Curiosity, defined as the intrinsic desire to know, is among the last unexplored frontiers of higher cognition, and we know very little about its neural mechanisms. We propose to address this question by developing a program for studying curiosity using an integrated empirical/computational approach in humans and non-human primates. We examine the hypothesis that curiosity is a family of mechanisms that evolved to allow animals to maximize their knowledge of the useful properties of the world – i.e., the regularities that exist in the world - using active, targeted investigations. In two experiments, we probe two processes that contribute to curiosity-based exploration. In experiment 1 we examine how agents ascribe value (“interest”) to surprising events, by (1) developing a new behavioral task where children and monkeys make tradeoffs between exploring for sources of reward versus exploring a surprising item, and (2) investigating single-neuron responses related to curiosity-based exploration in cortical areas implicated in the control of attention. In experiment 2 we ask whether subjects show a more sophisticated form of curiosity guided by learning progress – a meta-cognitive tracking of the amount of learning that the individual can make in a task - using new behavioral paradigms where children or non-human primates see a set of symbolic learning problems and freely choose which ones to explore. To quantitatively model curiosity we use the framework of Bayesian Reinforcement Learning, which allows us to infer the agent’s beliefs about the probabilities of various events (rewards, surprises, or learning), the value they place on sampling different events, and how this value depends on the task context. The studies closely integrate the expertise of the 3 member teams in developmental psychology (Kidd), neurophysiology of non-human primates (Gottlieb) and computational modeling of active learning in robotic systems (Oudeyer). Our goal is to develop an integrated theory that (1) incorporates curiosity in established quantitative frameworks of learning and decision making, (2) links it with core cognitive functions such as selective attention, (3) compares its expression in humans and non-human primates, and (4) begins to elucidate its neural mechanisms.

In the brain, the balance between excitation and modulation plays a crucial role in numerous cognitive processes and pathological impairments of this balance may underlie several neurological disorders. Indeed, dysregulations of two neurotransmitter receptor families, glutamate NMDA (NMDAR) and dopamine (DAR) receptors, are believed to play a direct role in the emergence of psychotic disorders such as schizophrenia. Thus, understanding how these two neurotransmission systems communicate is of growing interest. Intensive investigations have identified intracellular and genomic cascades involved in this dialogue. However, the recent discovery that NMDAR and DAR diffuse and physically interact at the surface of neurons profoundly changed our view of neurotransmitter signaling. A major challenge is now to unveil the contribution of DAR/NMDAR complexes in the regulation of living brain circuits. To this aim, we will combine complementary expertise to investigate the surface crosstalk between NMDAR and DAR both in physiological and psychotic disorder contexts, focusing our attention on D1R, D2R, and NMDAR in hippocampal, prefrontal and striatal circuits. We will assess the roles of this dynamic receptor interplay from a multi-scale perspective. We will first investigate the rules of the DAR/NMDAR surface dialogue at the single molecule level by mapping all interaction sites and monitoring receptor distribution and diffusion using multi-color single molecule imaging in vitro and in brain slices at several developmental stages, both in control and in models of schizophrenia. We will then investigate whether the DAR/NMDAR surface crosstalk regulates glutamatergic transmission along the dendritic tree, its impact on NMDAR-dependent plasticity, and its role in dendritic outgrowth and spine maturation during development using two-photon calcium imaging, electrophysiological recording and competing peptides. Finally, we will investigate the influence of the DAR/NMDAR interplay on physiological and pathological network dynamics and behaviors using multi-electrode array recordings, optogenetic release of dopamine, competing peptides and “data-mining” statistics. In conclusion, we will join international forces to shed the first lights on this unexpected dynamic integration level using nanoscopic, macroscopic and mesoscopic approaches.

The oceans are teeming with microbial life, which impacts global biogeochemistry, climate and human health. Omics methods enable us to identify "who is there" and their genetic potential, but understanding how these organisms interact in nature and how they affect biogeochemical processes remains a major open challenge. A crucial component of this puzzle, at the heart of the cycling of nutrients in the biosphere, is the coupling between organisms that fix carbon using solar energy (phytoplankton) and microbes that rely on organic carbon for energy and growth (heterotrophs). The diversity of microbial species and the richness of their metabolism make the problem of predicting how each pair of species will interact impossible to address using traditional approaches. We propose to tackle this challenge through a tightly integrated combination of genome scale modeling and laboratory experiments, to identify genomic traits dictating how environmentally-relevant microbes interact. We will generate a library of ~100 heterotrophic bacteria representing major marine lineages and fully sequence and annotate their genomes. We will implement genome-scale (dynamic flux balance) models of each of these organisms, as well as of four key phytoplankton species, calibrating these models using high-throughput measurements of growth under different conditions. We then grow binary phytoplankton-heterotroph co-cultures in the lab and compare the results with in-silico models of the interacting genomes, studying key interactions in more detail. Recognizing that microbes in the ocean are seldom in steady-state, our work will encompass exponential growth, stationary stage and culture death. Most importantly, missing or incorrectly predicted interactions will give us an opportunity to revisit our models, and suggest the mediation of alternative processes such as allelopathy or other types of chemical signaling. This study will provide the first detailed "roadmap" linking genomic traits (genes and metabolic pathways) and rate measurements with species interactions in environmentally-relevant microbes. Our approach, which - we anticipate - will be embedded in a not-so-distant future in global-scale models of the Earth System, will provide a critical stepping-stone towards predicting how marine microbial systems will evolve in a changing world.

Monomeric actin is readily detectable in the nucleus of mammalian somatic cells. Whether this pool of actin forms filaments has been debated for decades. Recent advancements have established that, indeed, nuclear actin can assemble dynamic filamentous structures in response to external stimuli. However, how nuclear actin filaments exert their biological function remains an unanswered question in cell biology. This is particularly relevant given the highly dynamic nature of nuclear actin filaments, which reside within the intricately organised nucleus that harbours the genome in the form of chromatin. Thus, through this collaboration, we aim to address this by developing and applying novel approaches for optogenetics, advanced cell-imaging and next generation sequencing. Accordingly, we will employ tools to spatiotemporally control nuclear actin filaments with light, and determine their role in regulating chromatin organisation and nuclear structure. Further, we will determine the cell and biological consequences of actin filament-driven chromatin organisation/re-organisation in relation to cell division and cellular reprogramming. By completing these studies, we envisage to advance our understanding of the biological functions of nuclear actin filaments in a manner that will encompass nuclear actin polymerisation as a key mediator of chromatin organisation and regulation. Beyond this, findings from our studies may have translational potential in areas of regenerative medicine, and may delineate new mechanisms that underlie ageing and degeneration.

Retinotopy, the pattern of axonal projections in visual processing centers that preserves the spatial arrangement of photoreceptor (PR) in the retina is a key feature of any complex visual system. I offer to investigate how retinotopy is built in the Drosophila visual system focusing on the medulla neuropile. Medulla neurons are generated sequentially by the Outer Proliferation Center and build 800 columns onto which inner PRs (R7 and R8), also sequentially generated along a posterior to anterior axis in the eye disc by the progression of the morphogenetic furrow, project retinotopically.

To find what are the medulla neurons that support PR retinotopic projections, I will first generate tools to visualize medulla column generation and test by a genetic approach several neuronal populations. I will then determine whether developmental synchrony between the waves of differentiation in the eye disc and medulla is required along the antero-posterior axis for PR retinotopic projection onto medulla columns. I will genetically modulate the speed of both waves in order to desynchronize them and look for retinotopic defects. I will then investigate how those two waves are coordinated. In parallel, I will find genes responsible for dorso-ventral patterning of the medulla by a differential transcriptomic strategy. I will purify ventral medulla neurons by intersectional approaches and compare their expression profile to the entire medulla neuron population.

Completing those three aims will allow me to uncover the developmental rules and signaling pathways responsible for building a complex and immensely precise architecture such as neuronal retinotopic maps.

Enhancers and core promoters are key regulatory elements underlying the precise spatio-temporal regulation of gene expression. Despite recent efforts to map and characterize these elements genome-wide, it is still unclear how their activities are encoded in the genome. Moreover, we are just beginning to unravel the role of the specificity between enhancers and core promoters in transcriptional regulation.
Novel genome-wide activity-based assays for identification of enhancers and core promoters (STARR-seq and its variant) developed in the host lab provide a unique opportunity to quantify sequence-encoded activities in a highly controlled manner. In collaboration with the experimentalists I propose to apply STARR-seq in human cells to measure both enhancer and core promoter activities and assess their specificity. Using these data I will apply sequence analysis and modeling approaches with an aim to establish a quantitative relationship between sequence and activity for both types of elements. I am aiming to reveal differences and commonalities in sequence requirements for a genomic region to act as an enhancer or as a core promoter, allowing me to build a comprehensive model of transcriptional regulation in human. Given the diversity of mammalian core promoters, I will also test whether enhancers and core promoters exhibit mutual preferences and will attempt to uncover sequence determinants underlying such specificity. Finally, using published datasets I will assess how these intrinsic activities are modulated by the endogenous chromatin and sequence context. My results will further our understanding of gene regulatory elements and their interpretation by human cells.

Like human babies learning speech, young songbirds learn to produce song by imitating adults. Both babies and young birds need to listen to adult vocalizations, extract the relevant information and store it in the brain and then improve their own ‘babbling’ sounds step by step towards the adult version. Experiments on vocal learning have focused mainly on sounds, although sight also seems to play an important role. Babies of only 8 weeks of age already associate speech sounds with the correct mouth position required to make that sound. Moreover, people report that they hear the syllable ‘ga’ when in fact a loudspeaker plays ‘pa’ while a video screen shows the face of a speaker mouthing ‘ka’. This perceptual phenomenon is known as the ‘McGurk' effect. It reveals that sensory information from the ear and eye are integrated in the brain to form a combined, multimodal percept.
Like human speech, birdsong can be heard and seen. Young birds see their fathers moving their beaks while hearing their song. There is substantial evidence to assume that the combined exposure to acoustic and visual cues enhances song learning not only in human but also in bird babies. We aim to uncover the role of this multimodal perception and its underlying neural architecture in vocal learning. Focusing on the zebra finch, the prevalent animal model for molecular, neural and developmental aspects of human speech we will adopt a robotic approach that allows full experimental control over auditory and visual cues.
Simultaneously recording acoustic and visual cues of singing adult birds, we will analyze synchrony between different song elements and the opening and closing of a bird's beak. We will use this to develop a robotic zebra finch that allows us to create matched and mismatched multimodal stimuli. Juvenile birds will be raised with various tutoring regimes to assess the relative roles of unimodal versus multimodal cues, life versus robot cues, and matched versus mismatched cues. Upon reaching adulthood, tutored birds will be tested on their song copy performance (males only), song preference (females only), or discrimination ability (all birds). Finally, we will use a subset of tutored birds to study underlying neural processes by using molecular tools that allow us to pinpoint where in the brain multimodal information is processed and how this is linked to vocal learning.

The adult mammalian stomach epithelium is constantly renewed by proliferative isthmus stem/progenitor cells (ISPCs) and maintains its homeostasis under hostile luminal conditions. In the gastric corpus epithelium, differentiated Troy+ chief cells were identified as a novel stem cell population with high plasticity. Interestingly, Troy+ stem cells (TroySCs) can switch between a dormant and active state. TroySCs proliferate very slowly in homeostasis, whereas they rapidly divide upon ISPC loss facilitated by 5-FU treatment. This suggests its role as a reserve stem cell for the ISPC. However, TroySCs are also activated upon parietal cell loss despite the presence of actively cycling ISPCs. Thus, the role of TroySCs still remains vague in homeostasis and regeneration from various injuries. Here, I propose to investigate a potential role of TroySCs, beyond that of the reserve stem cells, by combining state-of-the-art mouse genetics, single cell transcriptome analysis, and mathematical modeling. First, I will characterize the population dynamics of the corpus epithelial cells under homeostasis and regeneration by lineage tracing and single cell analysis in mice. Second, based on the cell population data, I will construct a mathematical model for the corpus epithelium and theoretically investigate the function of TroySCs by perturbing their dynamics. Third, I will experimentally examine the role of TroySCs using in vivo and in vitro functional genetics. This work will reveal an essential role of quiescent stem cells in homeostasis and pathogenesis and shed light on a fundamental question about why quiescent and active stem cell populations coexist in various adult tissues.

Engineering of recombinant pathways in microbial hosts is a powerful tool to provide access to sustainable building blocks for the chemical industry. Such a bottom-up synthesis route has recently been established for monomeric phenylpropanoids. However, the yield and diversity of products obtained are still lagging behind their natural plant biosynthetic pathways. The aim of the herein described project is to explore and develop tools for the reconstitution of plant metabolic pathways in bacterial hosts: namely, tools for the availability of bacterial strains as framework, for protein engineering and for identifying novel pathway enzymes for crucial product tailoring steps.

Therefore, I propose to investigate the applicability of Corynebacterium glutamicum as a bacterial chassis for plant metabolic pathways in general and the phenylpropanoid pathway in particular. I am going to develop genetic tools based on the CRISPS/Cas9 system to allow the fast incorporation and screening of various pathway enzymes and promoter combinations. I furthermore propose to investigate the effect of tethering Cytochrome P450 (P450) enzymes – a typical bottleneck in reconstituted pathways - to their redox partners, on in vivo P450 activity. Lastly, I propose to investigate the correlation of sequence, structure and function of crucial product tailoring O-methyltransferases from various organisms to enable the classification of such enzymes based on sequence homology.

The proposed study will not only increase the efficiency of the synthetic phenylpropanoid pathway but provide tools to further our abilities in manipulating microbial hosts for fermentative production of valuable chemicals.

The biggest challenge in glioblastoma research is to understand the inherent cellular heterogeneity. While much research has been dedicated to glioblastoma stem-like cells (GSCs), a small population of tumor cells that resides at the apex of a differentiation hierarchy and underlies therapy resistance, differentiated glioblastoma cells have not received the same attention.

I hypothesize that glioblastoma is characterized by a previously underestimated extent of cellular differentiation. Dedicated differentiated cell types provide the tumor with a selective advantage, e.g. by promoting angiogenesis and evading the immune system, and by supporting GSCs with essential maintenance and cell division cues. Therefore I propose to accurately define the cellular composition of primary human glioblastoma using microfluidics-enabled transcriptome profiling of thousands of individual cells. Using sophisticated computational methods, this dataset will reveal previously unrecognized cell types, and inform on their roles in tumor formation. Additional epigenetic characterization of tumor cell subpopulations will define cell type specific gene regulatory networks and inform on the molecular consequences of common genetic alterations.

I further hypothesize that tumors of different patients are composed of varying stem-like and differentiated cell types and that cell type frequencies differ between patients. Incorporating the new information on tumor heterogeneity will allow me to redefine glioblastoma subclassification. This will lead to more accurate patient prognoses, and ultimately to the development of subtype-specific therapies and the design of more targeted clinical trials.

The endosomal system is regulated by the interplay of distinct endosomal classes and its interactions with other cytoplasmic organelles within the cell. Identifying the molecular players and mechanisms that regulate the endomembrane system is essential because defects in the system are implicated in human disorders. The previous genome-wide RNAi screen performed in the host lab found numerous metabolic and signaling genes known to be localized to other cellular organelles that affected epidermal growth factor (EGF) and transferrin trafficking, underscoring the importance of inter-organelle communication. However, little is known about the underlying molecular mechanisms. In this proposal, I will perform a focused RNAi screen using a quantitative multiparametric analysis in order to identify factors governing intra-cellular positioning and functional interactions between distinct endosomal classes, such as early and recycling endosomes. I will also search for organelle-specific genes belonging to endoplasmic reticulum, mitochondria, lipid droplets, and peroxisomes that are functioning at the membrane interface with endosomes for inter-organelle tethering and signaling. Finally, I will investigate the physiological function of candidate genes in a primary cell culture system. The project outcome will lead to a better understanding of the endosomal system and the molecular mechanism of inter-organelle communication.

Neuroscience research using rodents as an animal model relies on the assumption that results should generalize across species to primates and ultimately to humans. However, many brain areas, including the neocortex, have species specific functional organizations. The mouse lemur (Microcebus murinus), the World’s smallest primate, has the potential to become an ideal animal model bridging the gap between rodents and primates. It has most the advantages of the rodent model (small brain size, quick reproduction, relatively short life cycle), but additionally offers the evolutionary closeness of primates. Therefore, the mouse lemur promises to revolutionize the transferability of experimental results from small sized animal models to human applications. In this project, three labs will combine their expertise in primate behavior, in-vivo optical imaging, and cutting edge histology and molecular biology to explore the functional organization of the mouse lemur cortex, as well its behavioral and cognitive capacity. This collaborative project will lay the groundwork to establish the mouse lemur as a novel neuroscience model system.

In order to ensure genome stability, DNA repair is highly regulated by the cell division cycle. A major, but largely unexplored question pertains to mechanisms that promote genome stability when DNA damage occurs on segregating chromosomes. My host laboratory discovered that cells suppress the repair of DNA double-strand breaks (DSBs) in mitosis to prevent chromosome segregation errors. These occur as a consequence of repair-mediated telomere fusions. The overarching objective of my project is to address the biological significance of mitotic DSB repair inhibition in vivo by generating a transgenic mouse in which I can conditionally de-suppress DSB repair in mitosis. This system will enable me to identify the tissues and developmental processes sensitive to the genome instability caused by mitotic DSB repair and to test whether inhibition of mitotic DNA repair is a tumour suppression mechanism. In parallel I will elucidate the molecular mechanism that causes the observed telomere fusions. Based on previous results, I hypothesize that the kinase Aurora-B mediates mitotic telomere uncapping through targeting of the telomeric Shelterin complex. I will test whether active Aurora-B localizes to telomeres using a FRET-based activity sensor and identify its target among the Shelterin subunits. Since telomere fusions are enhanced upon exposure to ionizing irradiation, I will also clarify the crosstalk between Aurora-B and the DNA damage response. This project comprises phenotypic animal studies and mechanistic cell based studies and thus represents a major departure from my previous work on the genomics of yeast DNA replication.

Muscle resident stem cells, Satellite Cells (SCs), maintain tissue homeostasis and regenerate skeletal muscles. In the event of an injury or stress, SCs break from quiescence, proliferate and differentiate or self-renew. Metabolic activity controls stem cell proliferation and differentiation in young healthy mice. However, whether metabolic activity is altered during aging in SCs and/or niches is poorly studied. Furthermore, whether cell autonomous or non-autonomous metabolic effects drive age-dependent SC functional decline is completely unknown. Our objective of this proposal is to use metabolic profiling in SCs and their niche during aging to identify a novel stem cell-to-niche communication mechanism. We speculate that upon aging, SCs accumulate lactate that causes a loss of stem cell function. In addition, we speculate that shuttling of lactate, the end product of glycolysis, from muscle fiber and taken up by SCs is a major contributor to the SC metabolic state and functional decline during aging. In this proposal, we will generate 1) metabolic profiles of adult and aged SCs and their niches, 2) in vivo inducible cell-specific genetic mouse models to delete lactate dehydrogenase A (LDHA) from SCs and niche, and 3) in vitro approaches to disrupt lactate signaling between the niche and SCs using lentiviral knockdown constructs targeting lactate transporters (MCT1-4) and receptors (GPR81). We will use muscle regeneration assays to evaluate the role of lactate signaling on stem cell function and tissue repair during aging in vivo. These data will provide novel insights toward stem cell-niche interactions as well as further our understanding of aging biology.

Throughout evolution, the human genome has been attacked by retrotransposons, parasitic DNA elements that spread through our genome by a copy-paste activity. I previously showed that SVA elements, the youngest class of retrotransposons in our genome, harbour a strong gene-regulatory potential, which is normally repressed by KRAB zinc finger protein ZNF91 (Jacobs et al., 2014, Nature). However, for reasons unknown, repression of retrotransposons is much less efficient in neurons, resulting in the activation of the hidden enhancer potential of SVA elements spread throughout the human genome. The importance of these SVA insertions for the evolution of human neural gene-regulatory networks, and how many genes have come to depend on SVA's regulatory influence, remains elusive. This research program uses 'cortical organoids’; 3-dimensional brain tissues derived from human and primate stem cells, to investigate how recent SVA insertions have impacted human neuronal gene expression. Furthermore, I will investigate how changes of the epigenetic landscape in neurons affect the activity of retrotransposons and the influence they have on nearby neural genes. Finally, I will explore the possibility that loss of epigenetic silencing of retrotransposons is responsible for dysregulation of genes associated with neurological diseases. Preliminary findings suggest a potential role for retrotransposons in susceptibility loci for Alzheimer's and Parkinson's disease. Finding further support for this notion in the current research program, will form the basis of a novel concept that can explain how changes in the epigenetic landscape can uncover a dormant genetic predisposition to disease.

The drive to seek rewards controls almost every aspect of our behavior, from stereotypic reflexive responses to complex voluntary actions. Thus it comes as no surprise that the symptomatology of neurological disorders that interfere with reward include deficits in the capacity to make even simple movements. To drive behavior the brain uses two major subcortical networks, the basal ganglia and the cerebellum. Experimental data and computational models suggest that the basal ganglia and cerebellum play different roles in the control of behavior. In the basal ganglia, reward signals guide action selection, but how reward signals are translated into behavior remains unclear. The cerebellum uses sensory error signals to optimize motor commands; however, whether the signaling in the cerebellum depends on rewards and how reward might be incorporated into the motor commands have yet to be deciphered.

We will explore whether and how reward signals interact with motor commands in the basal ganglia and cerebellum. We will take advantage of primate smooth pursuit eye movements as a powerful system to study the relationship between reward processing and motor behavior. We will record and manipulate activity in both the basal ganglia and cerebellum while animals are involved in novel behavioral tasks. The tasks extend the current state of the art concerning what is known about sensory or motor processing to study how reward is translated into behavior. The overarching goal is to unify research on the basal ganglia and cerebellum to understand the transformations and computations that translate reward drive into action and their implementations in the basal ganglia and cerebellum.

To understand how brains integrate sensory information and generate behavioural responses is a central goal of systems neuroscience. Larval Zebrafish have emerged as a very promising vertebrate model system to address this challenge because their small size and transparency enable optical access to the majority of neurons within the brain at cellular resolution. Important insights on circuit function have already been gained by two-photon imaging of neuronal populations in restrained larvae behaving in virtual environments – however, critical limitations of virtual environments as a replacement for real environments are widely acknowledged and remain a barrier to progress. An ideal solution to this problem would be to image larvae during natural, unrestrained behaviour, and this is the goal we aim to achieve in this project. It has so far not been possible to track naturally moving zebrafish, nor any other vertebrates, while imaging at cellular resolution. Here we propose to overcome this limitation by forming a novel collaboration across disciplines and three different laboratories. We will pool our collective expertise in optical systems design, wavefront-shaping, electrical engineering, and zebrafish neuroscience to perform an experiment that has until now been impossible: imaging comprehensive neural activity in a freely moving, untethered vertebrate. We will collectively design and validate a real-time optical tracking and imaging system to measure brain activity with single neuron resolution in a freely moving vertebrate. This will allow us to monitor, with unprecedented detail, the population activity of the reticulospinal system in larval zebrafish and understand how this population of ~ 300 supraspinal neurons combinatorially codes for the full range of locomotor and postural behaviors.

Microscopy of biological specimens is often performed at low levels of illumination to avoid damage. Under these conditions images are dominated by shot noise, the statistical fluctuations in the number of detected probe particles (e.g., photons or electrons). Better images can be obtained when correlated probe particles are used, which allows extracting more information per interaction with the sample. A way to do so is to pass the illumination multiple times through the specimen [1, 2]. We propose to design and construct a microscope where the specimen is placed at the center of a self-imaging cavity, in which the probe particles interact with the sample multiple times. An optical setup will be used to demonstrate the main benefits of a multipass microscope: contrast enhancement, sub-shot noise imaging, and imaging at low damage. Fast electro-optical switching techniques will be employed to, for the first time, show sub-shot noise imaging without postselection of the probe particles. Various imaging modalities will be explored, such as phase, absorption and polarization microscopy in both bright- and darkfield configurations. Finding the right imaging modality for specific specimens (e.g., living cells) will be at the focus of the project. In parallel, the feasibility of a multipass electron microscope will be explored using charged particle tracing simulations. We will construct and test a prototype as a first step towards the imaging of organic molecules and proteins with atomic resolution. [1] Giovannetti V, Lloyd S and Maccone L, Nat Photon 5, 222-229 (2011). [2] Higgins B L, Berry D W, Bartlett S D, Wiseman H M and Pryde G J, Nature 450, 393-396 (2007).

Both wild and crop plants must contain pathogen infections to survive. Prevailing theories on the evolution and spread of plant pathogens are based primarily on observations of nearly clonal hypervirulent pathogen lineages in agricultural systems, which are characterized by dense stands of genetically uniform individuals and a paucity of other species. Surprisingly little is known about how pathogens evolve in natural settings, where emergence of hypervirulence appears to be much less prevalent.

The central goals of this proposal are to reveal (i) the dynamics of bacterial pathogen colonization in natural plant populations, and (ii) the influence of several factors—pathogen diversity, host genetics and host microbiomes—on pathogen infection dynamics. My specific plan is to investigate the evolution and spread of the endemic plant pathogen Pseudomonas syringae in wild populations of Arabidopsis thaliana, using innovative high-throughput methods for culturing and genome comparisons of bacterial lineages. These observations will reveal associations of pathogen spread with geographic isolation of hosts, host microbiome composition, host genetics, and pathogen genome diversity. I will then test causal relationships for a subset of these associations through controlled laboratory infections. A unique aspect of my proposal is the hierarchical approach—identifying infection dynamics at the leaf, individual plant, and population level—and the integration of experiments in the laboratory with high-throughput investigation of natural infections.

Innate behaviors such as aggression and reproduction are essential for the survival of animals. Neuropeptides are implicated in the regulation of various innate behaviors by changing their basal arousal state and motivation level via modulating neural activity. Oxytocin (OXT) and vasopressin (AVP) are involved in various social behaviors such as aggression, mating, pair-bonding and social recognition. However, how these peptides exert their functions at the neural circuit level is not well understood.
I plan to study the role of OXT/AVP on the neural circuit of aggressive behaviors by addressing the following questions: (1) Whether if OXT/AVP is actually released onto the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl), which was previously shown to control both the appetitive and consummatory phases of fighting and mating? (2) What is the role of the neural activity patterns responding to OXT/AVP release during aggression? (3) How is the activity of OXT / AVP neurons controlled during aggression and from where do the OXT/AVP neurons receive their input? (4) Whether if OXT/AVP control other social behaviors in VMHvl in addition to aggressive behaviors?
In contrast to my previous research experience in neuroendocrinology, the proposed research will focus on how neuropeptides modulate innate behaviors at the circuit level. Therefore, this will be a good opportunity to extend my training from endocrinological to behavioral neuroscience.