Skip to main content
2019 -
Grant Awardees - Program

The repeatability of the genetic mechanisms underlying behavioral evolution


Dept. of Molecular Biosciences - Northwestern University - Evanston - USA


MRC London Institute of Medical Sciences - Imperial College London - London - UK


School of Biological Sciences - Monash University - Clayton - AUSTRALIA

Keen observers of nature have often wondered why diverse species seem to behave similarly. For example, different species of Hawaiian spiders spin similar web architectures, diverse anoles lizard species bob their heads with the same styles and speeds, and distinct species of damselflies avoid predators using the same techniques. These and many other striking examples are thought to represent the convergent evolution of behaviors. Does this convergence reflect changes in the same genes or does evolution act through many genetic routes to create the same behaviors? Genetic differences clearly play a role in behavioral variation, but it remains challenging to identify the genes that underlie evolution of behaviors. However, convergence in the genetic basis of developmental or physiological traits has been discovered with many specific examples of genes and mechanisms, so it is possible to use studies of convergence to discover how behaviors evolve. Therefore, we will use a powerful comparative system to discover the genes and molecular mechanisms that underlie convergent evolution of behaviors for the first time across divergent animals.
The Caenorhabditis nematodes offer a unique experimental platform to connect behavioral differences to genetic differences. Starting with the keystone model organism, C. elegans, and existing data, we will characterize and classify genetic differences across wild isolates from three species of Caenorhabditis - C. briggsae, C. elegans, and C. tropicalis. Whole-genome genotype data combined with high-throughput, high-content imaging of behaviors from these same wild isolates will be input into unsupervised machine learning algorithms to create a high-resolution genotype-phenotype map for a range of natural behaviors and examples of convergence. This map will be queried for signatures of shared genetic changes at orthologous genes to identify which variants are most important evolutionarily. The result will provide the first systematic glimpse into the genomic “knobs” that control behaviors at single-variant resolution across species and insights into the repeatability of the evolution of behaviors.

2019 -
Grant Awardees - Program

Studying sea urchin dermal photoreception to unravel principles of decentralized spherical vision


Dept. of Biology and Evolution of Marine Organisms - Stazione Zoologica Anton Dohrn - Napoli - ITALY


Dept. of Neurobiology and Behavior - Stony Brook University - Stony Brook - USA


Dept. of Evolutionary Morphology (FB1) - Museum fuer Naturkunde - Berlin - GERMANY


Lund Vision Group, Dept. of Biology - Lund University - Lund - SWEDEN

Sea urchins are marine animals genetically close to the vertebrate lineage. Being eye-less and lacking a central nervous system (NS), these animals instead feature dermal photoreceptors dispersed over their spherical body surface and feeding into a decentralized NS. However, sea urchins can visually resolve objects and move towards them, and they can detect looming visual stimuli from any direction and accurately point their spines towards them. Such performance is normally associated with proper eyes feeding information into a brain. Sea urchins thus offer access to a unique visual system of a type that to date has not been studied in terms of its information processing. This alternative solution to vision may also have potential biomimetic applications for robotic miniaturization, smart probes, and intelligent materials where dispersed light detectors control the properties of the material.
The core of the proposed project is to investigate and model the neural mechanisms of information processing, which enables sea urchins to perform spherical vision by deploying an obviously very different mechanism from today's technology, and also very different from visually guided behavior in most other animals. Our study includes molecular and morphological identification of cell types, measurements of behavioral responses and electrophysiological photoreceptor responses, mapping the connectome of sea urchin photoreceptors and NS, and theoretical modelling of the information processing underlying visually guided behavior. We will map the connectomics of the NS and record the activity from key positions in the processing of visual information and generation of locomotory responses. The data will be used for computational modelling of the entire process from visual input to motor control. Special focus will be given to behavioral decisions where small changes in stimuli cause behavioral switches. We will also use genetic approaches to test the agreement between theoretical models and actual behavior.

2019 -
Grant Awardees - Program

A spatiotemporal map of signalling processes controlling human stem cell renewal and differentiation

CARAZO SALAS Rafael Edgardo (UK)

School of Cellular and Molecular Medicine - University of Bristol - Bristol - UK

COHEN Andrew (USA)

Dept. of Electrical & Computer Engineering - Drexel University - Philadelphia - USA


Institute of Cell Biology - University of Bern - Bern - SWITZERLAND

The Personalized, Regenerative Medicine of the future will rely on being able to make replacement cells and tissues of choice at will and in a robust, predictive manner. However, key challenges have to be overcome before the promise of personalized stem cell therapeutics becomes a reality. This is because stem cell renewal/differentiation are stochastic processes, precluding the differentiation of a stem cell population into a homogeneously differentiated desired cell type, but also leading to spurious differentiation during renewal. This is thought to partly arise from heterogeneous single-cell signaling states among different cells of a population, which are not measurable using classical ‘population-average’ biochemical methods. A mechanistic understanding of how dynamic signaling processes control differentiation/renewal fates at the single-cell level might therefore significantly improve our capacity to robustly and precisely manipulate cell fates for tissue engineering purposes. We propose to use an integrated interdisciplinary strategy to map the dynamic, single-cell signaling programs that control differentiation/renewal using human Pluripotent Stem Cell (hPSC) differentiation into neural stem cells as a differentiation paradigm. Using multiplexed, genetically-encoded biosensors, we will quantitate hPSC single-cell dynamic signaling states by large-scale, multi-color, multi-day timelapse microscopy across millions of cells, to reveal with unparalleled precision how heterogeneous signaling states correlate with renewal/differentiation fates. Using computer vision approaches, we will automatically segment, track and lineage at scale each of the cells that were induced to self-renew or differentiate, and we will extract a panel of signaling, cell-cycle, pluripotency state, and cell morphodynamics features that quantify these dynamic processes. We will then mine these high-dimensional feature sets to build computational models that identify dynamic single-cell signaling patterns associated with robust fate transitions and predict actionable interventions that might cause those transitions. Lastly, using drug perturbations, and/or microfluidic/optogenetic actuators, we will quantitatively test those predictions by evoking synthetic dynamic signaling states that induce robust fate transitions. Our approach will help to significantly clarify the mechanistic basis of signaling-mediated human stem cell fate decisions, providing new avenues to robustly control stem cell fate. This might help establish a larger framework, broadly applicable to other hPSC lines and differentiation routes.

2019 -
Grant Awardees - Program

Unravelling an unusual biomineralization from nano to macro scale using advanced technologies


Dept. of Life Sciences - Imperial College London - Ascot - UK


Dépt. Adaptations du Vivant - UMR 7179 C.N.R.S/M.N.H.N - Paris - FRANCE

MOAZEN Mehran (UK)

Dept. of Mechanical Engineering - University College London - London - UK


Dept. of Biomedical Sciences - University of Guelph - Guelph - CANADA

Osteoderms are hard calcified tissues that form within the skin of some animals. They resemble bone, hence the name, but are fundamentally different in several respects. Crocodile and armadillo skin plates, and turtle shells are among the most familiar examples, reportedly forming a protective armour against external predators and aiding locomotion. However, although less visible, osteoderms are also present in many lizards.
In terms of their shape, spatial distribution, and interaction, lizard osteoderms show the highest diversity in the animal kingdom, yet we know little about what drives this extraordinary diversity, how it is controlled, or how it originated. It could be a biproduct of other genetic differences or, more likely, a natural optimization to enhance osteoderm function, protective or otherwise, under conditions specific to each lizard type.
This project brings together a multidisciplinary team of expert engineers, developmental and evolutionary biologists from the UK, Canada and France to investigate the mechanisms underlying the development, patterning, and evolution of osteoderms in lizards. The team will use a range of advanced techniques (e.g. genetic analysis, material testing, imaging, and computer simulations) to investigate lizard osteoderms from the first molecular signalling events and cellular interactions, through to organismal level. Osteoderm mechanical properties will be characterised both as single units and as sheets so as to understand their function during feeding and locomotion.
This is a basic science project focused on a novel biological tissue and its evolutionary implications, but with a systems approach that may shed light on pathological calcifications, as well as aiding the development of biomimetic materials and structures. Most importantly it will train the next generation of scientists, in a multidisciplinary and international setting, providing them with a fundamental knowledge of biological tissues and a diverse skillset with which to address the global challenges of 21st century.

2019 -
Grant Awardees - Program

Do hydrocarbons induce membrane curvature in photosynthetic organisms?


School of Biological Sciences - University of Auckland - Auckland - NEW ZEALAND


Dept. of Chemistry - Imperial College London - London - UK


School of Biological Sciences - University of East Anglia - Norwich - UK


Instrument Division - European Spallation Source ERIC - Lund - SWEDEN

The cell membrane is a double layer of lipid molecules. It plays a critical role in protecting the cell from its environment and in separating the different processes that take place within its interior. Membranes must change their shape in order for the cell to function, especially during cell division, and this depends on membrane curvature. At present, cells are only known to induce curvature by accumulating lipids in one of the layers or using specialised proteins. Our goal is to investigate a new mechanism of inducing membrane curvature by accumulation of hydrocarbons in the middle of the lipid layers that has not been observed before in nature.
These hydrocarbons are like the components of diesel fuel, and are found in photosynthetic cyanobacteria and algae – some of the most abundant and widespread organisms on Earth. Production of hydrocarbons in cyanobacteria or other microbes could substitute for liquid fuels derived from petroleum. As well, cyanobacteria and algae release hydrocarbons into the environment, where they are degraded by other bacteria that clean up oil spills. However despite their environmental and biotechnological importance, the exact cellular role of hydrocarbons has not been determined.
We recently discovered that hydrocarbons are essential for maintaining optimal cell size, growth and division, processes that require cell membranes to curve and bend, and found that cells lacking hydrocarbons have lipid membranes that are less curved or flexible. We showed that hydrocarbons integrate into the cell membranes, and used computer simulations to predict that this induces membrane curvature. To investigate this further, we have assembled a team of scientists from the UK, Sweden and New Zealand. By combining our different skills, we will analyse how hydrocarbons affect the physical properties of algal and cyanobacterial membranes by 1) running computer simulations; 2) studying membranes purified from algae and cyanobacteria; and 3) carrying out experiments on live cells. Together, these simulations and experiments will allow us to explore and quantify how hydrocarbons affect curvature and other membrane properties, and so conclusively establish the role of hydrocarbons in cells. As well as improving our understanding of biology, this information will assist the use of microbes for biofuel production and oil spill cleanup.

2019 -
Grant Awardees - Program

How complex behavior is encoded in the genome and wired in the brain


Dept. Genes - Circuits - Behavior - Max Planck Institute of Neurobiology - Martinsried - GERMANY

STREELMAN Jeffrey Todd (USA)

School of Biological Sciences - Georgia Institute of Technology - Atlanta - USA

Despite effort, it remains incredibly difficult to identify the cellular basis, and/or the causative genetic variants, underlying complex behavior. Understanding how behavior is encoded requires solving a dual problem involving both neurodevelopment and circuit function. Genes build nervous systems; nervous systems are activated to produce behavior. Streelman and Baier will collaborate to develop a unique model system to chart the complex path from genome to brain to behavior, in vertebrates from natural populations. In Lake Malawi, male cichlid fishes construct sand ‘bowers’ to attract females for mating. Bower building is an innate, repeatable natural behavior that we quantify in the lab. Males build two bower types: 1) pits, which are depressions in the sand, and 2) castles, which resemble miniature volcanoes. Species that build these two bower types can interbreed in the lab. Remarkably, first-generation hybrids of pit- and castle- species perform both behaviors in sequence, constructing first a pit and then a castle bower, indicating that a single brain containing two genomes can produce each behavior in succession. Moreover, brain gene expression in these hybrids is biased towards pit- alleles during pit digging, and castle- alleles during castle building. This phenomenon of allele-specific expression matched to behavior is compelling and offers the chance to identify the genome regulatory logic and neural circuitry underlying complex behavior. Streelman’s group will use single-cell RNA-sequencing to pinpoint specific cell populations that mediate context-dependent allele-specific expression in male bower builders. Baier’s team will use genome editing and optogenetic tools to manipulate the neurons that matter in the brains of behaving Malawi bower builders. Our collaborative work will thus identify the neurons responsible for biased allelic gene expression matched to behavior, and then manipulate those neurons to modify behavioral output. Achieving our goals will demonstrate how the genome is activated in particular cell types to produce context-dependent natural social behaviors.

2019 -
Grant Awardees - Program

3D atomic-scale movies of molecular machines in action


Dept. of Biochemistry - University of Washington - Seattle - USA


Dipartimento di Elettronica, Informazione e Bioingegneria - Politecnico di Milano - Milan - ITALY


Dept. of Biochemistry - University of Zurich - Zurich - SWITZERLAND

WEISS Shimon (USA)

Dept. of Chemistry and Biochemistry, Dept. of Physiology - University of California, Los Angeles - Los Angeles - USA

Capturing the dynamic 3D atomic-scale structure of a macromolecular machine while it performs its biological function remains an outstanding goal of biology. Conventional structural tools (e.g. X-ray crystallography, NMR & cryoEM) only provide ‘snapshots’ of stable states along a reaction pathway. Reaction intermediates, and in particular short-lived intermediates, are hard to capture and characterize with such conventional techniques. Here we propose to combine (prior) information from multiple existing static structures of stable states with dynamic datasets of inter-atomic distances obtained by high-throughput non-equilibrium single-molecule FRET (smFRET) measurements in a microfluidic mixer using novel time-resolved multi-pixel single-photon avalanche diode detector. These measurements will be performed on libraries of molecular constructs, sampling multiple inter-atomic distances as function of reaction time. These measured distance distributions will then serve as multiple intra- and inter-domain distance constraints which, together with prior information (available structures), will enable the Rosetta software to achieve large-scale energy optimization-based refinement of time-resolved ‘snap shots’ of complex structures with improved accuracy. These time-resolved Rosetta structures together with intermediary molecular dynamics simulations will allow solving the 3D atomic-level structure of the macromolecule for each sampled reaction time point, eventually producing a 3D structural dynamic movie of the macromolecule in action. To demonstrate the utility of the proposed method, we will solve the dynamic structure of RNA polymerase during transcription initiation (promoter binding, bubble opening, abortive initiation, promoter clearance) and a pair of intrinsically disordered proteins (IDPs) involved in transcription regulation (ACTR and NCBD) that adopt a fully folded structure during a coupled folding and binding reaction. In addition to elucidating outstanding questions in transcription by combining detector developments, high-throughput and time-resolved out-of-equilibrium single-molecule FRET measurements with new experimentally-constrained molecular structure computational approaches, this multidisciplinary project will result in a new generic toolkit applicable to a large array of enzymes, proteins and molecular machines.

2019 -
Grant Awardees - Program

nFlare: an innovative light approach to study and modulate neuronal activity in vitro and in vivo


Dept. of Neurobiology- neuron physiology and technology lab - International School for Advanced Studies SISSA-ISAS - Trieste - ITALY


Dept. of Chemical Engineering and Biotechnology - University of Cambridge - Cambridge - UK


Dept. of Chemistry - The University of Chicago - Chicago - USA

To understand how the brain represents the world is a central theme in neuroscience. Neural circuits encode information in terms of rate, timing and synchrony of action potentials arising from the activity of a complex spatial organization of excitatory/inhibitory neurons. The identity of the active neurons at any given time has a profound effect onto the final outcome and regulates fundamental human psychophysical behavior. Attempts to decode the complex behaviors in neurons has led to development of several neuromodulation and sensing tools, by which neural activity can be controlled by microelectrodes or through genetically altering specific neural circuits, ultimately to deliver electrical impulses. Unfortunately, these techniques introduce strong perturbations to the observed system, without reaching the desired spatio-temporal resolution. Experimental approaches that allow non-invasive activation of specific phenotypic groups of neurons could introduce systematic variation of the timing of signals revealing how neural ensembles encode information. Here we propose a novel (nano)tool to alter membrane potential in specific neuronal phenotypes in a spatiotemporally controlled manner.
The nFlare project will develop a novel research paradigm in neuroscience based on a new class of injectable nanodevices delivered to neurons and anchored to their membranes. These nanotools have the ability to depolarize cell membranes or to deliver active biomolecules. Electric or chemical stimulation of single cells will be achieved using deep-penetration near infrared excitation light, to reduce invasiveness.
nFlare core aims are: i) the development of nanodevice components able to generate photoelectrochemical current upon illumination with light; ii) state-of-the-art biochemical functionalization of the nanodevice to target specific neurons and to reduce inflammatory response; iii) applicability of such nanoscale devices as high spatio-temporal neuronal activity modulators in 2D and 3D in vitro neuronal networks followed by in vivo validation.
Selective modulation of neural circuits by artificial stimulation of neuronal membrane or controlled delivery of environmental factors could help answering fundamental neurobiological questions.

2019 -
Grant Awardees - Program

Navigating the waters – A neural systems approach to spatial cognition in fish


Dept. of Zoology - University of Oxford - Oxford - UK


Dept. of Active Sensing - Bielefeld University - Bielefeld - GERMANY


Division of Biology / Mueller-lab - Kansas State University - Manhattan (Kansas) - USA


Dept of Biomedical Engineering and Dept. of Life Sciences - Ben-Gurion University - Beer-Sheva - ISRAEL

In 2014, the Nobel Prize in Physiology was awarded for the discovery of place and grid cells that process spatial cues in the mammalian hippocampal formation;, the key structure for both navigation and episodic memory1. Place and grid cells, and additional cell types form the central building blocks in the current circuit models of navigation in mammals. However, a cohesive picture of how these circuits compute space and enable navigation has not been achieved. In fact, emerging evidence suggest that these navigation circuits are highly diverse in cellular phenotypes and functionality; they do not only map aspects of space but also elements like sound, time, and reward. How neural systems of spatial cognition have evolved outside of the mammalian clade is not clear, and comparative studies are critically needed to gain insights to basic functional constraints and structural requirements underlying these neural circuits.
The international research team of four PIs proposes a broad comparative systems neurobiological approach using teleost fish for integrative studies on higher navigation circuits. These fish are ideal models because they have conquered diverse spatial ecologies and show highly specialized sensory adaptions. Also, their brains exhibit an overall lower complexity to mammals, and are highly accessible to experimental manipulation. To establish systematic research on teleostean spatial cognition, the project combines neuroethological, electrophysiological, neuroimaging, and computational methodologies. Introducing a powerful electrophysiological recording technology in freely-moving fish and generating long-needed anatomical atlas resources, the project analyzes four teleost species with differing spatial ecologies. The team will uncover how different sensory modalities like vision, perception of depth, and active electrolocation are integrated during spatial navigation tasks, thereby investigating how top-down mechanisms modulate sensory integration of spatial learning.
Finally, the team will test specific hypotheses developed in small-scaled laboratory setups in an unconstrained natural environment. Here, the group will measure the activity of neurons in freely moving fish that explore a coral reef habitat. This will be the first ever attempt to analyze brain activity underlying navigation in the wild. Altogether, the project will provide new perspectives on the evolution, function, and mechanism of memory systems in animal navigation.

2019 -
Grant Awardees - Program

Imaging viral RNA genome assembly with high spatial and temporal resolutions inside infected cells


Dept. of Physics - Massachusetts Institute of Technology - Cambridge - USA


Faculty of Biology and Astbury Centre for Structural Molecular Biology - University of Leeds - Leeds - UK


Dept. of Virology - Institut Pasteur - Paris - FRANCE

Sporadically, novel and potentially devastating pandemic influenza A viruses (IAVs) are generated through genome reassortment between human and animal co-infecting IAVs. Such pandemic viruses emerge as a consequence of the segmentation of IAVs genome into a bundle made of 8 distinct viral RNAs (vRNAs). However the molecular mechanisms of vRNA intracellular transport and assembly into vRNAs bundles, which are critical for reassortment, remain largely unknown. Our project aims to elucidate these fundamental aspects of IAV life cycle by developing innovative approaches.
We challenge the original model that newly synthesized vRNAs, in the form of viral ribonucleoproteins (vRNPs), are transported across the cytoplasm on Rab11-dependent recycling endosomes. Based on our recent work, we hypothesize that the concomitant transport and assembly of vRNPs is driven by their physical association with remodelled endoplasmic reticulum (ER) membranes and Rab11-dependent transport vesicles distinct from recycling endosomes.
We will set up a cellular system which resembles the natural respiratory tissue targeted by IAVs, while being amenable to simultaneous imaging of the endogenous Rab11 protein and tagged vRNAs. We will develop two cutting-edge and complementary imaging methods: dual-color single molecule fluorescence in situ hybridization (FISH) in live cells for the tracking of distinct vRNAs that diffuse concomitantly, and cryo-Focused Ion Beam combined with electron microscopy in situ hybridization (EMISH) to image individual vRNPs and their transport vesicles at molecular resolution. We will further assess the role of cellular ER-shaping proteins by performing CRISPR/Cas9-mediated knockdowns, and by monitoring changes in the viral-induced remodelling of ER and biogenesis of vRNP transport vesicles by live fluorescence imaging and cellular EM.
The proposed research will require the very close collaboration between three partners with distinct but complementary expertise. The approaches developed jointly are poised to revolutionize our understanding of IAV multi-RNA genome transport and bundling, and thus help in the broader goal of achieving better prevention and treatment of influenza disease. Additionally, the proposed technical developments in live cell FISH and cellular EM, will have impact on other fields of studies well beyond the scope of the proposed project.

2019 -
Grant Awardees - Program

Phase separation of glycolytic machinery as a fundamental mechanism in energy metabolism


Dept. of Cell Biology; Program in Cellular Neuroscience, Neurodegeneration and Repair - Yale School of Medicine - New Haven - USA

HYMAN Anthony (UK)

Dept. of Cell division - Max Planck Institute of Molecular Cell Biology and Genetics - Dresden - GERMANY

Glycolysis is a fundamental energy metabolic pathway which consists of ten enzymatic steps. Unlike the mitochondrion, which is a membrane-bound organelle, glycolytic enzymes are soluble proteins in the cytosol. Based on biochemical evidence, glycolytic enzymes have long been hypothesized to form functional complexes to sustain the rates of glycolysis. This purported complex, called the glycolytic metabolon, was a subject of intense study and debate thirty years ago. Still today we do not yet understand how these purported complexes are organized in cells to sustain local energy metabolism, or their physiological importance. This gap in knowledge results from the fact that when glycolysis was being rigorously examined forty years ago, the techniques did not exist to conclusively answer these questions. The main challenge in addressing these questions lay then, as now, in the ability to both examine the localization of the glycolytic enzymes in living cells, while understanding the biophysical and biochemical mechanisms of their association, and its implications in cellular physiology. We have established a collaboration to address these fundamental questions by making use of our joint expertise in vitro reconstitution and C.elegans physiology, using the energy demands of the C.elegans synapse as a model system.

2019 -
Grant Awardees - Program

An integrative approach to decipher flowering time dynamics under drought stress


Dept. of Biosciences - Università degli studi di Milano - Milano - ITALY


Dept. of Agricultural and Environmental Biology/Lab of Plant Breeding and Genetics - The University of Tokyo - Tokyo - JAPAN


Dept. of Integrative Biology - University of Texas at Austin - Austin - USA

Plants live in an ever-changing environment which is not always compatible with their survival. A major life threatening condition is drought stress. While most plants can deploy an array of physiological countermeasures to endure remarkable levels of stress, there is a huge variability in the different strategies that plants choose to adopt to deal with drought stress. Many plants evade detrimental stress conditions by activating their reproductive development (flowering) earlier compared to non-stress conditions, a strategy known as drought escape (DE). Notably, even in the most water-rich environments plants face unpredictable dry periods, yet how this information affects the floral network at the molecular levels is unknown.
We will address this question with a blend of molecular and genetics-based approaches. We will leverage known mutants with altered DE to identify candidate mechanisms that are drought sensitive and can act as molecular switch to activate flowering. To comprehensively define DE mechanisms utilized under natural conditions we will assess the variability of the DE response in natural plant populations and in crops, which were selected by human intervention for the different field scenarios. Our targeted large-scale screens will allow us to identify naturally occurring variants in the DE process and decipher the molecular mechanism responsible for DE activation. This information will provide breakthroughs in our understanding of novel regulatory mechanisms that play a role in driving developmental adaptations across extremely variable environmental conditions, their natural genetic variation and the selective forces that maintain such variation in populations, an important aspect for predicting and dealing with the effects of climate change. Finally, because flowering time is a major component of yield potential in crops, the defined mechanisms will help us develop breeding strategies targeted for sub-optimal irrigation scenarios to produce crops with ameliorated performances under drought conditions.

2019 -
Grant Awardees - Program

Regrowing the brain: evolution and mechanisms of seasonal reversible size changes in a mammal


Dept. of Ecology and Evolution - SUNY Stony Brook - Stony Brook - USA


Dept. of Migration and Immunoecology - Max Planck Institute for Ornithology - Radolfzell - GERMANY


Dept. of Health Science and Technology - Aalborg University - Aalborg - DENMARK

Organisms need strategies to survive when conditions are hard. For mammals, winter is particularly difficult - they have to invest large amounts of energy into keeping warm, while food availability is low. For this reason, many mammals migrate or hibernate. However, what to do if you are too small to migrate long distance, burn your energy fast, and cannot hibernate? The common shrew is such a mammal and has evolved an astonishing strategy: each individual shrinks in winter by up to 20% and then regrows in the spring by about 13%. This size change, thought to allow shrews to survive on fewer resources because of the smaller size and linked lower energy requirements, include not just overall size, but specifically organs that do not usually change size in fully grown animals, such as the brain, heart and liver.
The process of neurological degeneration and regeneration is of great interest, since many central nervous system diseases (e.g., Alzheimer’s, multiple sclerosis) involve degeneration, but ongoing research for therapies to reverse this process has been of limited success. As one of only a few recorded examples of mammalian brain regeneration, understanding how the shrew regrows its brain can accelerate research that leads to future therapies.
To answer the question of how the shrew shrinks and then regrows its brain, we will establish this unusual species as a new model, by studying the biological, molecular, biochemical and genetic processes behind this reversible size change. Besides establishing a database of information that can be mined and researched in years to come to discover the pathways that generate this cycle in the shrew, we will test a metabolic model of neurological change by artificially blocking molecular access to fats. Thus, the cross-disciplinary study of this wintering adaptation may help us understand more about regeneration in mammals in general, and the brain in particular.

2019 -
Grant Awardees - Program

Molecular approaches to study individually identified mechanosensory neurons of the leech


Instituto de Fisiologia Celular-Neurociencias - Universidad Nacional Autónoma de México - Ciudad de Mexico - MEXICO


Dept. of Life Science - National Taiwan University - Taipei - CHINA, REPUBLIC OF (TAIWAN)


Institute FBMC - University of Buenos Aires - Caba - ARGENTINA


Dept. of Molecular and Cell Biology - University of California, Berkeley - Berkeley - USA

To study how nervous systems arise and function, scientists use animal models in which it is possible to integrate research on fundamental processes across different levels of organization from genes to behavior, and from the zygote to the adult. The medicinal leech (genus Hirudo) provides one useful model, because its nervous system is much simpler and easier to work with than vertebrate or mammalian nervous sytems, even though it functions in a similar manner--Hirudo has been used to study phenomena of general importance such as: how glial cells function; how neurotransmitter are released; how synapses form and regenerate; and how neural circuits function to control behavior. Another leech (genus Helobdella) is used to study development and how development changes during evolution, giving rise to kinds of animals over hundreds of millions of years. These two leech species exhibit marked similarities of course, but also some differences. Technical considerations (small embryos for Hirudo; small adults for Helobdella) have made it difficult to integrate these two models, e.g. by applying molecular approaches in Hirudo or to study the adult nervous system in Helobdella. The goals of our project are: 1) to enhance the power of the Hirudo model by introducing newly-developed molecular approaches; 2) to implement approaches in Helobdella that will enable us to unite molecular and cellular approaches to developmental and behavioral neurobiology; 3) to develop new optical techniques for stimulating and recording neuronal activity without exogenous dyes or genetic manipulations.
The intellectual significance of the proposed work is twofold. First, it will enhance our abilities to answer fundamental questions regarding how nervous systems function and development by introducing cutting edge technical approaches to the cellularly simple, physiologically accessible leech models. Of equal importance, it will provide a new evolutionary perspective into neurobiology, by allowing us to examine similarities and differences between leech and other models, including arthropods, nematodes, and vertebrates which have all been evolving separately for more than half a billion years.

2019 -
Grant Awardees - Program

Decoding the biomechanics of flight-tone based acoustic communication in mosquitoes

GIBSON Gabriella (USA)

Dept. of Agriculture, Health and Environment - University of Greenwich - London - UK


Dept. of Mechanical Engineering - Johns Hopkins University - Baltimore - USA

The aerial courtship “dance” of mosquitoes has fascinated entomologists for over 150 years. This dance involves highly controlled variations in the frequency and intensity of flight-tones (i.e. sounds generated by the flapping wings) with concurrent changes in flight speed and direction, and enables recognition of conspecifics, display of fitness and transmission of mating interest. However, despite over a century and a half of research, significant knowledge gaps continue to exist in our understanding of this behavior. To decipher this courtship dance, entomologists have to integrate acoustic, energetic and flight information for untethered, free-flying mosquitoes, but the tools that can provide these data have, so far, not been available. In the current project, the two investigators combine their respective expertise in computational biomechanics and acoustics, and behavioral entomology, to generate unprecedented data and insights into the biomechanics and physics of courtship-associated acoustic communication in mosquitoes. In particular, by combining computational modeling with biological assays, the team will generate six-dimensional soundscapes of free-flying mosquitoes engaged in courtship and determine how these soundscapes are actively modified during courtship. We will also estimate for the first time, the energetic costs of courtship and mate-chasing, and the potential constraints this places on courtship behavior. Finally, the team will characterize the degree to which, carefully tailored exogenous sounds can alter and even disrupt courtship. The success of this novel approach could be transformative for future research into comparative auditory mechanisms of communication across a wide range of flying insects. In addition, the insights gleaned here could form the scientific foundation for novel insecticidal/surveillance traps and also lead to environmentally friendly strategies for diminishing mating success in mosquito species that are vectors for malaria, Zika fever and other devastating mosquito-borne diseases.

2019 -
Grant Awardees - Program

Spatiotemporal neurochemical dynamics of behavioral flexibility in the striatum


Dept. of Medical Neurobiology - IMRIC - The Faculty of Medicine - Jerusalem - ISRAEL


Dept. of Biochemistry and Molecular Medicine/ Tian Lab - Universiy of California, Davis/School of Medicine - Davis - USA


Neurobiology Research Unit - Okinawa Institute of Science and Technology - Onna-Son, Kunigami - JAPAN

The overarching goal of this proposal is to investigate the spatiotemporal coding of acetylcholine (ACh) and dopamine (DA) with high-resolution and precision in the striatum using state-of-the-art genetically encoded biosensors combined with modern optics in awake animal imaging. The striatum is crucial for movement, learning and flexible behavior, with striatal DA and ACh both playing key roles in these functions. While the role of DA is relatively well established, the role of ACh in natural behavior still remains enigmatic. Cholinergic interneurons (CINs), the major source of striatal ACh, are involved in processing contextual information that guides flexible behavior. Locally, CINs also exert control over striatal DA release, hijacking DA axons and making them release ACh by activating nicotinic receptors near their terminals. We propose to image the spatiotemporal dynamics of striatal DA and ACh using two-photon microscopy and endoscopy in awake mice engaged in tasks requiring behavioral flexibility. To image DA and ACh simultaneously during behavior we will extend the color-spectrum of DA and ACh biosensors. We will also further optimize the performance of these biosensors to make them suitable for robust in vivo application. Our combined interdisciplinary but complementary expertise – in biosensor engineering, imaging, modelling and behavior – is essential for our aims. We will ensure a coherent, interactive approach by sharing procedures, behavioral tasks, and biosensor technology, with regular planning sessions and feedback of results. A successful outcome of this program will reveal, for the first time, the spatiotemporal coding of neuromodulatory signaling by DA and ACh and how it shapes the function of striatal circuits during flexible behavior. We will also obtain a mathematical understanding of the genesis of the spatiotemporal dynamics. The newly engineered sensors developed in the program will have further broad applications in various biological systems of interest, which will ultimately pave the way toward a more complete understanding of brain function at synaptic, microcircuit, and behavioral levels.

2019 -
Grant Awardees - Program

In vitro reconstitution of synaptic plasticity: a minimalist approach


Dept. of Pharmacology - Graduate School of Medicine - Kyoto - JAPAN


Dept. of Molecular Structural Biology - Max Planck Institute of Biochemistry - Martinsried - GERMANY


Division of Life Science - Hong Kong University of Science and Technology - Kowloon - HONG KONG, CHINA

Neuronal circuits store information through the mechanism of synaptic plasticity, a process where synaptic transmission is strengthened or weakened. Long-term potentiation (LTP) is a major form of synaptic plasticity. It requires both activation of CaMKII and subsequent trafficking of receptors and other proteins to the postsynaptic site. Despite extensive research, the causative relationship linking these two processes is still unknown. Here, Hayashi (live imaging and electrophysiology), Zhang (structure biology), and Lucic (cryoelectron tomography) will team up and take a unique minimalist approach to reconstitute synaptic plasticity from purified proteins. We will reconstitute postsynaptic density (reconstituted PSD or rPSD) on a glass substrate using a group of key scaffold proteins (PSD-95, SynGAP, SAPAP, Shank, and Homer) and receptor such as NR2B. Once a key process is found in minimal system, we will test if the same mechanisms work in intact neurons. Finally, we will investigate the persistent modification of the rPSD induced by the activation of CaMKII, which is expected to act as a hub for trafficking of various proteins. The network organization of the resulting complexes in vitro and in situ will be determined by cryo-electron tomography. The final goal of this proposal is to understand the minimum essential machinery for activity dependent delivery of postsynaptic proteins.

2019 -
Grant Awardees - Program

Communication and the coordination of collective behavior across spatial scales in animal societies


College of Science and Engineering - James Cook University - Townsville - AUSTRALIA


Dept. of Ecology, Evolutionary Biology and Behavior - Michigan State University - East Lansing - USA


Dept. of Evolutionary Biology and Environmental Studies - University of Zurich - Zurich - SWITZERLAND

ROCH Marie (USA)

Dept. of Computer Science - San Diego State University - San Diego - USA


Dept. of Biology - University of Konstanz - Konstanz - GERMANY

We propose to use new tracking technology and computational modeling to determine how vocal communication influences collective behavior in animal societies. Canonical examples of collective movement such as bird flocking and fish schooling involve cohesive groups making short-term decisions in a shared context. However, many animals form stable social groups that coordinate and cooperate over extended time spans, across varying distances, and in diverse contexts. In these stable animal societies, group members must make decisions despite varying access to information and exposure to the costs and benefits of coordinating. Moreover their decisions are likely to be shaped by the long-term social relationships among group members. To achieve coordination in such systems, many species use sophisticated signaling systems, such as vocal communication, that transfer information among group-mates. Animals can flexibly control the vocalizations they produce independent of their movements, resulting in a complex interplay between signaling and movement that ultimately drives group-level outcomes such as collective decisions and coordinated actions.
To understand the mechanisms underlying coordination in animal societies, we will record movements and vocal signals concurrently from all members of wild animal groups at a high resolution, and across varying degrees of spatial dispersion. We will compare three mammal species that face a common set of coordination task, but differ in cohesiveness: meerkats form highly cohesive groups, coatis are moderately cohesive, and spotted hyenas live in fission-fusion societies. In each species, we will 1) fit at least one entire social group in the wild with tags that continuously record fine-scale movements and vocalizations, 2) combine supervised and unsupervised machine learning to identify animal calls and movement states, 3) develop modeling approaches to reveal how animals integrate spatial and acoustic information, how information flows through groups, and how social interactions give rise to collective outcomes, and 4) conduct audio playback experiments to isolate causal factors driving collective dynamics. Combining these approaches with long-term data from field studies will shed light on both unifying features underlying coordination mechanisms across animal societies and differences imposed by distinct constraints.

2019 -
Grant Awardees - Program

Imaging sensory processing and memory storage in the octopus brain


Dept. of Neurobiology, Silberman Institute of Life Sciences - Hebrew University - Jerusalem - ISRAEL

NIELL Cristopher M. (USA)

Institute of Neuroscience - University of Oregon - Eugene - USA

Octopuses have highly complex brains and are capable of many advanced behaviors that involve cognitive abilities. However, their brains and nervous system evolved completely independently from those of vertebrates, and it is largely unknown how the brains of such seemingly “alien” animals perform vertebrate-like sensory and cognitive functions with this distinct brain organization. In this proposal, we will study how visual sensory information is processed and stored in the octopus memory system. In order to overcome the technical obstacles to achieve this, we will bring together two labs with complementary expertise. The Niell lab studies the visual system of mouse, using calcium imaging of neural activity to understand how cortical circuits perform the computations that underlying visual perception and behavior. The Hochner lab studies learning and memory in the octopus vertical lobe. They have used electrophysiological tools and behavior to show that the vertical lobe is organized in a simple fan-out fan-in architecture and demonstrates robust activity-dependent synaptic plasticity. However, these current experimental methods are not sufficient for understanding how learning and memory networks store sensory features that are likely represented sparsely in the activity of many individual neurons.

Together, we will implement two-photon calcium imaging techniques for the octopus brain, to directly observe how sensory information from the eye is processed and represented in the visual system as it is conveyed into the central brain. We will then measure how this information is stored in patterns of activity across the large population of small neurons in the memory centers of the octopus brain, within a learning paradigm. In other words, we will watch memories being formed from a visual input. We will also perform manipulations that will allow us to determine the role of synaptic mechanisms and neuromodulation that enable this storage and its modulation by reward and punishment signals. The result of this collaborative endeavor will be a comprehensive view of neural information processing, from sensory input to memory formation, in the unique and enigmatic brain of the octopus.

2019 -
Grant Awardees - Program

Synthetic biocompounds to direct neuronal circuit assembly


Dept. of Basic Neuroscience - University of Geneva - Geneva - SWITZERLAND

LIM Wendell (USA)

Dept. of Cellular and Molecular Pharmacology - University of California, San Francisco - San Francisco - USA

The cerebral cortex is composed of distinct subtypes of neurons organized in circuits allowing high-order functions such as integration of sensory stimuli and sensorimotor transformations. These different neuronal subtypes are connected with neurons located both within and outside of the cortex. Intracortical connectivity is mostly mediated by layer (L) 2/3 neurons, which form synapses with other cortical neurons within and across areas; instead neurons located in L5B project to sub-cerebral targets and are responsible for cortical output.
While the molecular diversity of cortical neurons and their circuit organization is increasingly understood, it is still difficult to genetically manipulate cortical neurons based on which circuits they belong to; the ability to do so would, however, be a critical skill to repair circuits when they are affected by injuries or neurodegenerative diseases. To address this challenge, here we combine our expertise in developmental neurobiology (DJ) and in bioengineering (WL) to develop a strategy to manipulate gene expression in cortical neurons in a circuit-dependent manner. We do so by engineering artificial synaptic contact-dependent signaling cascades to drive new cellular features.
Specifically, we will:
1. Assess the in vitro molecular identity and connectivity of pure populations of L2/3 and L5B cortical neuronal types and manipulate these cellular features by direct reprogramming of L2/3 neurons into L5B neurons (Aim 1).
2. Manipulate gene expression and cellular features of L2/3 neurons in vitro in a synaptic-contact dependent manner by developing a synaptic version of the synthetic notch (synNotch) receptor system (synsynNotch) (Aim 2).
3. Manipulate axonal projections of specific populations of intracortically-projecting neurons in vivo using the synsynNotch system (Aim 3).
Together, these experiments will increase our understanding of the mechanisms controlling cell-type specific circuit assembly and allow us to functionally interrogate this process through circuit-specific manipulation of gene expression.