. We also aim to determine how the allocation of interneurons into specific cortical layers influences their function. This project is now possible due to the unique combination of our detailed know-how on the early development of cortical interneurons, including a variety of genetically modified mice available to us, and the application of new technologies to specifically target synchronically generated populations of interneurons. Our multidisciplinary approach, combining mouse genetics, in vivo functional genomics and electrophysiological methodologies represents a technological breakthrough that should accelerate our understanding of the general principles guiding the assembly of neuronal circuits in the cerebral cortex.

2 493 481 €

Start date: 2012-04-01, End date: 2017-09-30

I seek to unify evolutionary and biomechanical research by achieving a “functional synthesis” in evolution that causally links phenotypes (anatomy) to actual performance. Did early, bipedal dinosaurs evolve advantages in their locomotor performance over other Late Triassic archosaurs (“ruling reptiles”)? This “locomotor superiority” hypothesis was first proposed to explain what made dinosaurs distinct from other Triassic taxa, perhaps aiding their survival into the Jurassic. However, the hypothesis remains untested or unfairly dismissed. I will test this question for the first time, but first I need to develop the best tools to do so. Extant archosaurs (crocodiles and birds) allow us to experimentally measure key factors (3D skeletal motions and limb forces; muscle activations) optimizing performance in walking, running, jumping, standing up, and turning. We will then use biomechanical simulations to estimate performance determinants we cannot measure; e.g. muscle forces/lengths. This will refine our simulations by testing major assumptions and validate them for studying extinct animals, overcoming the obstacle that has long limited researchers to qualitative, subjective morphological inferences of performance. Next, we will use our simulation tools to predict how ten Late Triassic archosaurs may have moved, and to compare how their performance in the five behaviours related to locomotor traits, testing if the results fit expected patterns for “locomotor superiority.” My proposal pushes the frontiers of experimental and computational analysis of movement by combining the best measurements of performance with the best digital tools, to predict how form and function are coordinated to optimize performance. Our rigorous, integrative analyses will revolutionize evolutionary biomechanics, enabling new inquiries into how behaviour relates to underlying traits or even palaeoecology, environments, biogeography, biotic diversity, disparity or other metrics.

2 498 719 €

Start date: 2016-10-01, End date: 2021-09-30

What is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also for building accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. We will directly test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiological, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum. We will define the computational rules for integration of synaptic input in dendrites by examining the responses to different spatiotemporal patterns of excitatory and inhibitory inputs. We will use computational modeling to extract simple rules describing dendritic integration that captures the essence of the computation. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs to dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will manipulate dendritic function using molecular tools, in order to provide causal links between specific dendritic computations and sensory processing. These experiments will provide us with deeper insights into how single neurons act as computing devices, and how fundamental computations that drive behaviour are implemented on the level of single cells and neural circuits.

2 416 078 €

Start date: 2010-06-01, End date: 2016-05-31

Understanding the process of spontaneous mutation is fundamental for understanding the genetic basis of quantitative variation, the threat posed by declining population size in conservation biology and the distribution of nucleotide variation in the genome. I will address these and other unanswered questions concerning the evolutionary impact of spontaneous mutation using the house mouse as a model system. With the first, highly replicated mutation accumulation (MA) experiment in any vertebrate, I will study the impact of mutation accumulation on fitness and other quantitative traits and on genomic variation. I will pay particular attention to the effects of mutations in the heterozygous state, since this is important for resolving two important questions: 1. The threat posed by deleterious mutation accumulation in humans, where natural selection has weakened in many populations, and in endangered species, where declining effective population size has made selection less effective, and 2. The extent by which new mutations sustain response to artificial selection. By characterizing many thousands of mutation events by genome sequencing of MA lines and wild mice, I will determine the molecular spectrum and the factors explaining mutation rate variation across the genome. I will exploit this new knowledge to address the long-unanswered question of the causes of correlations between nucleotide diversity and the recombination rate and the density of conserved genomic elements. I will develop new approaches, incorporating the simultaneous action of mutation, selection, drift and recombination, to determine the contributions of background selection and selective sweeps to variation in nucleotide diversity, and to quantify the contributions of coding and noncoding mutations to fitness variation. The project will lead to substantial advances in the understanding of the role of new mutations in explaining phenotypic and molecular diversity in mammals.

2 499 331 €

Start date: 2017-01-01, End date: 2021-12-31