Gene E. Robinson - US grants

DESCRIPTION (Adapted from Applicant's Abstract): A challenging problem in behavioral biology is to unravel the influences of genes and the environment on the development of behavior, particularly behavior that is characterized by a high degree of plasticity. Plasticity in the behavioral development of the honey bee, Apis mellifera, offers unique opportunities; its expression in an insect invites rigorous experimentation while its complexity makes it a relevant model. The bee will thus be used to develop a new model system to study this problem. It has been demonstrated recently that plasticity in the behavioral ontogeny of the bee is a consequence of modulation of juvenile hormone titers by extrinsinc factors, and stimuli that can affect juvenile hormone titers and behavioral development do elicit variable responses in genetically distinct individuals. These discoveries, coupled with the results of a theoretical analysis of bee behavior, suggest the following four lines of inquiry: (1) a test of the hypothesis that there are juvenile hormone-binding cells in regions of the bee brain devoted to olfaction, which is a critical prediction of the more fundamental hypothesis perception; (2) an analysis of the role of neuromodulators in regulating the development of behavioral plasticity, by testing the hypothesis that juvenile hormone (JH) affects CNS behavioral response thresholds via its effects on brain titers of biogenic amines; (3) an analysis of how the bee obtains and responds to information on changing conditions in the colony, based on the hypothesis that perception of specific environmental and social stimuli influences plasticity in behavioral development via effects on juvenile hormone blood titers and biosynthesis; (4) examination of whether genetic differences in the plasticity of endocrine-mediated behavioral development are a consequence of differences in information-processing or differences in rates of behavioral development.

As individuals age and pass through different stages of life, their responses to the world around them change in both predictable and unpredictable ways. These changes often involve how well, how rapidly, and what an individual learns. One of the most challenging problems in biology is to understand how changes in brain structure relate to development of behavior in adults; of particular interest are age-related changes in behavior involving learning and memory. Dr. Robinson and Dr. Fahrbach will capitalize on exciting data that indicate changes in circulating juvenile hormone (JH) influence both the behavioral development of worker bees and the determination of caste. It is known that worker bees perform a complex series of behaviors during their short (20-42) days of life. Younger bees rear the next generation; middle-aged bees maintain the hive and guard the colony; the most mature bees forage outside of the hive for nectar and pollen. Foraging is an extremely demanding task involving learning and memory, and advanced forms of communication. These striking changes in behavior are mediated by changes in juvenile hormone. Juvenile hormone also causes the permanent differentiation of females into either queens or workers. Drs Robinson and Fahrbach are using these systems to define the neural pathway through which hormone action on the brain causes transient or permanent changes in behavior. They will investigate how juvenile hormone influences neurogenesis or neural circuitry during periods in which behaviors are changing. In the long term, the goal to use this excellent model system to provide information on how learning and memory are affected by hormones. In addition, the honey bee is an important insect for agriculture. Therefore, greater understanding of the plasticity of behavior may contribute its continual role as an important agricultural pollinator.

This award provides funds to the Department of Entomology at the University of Illinois at Urbana to establish a summer research program that focuses on the behavior and neuroanatomy of honey bees. Students will have the unique opportunity to combine compelling fieldwork with modern laboratory techniques. Student training will be a three-fold process. First, lectures will be given on the structure and function of the insect nervous system; the hormonal regulation of insect metamorphosis and neural development; the hormonal regulation of insect behavior; and experimental design. Second, students will receive practical training in the safe handling of colonies of honey bees and in observation of honey bee behavior, and ample opportunity to practice these new skills. Third, students will also receive laboratory instruction in histological techniques for the light microscopic study of the insect nervous system. Each student will then carry out a research project in which an aspect of bee brain morphology, cell number, neurochemistry, neurotransmitter expression, gene expression, or hormonal responsiveness etc. is studied in bees of known age and behavioral status. The goal of this project is to introduce students who already have an interest in neuroscience and behavioral biology to the value of social insects as models for the study of the neurobiology of complex behavior. This project represents and extension of an ongoing collaboration between two laboratories in the Department of Entomology and the Neuroscience Program at the University of Illinois at Urbana-Champaign. It will be based in the Bee Research Facility and two other well-equipped laboratories in the Department of Entomology.

9322202 Fahrbach This award provides support to the University of Illinois to continue a successful REU program. Summer research programs will be focused on the behavior and neuroanatomy of honey bees. Students will have the opportunity to combine compelling fieldwork with modern neuroanatomical techniques. Student training will be a three-fold process. First, lectures will be given on the structure and function of the insect nervous system; the hormonal regulation of insect metamorphosis and neural development; and the experimental study of animal behavior. Second, students will receive practical training in the safe handling of colonies of honey bees and in observation of honey bee behavior, with ample opportunity provided to practice these new skills. Third, students will receive laboratory instruction in histological techniques for the light microscopic study of the honey bee nervous system, including many aspects of stereology. Students will then be divided into two teams of three students each. These teams will then carry out a research project in which an aspect of brain organization, nerve cell number, gene expression, or hormonal responsiveness, etc. is studied in bees of known age and behavioral status. The goal of this project is to introduce students who already have an interest in behavioral biology to the value of social insects as models for the study of the neurobiology of complex behavior, including learning and memory. This project represents an extension of an ongoing collaboration between two laboratories in the Department of Entomology and the Neuroscience Program at the University of Illinois at Urbana-Champaign. It will be based in the University of Illinois Bee Research Facility and in the co-PIs laboratories in the Department of Entomology. This unusual combination of field and laboratory research environments coupled with the different but complementary backgrounds of the co-PIs will provide undergraduates with a rich summer research experience. The program currently proposed reflects the success of a past REU Site program centered around the same theme (offered Summer 1992), with a new emphasis on research teamwork as a means of helping students complete meaningful research projects. ***

Proposal # 9423164 Susan E. Fahrbach, PI Gene E. Robinson, co-PI Behavioral development occurs in many species, including humans. As individuals age and pass through different stages of their life, their genetically determined behavioral responses to specific environmental stimuli change in predictable ways. Often these changes involve increasingly complex behavioral responses that involve learning. The goal of Drs. Fahrbach and Robinson is to understand how changes in brain structure relate to the development of behavior, particularly behavior that is characterized by a high degree of plasticity. Dr. Fahrbach and Dr. Robinson will test two hypotheses that explain the role of neuroanatomical plasticity and behavioral plasticity. The first hypothesis predicts that changes in brain structure occur in anticipation of changes in behavior, perhaps as a result of a specific neuroendocrine signal. According to this hypothesis, the neuroanatomical changes are necessary to support the transition to a more complex behavior. The second hypothesis predicts that changes in brain structure occur as a consequence of changes in behavior. According to this hypothesis, the neuroanatomical changes are necessary to support the continued performance of a more complex behavior. Drs. Fahrbach and Robinson will explore these hypotheses by studying brain structures insects after endocrine and experiential factors are experimentally manipulated. Studies of brain region volumes, synapse formation and molecular events leading to neural plasticity will be undertaken. The principal significance of this research will be to contribute to our understanding of the neuroanatomical basis for hormone-mediated behavioral plasticity in adult animals and humans.

DESCRIPTION (Adapted from the Investigator's Abstract): An important function of chemical communication in social life is to coordinate the timing of physiological and behavioral development. Postembryonic development occurs in many species, including humans. As individuals age and pass through different stages of their lives, their physiological and behavioral responses to specific situations change. The goal of this project is to contribute to our understanding of how chemical communication influences physiological and behavioral development. Studying pheromone regulation of endocrine and behavioral development in the honey bee offers a unique opportunity: the occurrence of this phenomenon in an insect invites rigorous experimentation while its complexity makes it a relevant model. Hormonal and neuroanatomical studies of behavioral development have demonstrated that the bee possesses some of the same type of regulatory mechanisms that vertebrates do. Moreover, recent results indicate that the regulation of endocrine-mediated behavioral development in the honey bee is strikingly similar to pheromone regulation of reproductive development in some mammals. The bee will be used in a novel coupling of established techniques in pheromone biology, endocrinology, and behavior. Primer pheromones that inhibit endocrine-mediated behavioral development will be identified; few such primer pheromones, from any species, have yet been conclusively identified. Preliminary results strongly suggest that the pheromones are known compounds from the queen and worker mandibular glands. The experiments will involve exposing bees to the putative pheromones and measuring juvenile hormone blood titers, juvenile hormone rates of biosynthesis, and rates of behavioral development under both laboratory and field conditions. Studies also will determine how the pheromones interact with one another, how they are communicated under different social conditions, and whether their effectiveness depends on tactile communication. In addition to the techniques mentioned, these experiments also will involve established methods of quantifying mandibular gland compounds by gas chromatography and rearing individuals either in social groups or in complete isolation. The regulation of pheromone production also will be studied. Preliminary results support the hypothesis that pheromone production is regulated by the corpora allata, the gland that produces juvenile hormone. This hypothesis will be rigorously tested by performing hormone treatment experiments and by taking full advantage o the range of behavioral manipulations possible with bees to dissociate age from endocrine and behavioral status.

Biogenic Amines and Division of Labor in Honey Bee Colonies
Non-technical Abstract
Gene E. Robinson, Principal Investigator

The goal of this project is to determine whether the biogenic amines octopamine and serotonin influence the rate at which honey bees mature from working in the hive to taking on the more complex duties of foraging for nectar and pollen. If biogenic amines do function in this way, studies will be undertaken to determine whether they interact with endocrine signals to effect this regulation. The research will involve measurements of biogenic amines in the brains of individual bees, treatments of biogenic amines and hormones, and detailed behavioral analyses.

Biogenic amines are known to exert short-term modulatory effects on a variety of behaviors in animals and humans but it is not known whether they also regulate long-term, developmental transitions from one behavioral phase to another.

With the advent of technologies spawned by the Human Genome Project, the behavioral sciences are poised to make revolutionary advances. However, one problem that currently prevents the behavioral community from embracing genomics is that techniques of manipulating gene expression are only possible for a few species. Treatment with double-stranded (ds) RNA is providing to be a very effective techinique for interfering with gene expression in C. elegans and D. melanogaster. The 'RNAi' effect is highly specific and is stronger
and more consistent than treatment with antisense oligonucelotides. Dr. Robinson seeks to extend the use of RNAi to the honey bee, a model organism in sociobiology that lacks technology for germ-line transformation. Dr. Robinson will test the hypothese that dsRNA from the period (per) gene suppreses per mRNA and causes changes in two behavioral processes: locomotor behavior circadiean rhythms in the laboratory, and division of labor, i.e., the transition from working in the hive to foraging, in the field. The bee per system is an ideal test case for progmatic reasons related to the molecular and behavioral assays available in my laboratory and the observation from Drosophila that per is not a lethal gene. Testing the effect of RNAi on the bee per system also is compelling for two scientific reasons. First, it will provide insight into the striking and previously unimagined changes in per mRNA levels in the bee brain that occur in association with division of labor. Second, it will provide a powerful demonstration of the versatiality of the RNAi technique. If RNAi does not suppress per mRNA in bees, this result also will be of high impact, because it will provide the first cautionary note in the literature that RNAi may not be the panacea that we all hope it will be.

0000262
Robinson

This one-year award will support US participation in an international workshop, New Approaches to the Study of Genes, Brain, and Behavior with Honey Bees, to take place in Bellagio, Italy, on June 26-30, 2000. Gene Robinson of the University of Illinois, and Alison Mercer, University of Otago, New Zealand, will organize the workshop. The workshop involves US researchers' participation in a forum for a multidisciplinary group of researchers from the US, Europe, and Asia to develop opportunities for future collaboration on emerging technologies in neuroscience and genomics, enhancing the value of the honey bee as a model for integrated studies of behavior, neurobiology, and genetics. The focus of the meeting will be on studies of behavior that demonstrate, at the molecular level, the influences of genes, the environment, and their interaction. The goal of these studies is to explain the function and evolution of behavioral mechanisms that integrate the activity of individuals in a society, neural and neuroendocrine mechanisms that regulate behavior within the brain of the individual, and the genes that encode these brain mechanisms and thereby influence social behavior.

Molecules that regulate circadian rhythmicity are also thought to influence the functioning of processes at different temporal scales. The goal of this project is to test an important prediction of this model: given that behavioral and molecular data suggest an association between behavioral maturation and behavioral circadian rhythms in the honey bee, then social and neuroendocrine factors known to influence rate of behavioral maturation should also influence per expression. The following six lines of inquiry will be pursued. 1. Characterize the bee per gene: We have generated a full-length cDNA sequence and also have partially sequenced a genomic clone and will do comparative analyses (with H. Robertson). 2. Determine whether per mRNA levels in the bee brain change during behavioral maturation. Young bees, which work in the hive, have no behavioral circadian rhythms while older bees, which forage on flowers, do; per mRNA levels in the brain change in association with this behavioral maturation. This correlative analysis provides baseline data for the treatment experiments in Aims 4-6. 3. Localize and measure levels of brain PER. Preliminary immunocytochemical results indicate that maturational changes in per mRNA are reflected at the protein level. Continued analyses will be coupled with in situ hybridization to provide additional confirmation (with S. Fahrbach and K. Siwicki). Results of this correlative study will also be used to provide a baseline for Aims 4-6. 4. Determine whether changes in social environment, known to influence behavioral maturation, also influence per expression in the brain. We will take full advantage of a uniquely powerful set of behavioral manipulations to dissociate chronological age, stage of behavioral maturation, and experience, all while working with bees that are highly related to each other. Preliminary results support this hypothesis. 5. Determine whether juvenile hormone and octopamine manipulations, known to influence behavioral maturation, cause changes in both rhythmic locomotor activity and 6. per expression. Preliminary results for locomotor activity support this hypothesis. We hypothesize that juvenile hormone analog and octopamine treatments will increase per expression while allatectomy and octopamine antagonist treatment will decrease it. The principal significance of this research is that it attempts to experimentally determine for the first time whether the expression of a clock gene is dependent upon a broader array of influences than those strictly associated with circadian rhythmicity.

Lay Summary -
Collaborative Research: Fahrbach and Mesce

Insect metamorphosis is accompanied by extensive reorganization of the central nervous system. These changes are regulated by steroid hormones, and during metamorphosis insect neurons and glia express nuclear steroid hormone receptors. A notable feature of metamorphosis in the nervous system of moths and butterflies is the formation of compound ganglia from individual segmental ganglia. In the moth Manduca sexta, a large species easily reared in the laboratory, compound ganglia form shortly after the caterpillar pupates. This collaborative project will test a model of compound ganglion formation in which two classes of glial cells are the primary steroid targets. In this model, the giant glial cells of the interganglionic connectives move clusters of neurons by changes in their cytoarchitecture while the perineurial glial cells that wrap the central nervous system alter their adhesive properties to permit the neurons to move freely. Experiments to be conducted at the University of Minnesota in Dr. Mesce's laboratory will describe the motility of giant glial cells during the formation of compound ganglia and will study how damage to the giant glial cells affects ganglionic migration and fusion. These experiments are facilitated as a result of the recent discovery that a form of fasciclin II, a protein expressed on the surface of insect cells, can be used as a marker for the giant glial cells. Experiments to be conducted in Dr. Fahrbach's laboratory at the University of Illinois at Urbana-Champaign will determine the timing of perineurial glial cell proliferation during metamorphosis and study the effects of ablation of this cell population on ganglionic migration and fusion. In addition, antibodies targeted to specific isoforms of the insect steroid hormone receptor (the ecdysone receptor, EcR) will be used to determine which form of the receptor is expressed by glial cells. This is envisioned as a first step toward identifying steroid-regulated genes involved in regulation of the glial cytoskeleton and glial cell adhesion molecules.

Previous studies of metamorphosis of the insect nervous system have focused exclusively on neurons. This project will provide new information about the developmental modulation of glial cell cytoarchitecture and glial cell adhesivity during the postembryonic life of insects. The results are likely to generalize to all arthropods and, because the regulation of cell "stickiness" and cell shape are fundamental attributes of all multicellular organisms, to other animals as well.

Lay Abstract

The International Union for the Study of Social Insects is devoted to
integrated analyses of the biology of this important group of organisms.
It holds an international meeting once every four years that has emerged as
the premier forum for the dissemination of knowledge in this field. Funds
are requested to send a group of carefully selected graduate students to
the meeting that will be held in Sapporo, Japan in July-Aug, 2002. The
opportunity to attend this important meeting will have a significant impact
on the development of the careers of these students by allowing them to
begin to meet leaders of the field, develop contacts that can lead to
productive collaborations, and get feedback on their own work. Japan has a
well established tradition of excellence in social insect biology and
offers an outstanding venue for this meeting.

Organization of behavioral plasticity by neurochemicals
Gene E. Robinson, Principal Investigator

Many animals show profound changes in behavior as they grow up, and these changes are based on maturational changes in the structure and functioning of the brain. Like other forms of behavioral plasticity, behavioral maturation involves coordinated change in many different aspects of behavior and is accompanied by extensive changes in neurochemistry. Previous NSF funding led to the discovery that octopamine influences the behavioral maturation of the honey bee, specifically the age at which honey bees shift from working in the hive to foraging. Octopamine is a biogenic amine, which is a prominent class of neurochemicals that regulate behavior in many organisms, vertebrate and invertebrate, including humans. This proposal seeks to use octopamine to explore precisely which behavioral mechanisms need to be affected to orchestrate complex behavioral maturation. Research will determine whether octopamine acts to increase responsiveness towards specific environmental stimuli so that a bee with the occupation of foraging continues in that occupation because of the way that it reacts to certain stimuli. Other possibilities that will be tested is to determine whether octopamine promotes foraging behavior by increasing overall activity or improving the cognitive abilities that are essential for successful foraging. The research will involve detailed measurements of biogenic amines in the brains of individual bees, treatments of biogenic amines, and quantitative behavioral analyses. The honey bee has become an important model system for studies at the interface of neurobiology, behavior genetics. This research will provide useful insights into the neurochemical basis of complex behavioral changes experienced by many social animals, including man, and provide a demonstration of how brain chemicals influence the development of cognitively demanding tasks.

Biogenic amines are compounds that can act as modulators of nervous system function and behavior in vertebrates and invertebrates. Octopamine is one of these, and one of the most widely studied neuromodulators in arthropods. In honeybees, octopamine plays a role in controlling behavioral plasticity. Levels of octopamine are higher in the brains of forager bees that leave the hive to get food compared to levels in nurse bees that work inside the hive, and treatment with octopamine causes bees to forage precociously. A particular enzyme, tyramine beta-hydoxylase (TbH) is critical for biosynthesis of octopamine, so brain levels of octopamine depend at least in part on the activity of TbH. This collaborative project uses molecular, biochemcial and behavioral approaches to determine how TbH is regulated by both social and endocrine factors. Enzyme activity, gene expression, and metabolic biochemistry clarify how octopamine is synthesized and released in the antennal lobes of the brain of honeybees during development of the behavioral change. Results will be important to understanding how an important neuromodulator is regulated in the context of behavioral plastiticty and in socially regulated gene expression.
This work will have impact beyond neuroendocrinology to animal behavior and to agricultural applications. There is also an important component of student training at the predominantly undergraduate institution involved in the collaboration.

DESCRIPTION (provided by applicant): We propose to use the honey bee as a model to determine which of the mechanisms that can be manipulated to increase lifespan actually have been in nature. The queen bee is highly reproductively active but typically lives 10-fold longer than does the worker bee. Using the free radical damage theory of aging as a foundation, we will: 1) Determine whether queen-worker longevity differences are associated with differences in expression of genes encoding antioxidants, electron chain proteins, or both. We have complete or near complete sequence for 25 genes related to longevity: 15 antioxidant, 8 mitochondrial, and 2 signal transduction genes; 12 will be analyzed with real-time quantitative RT-PCR and the rest are on a Cdna microarray (below). Analyses will be supplemented with protein measures in selected cases. Preliminary results indicate striking differences in gene expression, especially early in life. Measurements of ATP production and effects of ROS damage will test the functional significance of the differences; 2) Determine the causal basis of some of the queen-worker differences in gene expression with transgenic flies. Three of the genes with some of the strongest queen-worker differences will be selected and transgenic flies made (up- and downregulation) in the laboratory of collaborator J. Tower. Collaborator K. Hughes will study their age-specific survival and reproduction, and developmental rate. Hughes will also work with long- and-short lived selected lines of flies to determine whether selection acted on some of the same genes that differ in queens vs. workers; and 3) Conduct a microarray survey to identify additional genes that differ in expression between queens and workers, to determine what related pathways are affected in association with differences in the specific genes studied in Aim 1. We will use our recently developed cDNA microarrays which represent ca. 6000 different bee genes, including additional antioxidant and respiration-related genes, and genes encoding different HSPs. The principal significance of this research is that it will identify naturally occurring molecular mechanisms promoting longevity. The value of the bee as an aging model will be enhanced significantly with the expected completion of genome sequencing later in '03.

One of the most important questions in biology is the origin of behavior: nature or nurture? This research will use genomic biology to liberate the study of behavior from the shackles of this dichotomy. The new paradigm is that the environment ("nurture"), which includes other individuals, impacts an inherited genome ("nature") by orchestrating gene expression during the lifetime of the animal. This project will analyze social behavior on an unprecedented whole-genome scale, using Apis mellifera the Western honey bee, as the model organism. Honey bees live in a complex society governed by an age-related division of labor, with each individual assuming many roles during her lifetime. Both genetic heredity and environmental conditions determine what role a bee performs, and when she performs it. The biology research will generate a unique database of gene expressions for all social behavior, recording brain gene expression for hundreds of individuals, each with a specific societal role. These microarray experiments utilize the recently sequenced genome, supported by state-of-the-art statistics. The informatics research will develop an interactive environment to analyze all information sources relevant to bee social behavior. These include genome databases from honey bee and related organisms, linked to complete scientific literature relevant to insect behavior. New text mining technology will integrate molecular description with information from physiology, behavior, neuroscience, and evolution. The BeeSpace environment will enable users to navigate a uniform space of diverse databases and literature sources for hypothesis development and testing. The software system will go beyond a searchable database, using statistical literature analyses to discover functional relationships between genes and behavior. This research will enable all scientists who study bee genes to live on the frontier of integrative biology, where biotechnology enables routine expression analysis and bioinformatics enables functional analysis unconstrained by pre-existing categories.

The broader impact of the interactive environment for functional analysis will be tested in an international community of laboratories studying honey bees and related organisms. Outreach for BeeSpace will provide integrated research and education experiences at the graduate and undergraduate levels, plus training courses and minority outreach at high school and middle school levels.

Names: Dr. Gene E. Robinson, PI and Amy L. Toth, Co-PI
Title: DISSERTATION RESEARCH: Nutritional influences on social insect division of labor

The aim of this dissertation research is to investigate the connection between nutrition and division of labor in the social insects. Completed work has shown the nutritional state of worker honey bees, as indicated by stored lipid, is closely related to behavioral role in the colony. Future work aims to broaden the scope of this research in three ways: 1) determine whether changes in worker bee nutrition cause changes in behavior, 2) explore a molecular mechanism linking nutritional status to changes in brain gene expression in honey bees, and 3) use comparative studies with other social insects to investigate the role of nutritionally-sensitive molecular pathways in social evolution. Because nutrition can interact with numerous other physiological processes, these studies will have profound implications for understanding the mechanisms controlling division of labor in social insects. To a more general audience, this work can provide important insights into how an individual's nutritional state can lead to neurophysiological changes that give rise to specific behaviors. At the same time, this research encourages the integration of research and education, as it provides opportunities for a number of undergraduate students to receive training and become involved in the scientific process.

Abstract for 0427089


One of the most urgent and vital challenges confronting society today is the vulnerability of urban areas to extreme and unpredictable events such as terrorism, earthquakes and the like. For example, in 2002, a total of 608 million people across the globe were affected by disasters resulting in 24,500 deaths and damage to property and to the environment estimated at $27 billion dollars. These significant human and economical costs emphasize the urgent need to improve the efficiency and effectiveness of first responses to extreme events. The objective of this grant is to develop and to test a conceptual framework designed to improve collaboration among the key actors involved in disaster relief operations. These key actors include firefighters, police officers, medical personnel, experts, the original civil engineers and constructors involved in the construction of the affected infrastructure, and the physical and technological infrastructure itself, including sensors and systems of sensors embedded in it. Theoretically derived information technology (IT)-based solutions to prepare against, respond to and recover from disasters will be developed and tested based on the proposed framework. The research team is composed of civil engineers, computer scientists, entomologists, psychologists, communication scholars and first responder professionals. Each studies the technological and social processes of collaboration from a different viewpoint. All of these viewpoints will be represented in the conceptual framework, which will explore three phases of first response: preparation, response, and recovery.

First responders face many challenges in the chaotic and inhospitable environment of disaster relief operations; including information unreliability and overload; coordination and communication breakdowns; and threats to personal safety and the vulnerability of physical infrastructure. This grant seeks to reduce uncertainty and improve collaboration among first responders. It will advance theory, research and practice regarding efficient and effective first response in several important ways. First, previous research initiatives regarding collaboration have focused on supporting interactions among people, instruments and systems running on fixed computers and devices, in complex, large scale, but fairly stable operating conditions. This research investigates collaboration in chaotic, volatile, and complex disaster relief environments, which requires interaction among both stationary and mobile users and among users and technological devices such as sensors and communication media. Second, it explores the role of civil engineer as a vital member of the first responder team, providing key knowledge of and experience with the affected physical infrastructure. And finally, it will enable first responders with an IT-based components platform to address issues pertaining to critical physical infrastructure, such as security and vulnerability, along with the expertise to prepare before, respond to and recover after a disaster occurs.

DESCRIPTION (provided by applicant): We will couple a novel model (honey bee) with powerful new genomic resources (cDNA microarray and a soon-to-be-completed complete genome sequence) to study how pheromones regulate gene expression in the brain. Endocrine-mediated behavioral development in the bee is regulated in a manner strikingly similar to the regulation of mammalian reproductive development, by primer pheromones, and honeybee queen mandibular pheromone (QMP) is one of the few chemically characterized primer pheromones known to affect endocrine-mediated physiological and behavioral development. We will: 1) Determine how Kr-hl expression is related to pheromone regulation of behavior, Kr-ht, the first pheromone regulated gene identified in a higher brain center, is a transcription factor and is regulated in two socially relevant ways. We will test the hypothesis that QMP repression of Kr-hl expression is related to this pheromone's inhibitory effects on endocrine-mediated behavioral maturation with a set of social, behavioral, and pharmacological manipulations. 2) Determine the effect of Kr-hl expression on brain cell neuroanatomy and synaptic structure using immunocytochemistry and the powerful MARCM technique in Drosophila and complementary approaches in bee (with Tzumin Lee). 3) Identify downstream targets of Kr-ht transcriptional regulation. As a transcription factor, Kr-hl presumably functions by controlling expression of other genes that would play more direct functional roles in neuronal remodeling or regulating foraging behavior. We will use a multi-pronged approach to identify these genes involving, identification the consensus binding sequence of the bee and Drosophila Kr-hl proteins; bioinformatics (with Hugh Robertson); characterization of proteins associated with Kr-hl by peptide sequencing and chromatin remodeling assays; microarray experiments in both bees and flies; and chromatin immunoprecipitation (with Craig Mizzen) The principal significance of this research is that it will improve our molecular understanding of how chemical communication influences neural and behavioral plasticity.

DESCRIPTION (provided by applicant): This project will explore the molecular pathways involved in reward perception and reward-seeking behavior in the honey bee. Most drugs of abuse usurp neural circuitry involved in pleasure and reward seeking; discerning how reward is processed in the brain is essential for understanding how drugs of abuse generate addictive behavior. Forager bees express an excessive reward-seeking drive that is regulated by social feedback, and we will develop this as a natural model for studying reward motivation in a social context. Foragers perform symbolic dances that communicate their estimation of the profitability of their foraging trip to hive-mates. The dance language is a 'declarative' report of reward quality providing a unique system to study reward perception in a simple animal model. We will 1. examine how the biogenic amines modulate reward-directed behavior in the bee. Preliminary results indicate aminergic involvement. We will combine pharmacological treatments with assays of dance and foraging behavior to examine how dopamine, serotonin and octopaine contribute to reward perception and reward-seeking drive in the bee. 2. examine how cocaine distorts reward processing and social behavior in bees. We will study how low doses of cocaine misdirect foraging effort, sensitivity to social feedback on foraging effort and perception of reward reported through dances. The principal significance of this research is that it will establish a new model system for studying the molecular pathways of excessive reward-directed behavior in a simple nervous system. This will set the stage for the use of new and emerging genomic technologies for the bee to explore pathways identified in reward processing in detail, to further develop the bee model system. Extensive conservation of nervous system function at the molecular level across the animal kingdom indicates that the principles of reward coding we aim to elucidate in the bee will have general relevance.

This project is designed to elucidate mechanisms that translate experience into changes in brain structure that allow adult animals to enhance their behavioral performance. Our model system, foraging-induced growth of the mushoom bodies (insect brain center for learning and memory) in the honey bee, permits nvestigations at the behavioral, cellular, and molecular levels. Our proposal is based on the surprising, but robust, demonstration that treatment of caged bees with a muscarinic agonist, pilocarpine, results in brain plasticity identical to that produced by a week of real foraging experience. We will: 1. determine how signaling via cholinergic pathways is related to foraging-induced increases in the volume of mushroom body neuropil using a novel experience-replacement technique; 2. determine the cellular phenotype of pilocarpine- induced changes in mushroom body neurons (Kenyon cells) using the Golgi technique; and 3. identify genes expressed in the mushroom bodies responsive to signaling via muscarinic pathways using whole bee genome microarrays, and then confirm and extend these results with quantitative RT-PCR and in situ hybridization. The bee provides a superb model system for these studies because appropriate tools, such as a sequenced genome, are now available, and because it is possible to rigorously manipulate the experience of the bee under naturalistic conditions and study effects at the neuroanatomical and molecular levels. The principal significance of this research is that it will reveal how experience is coupled to brain plasticity. Extensive conservation of nervous system function at the molecular level across the animal kingdom makes the results of our investigations on an insect broadly applicable within the field of behavioral development. This research is relevant to public health because experiments that can be efficiently performed using the simpler insect nervous system are likely to reveal how learning changes the brain in all animals, including humans. Such understanding is the first step in the development of therapies to improve human learning after brain damage. Our results will also suggest directions for the development of treatments for the decline in mental function that accompanies human aging.

There was a time, not so long ago, when the various academic disciplines sat comfortably side-by-side, each with its distinctive literature and personality. The dramatic proliferation of scientific knowledge, not to mention the considerable shifts in social attitudes brought about by the international traumas of modern life, have altered even the entrenched workways of university teaching and research. Multidisciplinary agendas are taking root and departmental walls are crumbling.
Consider the three seemingly disparate fields of political science, psychology, and biology. In decades past, political scientists excelled in studying the institutional dynamics of government; psychologists probed the human psyche employing Freudian and Pavlovian tools; biologists considered the workings of the cell a cutting-edge specialty. Today, political scientists have commenced investigations of human social behavior as an artifact of genetic activity; psychologists employ the technologies of neuroscience to characterize the function of various brain centers in decision making; biologists extract candidate DNA from the genomes of sundry species in the search for commonalities in performance and adaptation. Slowly but surely they are engaging in common cause.
A first-ever national meeting of political scientists, psychologists, and biologists, young and old, for the purpose of mounting a concerted drive toward formalized dialogue and a hopeful pooling of theories and methods will be organized. Put succinctly, the scholars involved in this confrence share a common vision: genes appear to play a role in orchestrating the software and chemistry of human behavior; environmental and heritable regulation of gene activity may be an important factor in influencing our politics; long-term, the world of politics could well be a significant force in determining which genes will spread their numbers and which will prove wanting. At this conference, participants shall read and critique one another''s papers and take the first steps toward a new world view of human behavior.
By including young scholars in this undertaking, a new generation will be prepared to conduct research in the nexus of these fields.

One of the most significant findings in biology in the past twenty years is that there is a shared set of genes that serve as the foundation for development in all animals, big and small, insect and mammal. Is the same true for social behavior? This proposal addresses this question with comparative genomic analysis, focusing on two species of social insects that are distantly related to each other, honey bees (Apis mellifera) and paper wasps (Polistes metricus). The hypothesis to be tested is that foraging involves the same genes in different species, even species that regulate foraging socially in different ways. To test this hypothesis, brain gene expression patterns will be compared. A large and diverse team of researchers will be assembled to perform this project with expertise in social behavior, honey bee biology, wasp biology, evolutionary biology, molecular biology, genomics, and bioinformatics. The genome of the honey bee already has been sequenced, so genomic information is readily available for this species. For the wasp, a new approach to obtain the requisite sequences has been developed and tested, and will be used. Results from this project will illuminate our understanding of the evolution of social behavior. Genomic information for the wasp will form a new public resource available freely to the scientific community. The project will provide interdisciplinary training opportunities for postdoctoral associates, graduate students, and undergraduates, including those at a small, liberal arts undergraduate institution. This project also will enhance the research experiences of two new faculty investigators.

A major challenge in biology is to understand how animal societies have evolved. Bees are especially interesting because different species display the full range of sociality that exists in nature, from solitary to communal to highly social, in which individuals ("workers") care for siblings rather than reproduce themselves. Molecular tools are just becoming available that permit a new approach to questions about sociality. This proposal builds on the availability of one gigabyte of genome sequence for 10 solitary and social bees, which the PI is obtaining at no cost to NSF in conjunction with a special award from Roche Inc. Genes will be identified that have changed during the evolution of insect societies; these might be prime movers in social evolution. Genes also will be used to test a prominent theory hypothesizing that worker behavior evolved from maternal care.

This project charts a new avenue of study on the evolution of societies. It will contribute to the development of genomic resources for important species, an NSF strategic goal that will have benefits across all of biology. It will also provide training to graduate students and undergraduates in an approach that integrates evolutionary biology, behavior, molecular biology, genomics, and bioinformatics.

This project will support the Illinois Summer Neuroscience Institute (ISNI) for three years. The Institute provides students with an introduction to neuroscience research, to graduate school, to careers in neuroscience, and to the neuroscience community. The ISNI is a one-week intensive introduction to neuroscience, targeting mainly students from underrepresented groups in science, in their first two years of undergraduate study. The ISNI is held at the campus of the University of Illinois at Urbana-Champaign (UIUC) and is organized and led by the UIUC Neuroscience Program. Students learn about state of the art questions and techniques from UIUC faculty who are experts in a broad range of areas within neuroscience. After hearing about research from the faculty, the students conduct a laboratory exercise that allows them to experience the challenge, excitement, and the inevitable frustrations of research. The exercises will take advantage of the expertise in insect neuroethology and Drosophila genetics at UIUC. The purpose of the Institute is to attract students to neuroscience who might not otherwise have the opportunity or exposure to the discipline and to the neuroscience community. The ultimate goal is to expand the pool of applicants, especially from underrepresented groups, to UIUC and to other neuroscience programs in the US.

DESCRIPTION (provided by applicant): The discovery that all organisms share similar sets of genes sets the stage to address one of the frontier areas for 21st century biology: elucidating the molecular basis of social behavior. What specific genes and regulatory sequences contribute to the development and function of brain circuits that support social behavior, is there a common "neurogenomic code" for social behavior, and, if so, how does it generate the spectacular diversity of social behavior that exists on this planet? Answering these questions presents a formidable intellectual challenge: there are many levels of neural and neuroendocrine regulation between genome and behavior, and social behavior adds an additional tier because it depends on interaction and communication between individuals. Answering these questions thus requires a large-scale collaborative project for the collection and analysis of large multi-dimensional datasets, describing various measures of genetic variation, neural function and behavioral context, across lifespan and in diverse organismal models. The Genetics and Genomics of Social Behavior (GGSB) Consortium is organized to bring systems biology to social behavior. It includes leading biologists studying aspects of social behavior in diverse model organisms, including birds, fish, mammals and social insects. Across these models, we will define a unified set of experimental protocols centered on the theme of communication: how do signals carrying information about social environment "get under the skin" to interact with the genome of the individual? Using 'omics technology, we will collect large-scale datasets -which we will make available as treasure troves for data mining by the entire community~to describe molecular variation in detail at multiple levels of biological organization. We will focus on brain transcriptomics, proteomics, metabolomics, epigenomics and gene regulatory networks, captured as a function of experience and genotype. These datasets will be a powerful resource for a growing research community. They will be catalytic by 1) facilitating the identification and solution of conceptual and technical barriers to understanding;and 2) promoting interactions directed at achieving synthesis across diverse model systems, paradigms and perspectives. They will bring needed new investigators with complementary skills into the field through meetings, web-based interactive activities, and collaborative research. Social behavior is a classic example of a high-level, emergent and complex phenotype, and only a Glue Grant can provide the scale of analysis necessary to achieve a transformation in our understanding of its molecular basis. Relevance: Understanding the relationship between genes and social behavior is of critical importance for human health, both to promote wellness and deal with mental illness. Social behavior pathologies figure prominently in many neuropsychiatric disorders such as autism, schizophrenia and depression, and available treatments are grossly inadequate in part because our understanding of the mechanisms of social behaviors is currently so limited.

DESCRIPTION (provided by applicant): An important challenge in developing treatments that induce weight loss and prevent weight regain is to identify regulatory mechanisms that can be targeted for drug therapy. Invertebrate models have commonly been used to discover new candidate genes for medicine. This proposal will use the honey bee for this purpose because the bee undergoes a striking, predictable and stable loss of abdominal fat as it grows up. Naturally occurring, stable weight loss occurs in few species, and not at all in major genetic model systems. The bee is well suited to this task because it not only undergoes stable weight loss but also is amenable to considerable manipulation. The goal of this project is to use a new animal model, state-of-the-art genomics and systems biology techniques, and a novel insect-mammal coupling to identify genes that are important in regulating weight loss. We will first test the hypothesis that age-related changes in gene regulatory networks (GRNs) in brain circuits and fat cells are associated with stable lipid loss. We will develop detailed profiles of gene expression for abdominal fat cells and for three populations of brain cells that are important for the regulation of lipid stores. We will utilize a probabilistic Hidden Markov Modeling approach to develop a quantitative model of gene regulatory networks (GRNs) in these cells in order to identify key regulatory genes whose expression is causally linked to lipid loss. We will then test the hypothesis that age-related changes in gene regulatory networks associated with stable lipid loss are endocrine-mediated. We will test this hypothesis with a systems approach that combines genome-wide ChIP-chip analysis, RNAi, microarray expression profiling, and modeling. Preliminary results from both microarray and ChiP-chip experiments support both hypotheses. Finally, these studies will be used to identify "switch" genes that will be tested by genetic manipulations in mouse or rat to determine whether these genes regulate adiposity in mammals. The principal significance of this research is that it will provide important new insights into the molecular basis of the regulation of adiposity. PUBLIC HEALTH RELEVANCE: A major goal in fighting the obesity crisis in the United States is to develop treatments that induce weight loss and prevent weight regain, but in order to achieve this goal it is necessary to have a deep understanding of the mechanisms that control body weight. Honey bees, unlike most other animals, are able to achieve stable loss of fat tissue as part of their normal adult maturation. The goal of this proposal is to use genomic and systems biology techniques to identify "switch" genes that enable stable weight loss in the bee, and to test that these genes regulate body weight and energy metabolism in mammals.

Technology is advancing rapidly in such areas as genomics, bioinformatics, and imaging, but not all species of plants and animals that are currently being studied for important biological questions can be used with the latest technology. This workshop will explore the need and importance of developing tools for new or emerging model systems that will enable scientists to address specific questions appropriate for understanding the complexity of life. This workshop will facilitate the achievement of this goal by identifying the "toolmakers" in the scientific community and the resources needed to develop important tools for a broad range of species that are best-suited for studying biological systems in a modern, integrative manner. At a broader level, this workshop will bring together researchers from many different disciplines to discuss what kinds of new tools and resources are needed. These discussions will result in the formulation of a broad and coherent set of goals to advance many different fields of biology. This workshop will include a great diversity of scientists in terms of their rank, areas of expertise, and institutional types and locations. In addition, scientists from groups underrepresented in Biology will be represented at the workshop.

Abstract The circuits in the brain that mediate our perception of reward, known collectively as the ¿reward system,¿ couple pleasure with the essentials of life: food and reproduction. The reward system also lies at the root of some of the most tragic, harmful, and costly behaviors in our society. These include addiction to substances of abuse, obesity-related behavior, dangerous thrill seeking behavior, and aberrant sexual behavior. Research that I performed on altruistic behavior in honey bees has led me to a new insight about the reward system. Finding that the same neurochemical system that modulates selfish behavior in solitary insects modulates altruistic behavior in the highly social honey bee, I conclude that not only is the reward system vulnerable to ¿hijacking¿- -coupling to stimuli with negative consequences-- over the course of a lifetime as mentioned above, but it also is vulnerable to hijacking in evolutionary time. I propose to use ¿omic technologies (high-throughput sequencing, transcriptomics, epigenomics, proteomics, and metabolomics) to understand in molecular terms how to ¿flip¿ the reward system, from selfish to altruistic behavior. These analyses will be performed on a carefully selected set of closely related species of bees, some social (with altruistic behavior) and some solitary (without). The insights gained from this novel synthesis of systems biology, neuroscience, and evolutionary biology will transform our understanding of drug addiction and other diseases of the reward system and provide the foundation for new forms of therapeutic intervention.

A new field of study has emerged very recently linking biology and politics. Scholars are investigating the ways in which human DNA affects the workings of the brain, and how the brain then affects political attitudes and behaviors. They are also analyzing and evaluating the ethical, legal, and social implications arising from the knowledge being generated by this research.

This project will establish a one-week program on biology and politics. Graduate students and junior faculty will be invited to the program to receive training in this developing area of scholarship. Natural science and social science enrollees will work side-by-side under the direction of faculty experts who have made responsible for making the biology and politics connection a reality. Armed with these multidisciplinary skills, they will return to their home campuses and establish their own teaching initiatives and enhance the flow of research productivity.

The broader impacts of this project will include providing graduate students and junior faculty with a unique opportunity to gain training in a cutting edge area of research. In addition, the training institute will serve as a foundation for organizing a graduate curriculum focusing on the new biology and politics linkage.

The University of Illinois at Urbana-Champaign is awarded a grant to advance the understanding of the evolution of complex traits, such as the development of multi-cellular body plans or an organism's social behavior. The PI will use the analysis of brain plasticity and social behavior as test-bed questions to build and test quantitative genomic models for the evolution of complex traits. Brain plasticity refers to the brain's ability to reorganize itself by forming new neural connections as a result of experience. The project will test the hypothesis that genetic pathways that mediate brain plasticity are enriched in conserved gene regulatory modules in brain tissues across species, by developing novel analytical models and computational tools for modeling the evolution of gene regulatory modules. The first model is an evolutionary model for genetic modules, which can be applied to identify conserved as well as species-specific genetic modules using and gene expression data in multiple species and phylogenetic distances. The second model can be applied to analyze the transcription networks implemented in related species with a conserved phenotype. The regulatory relationships between an orthologous set of TFs and target genes will be simultaneously modeled and identified in all the species under consideration. Both sequence data and gene expression data, when available, will be modeled. This project will deliver two software tools for integrated comparative analysis of genome and transcriptome data. by These software tools will be hosted on a dedicated server (http://sysbio.bioen.uiuc.edu/grn.htm) and made available to the entire research community through user-friendly web applications. The project will include the participation of undergraduate, graduate, and postdoctoral students, and the software will be used in a hands-on course taught by the investigator at a bioinformatics camp for young women.

This Integrative Graduate Education and Research Traineeship (IGERT) award is built around two grand challenges in biology: 1) How do genomes interact with the environment to produce biological diversity? and 2) How are biological systems integrated from molecules to ecosystems? Our training model is aimed at preparing students so that they are empowered to learn how an organism?s traits emerge from, and are continually shaped by, a complex interplay of genetic information stored in DNA and environmental information that an organism experiences throughout its life. This training will equip students with the knowledge, tools and perspectives needed to address pressing scientific and societal problems, including: effects of climate change on agriculture and food security; responses of organisms and ecosystems to anthropogenic influences on landscapes; emergence of infectious diseases, and influences of genes on behavior.

This proposal uses a ?back-to-the-future? educational model that asserts that the best way to use genomics to address grand challenges in biology is to have a graduate program that blends state-of-the-art training in genomics with an integrated, taxon-oriented, perspective. Our guiding principle is that to be able to use powerful new genomic resources as effectively as possible, students need to have strong foundation in the basic biology of the organisms they are studying. Another cornerstone of this IGERT is the recruiting and mentoring of underrepresented minorities into a scientific discipline. Because genomic topics often deal with provocative issues, students will also get training in scientific ethics and on how to communicate sensitive topics to the public.

IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.

This INSPIRE award is partially funded by the Perception, Action, and Cognition Program in the Division of Behavioral and Cognitive Sciences in the Directorate for Social, Behavioral and Economic Sciences, the Animal Behavior Program in the Division of Integrative Organismal Systems in the Directorate for Biology, and the Dynamical Systems Program in the Division of Civil, Mechanical & Manufacturing Innovation in the Directorate for Engineering.

The project explores the question of how the activities of individuals become integrated into a smoothly functioning society: What are the dominant mechanisms? How resilient are they? How do they depend on the properties of individual society members? To this end, investigators from engineering, biology, psychology and linguistics will work together to study bee colonies and groups of humans to understand how organization and coordination emerges from these multi-agent systems and the factors that influence their robustness and resilience to perturbations. The project relies on quantitative observations of the dynamic emergence of patterns of interaction and coordination using an unprecedented, 24/7 monitoring system of a beehive as well as in groups of humans under controlled conditions designed to distinguish between failed and successful coordination. The investigators will pursue a combined theoretical, experimental, and computational framework for characterizing the resultant parallel and asynchronous communication systems. The work depends crucially on the interdisciplinary framework and the direct involvement of content expertise from the disciplines represented by the investigators. For example, the human transportation network is designed to resemble the coordinated delivery of nectar through a beehive, but with options for varying the number of different materials transported, the size of arena, the flow rates of the materials, and so on.

The investigators are exploring whether a comprehensive computational framework can be discovered to understand, predict and prevent the collapse of very different types of communities (bees and human networks). The research results are expected to provide insight into how to manipulate the behavior of a complex system, for example to address societal challenges associated with the collapse of pollinating bee colonies or the destructive behavior that is often associated with phases of social transition in groups of humans.

Proposal #: 13-37732
PI(s): Lumetta, Steven S.
Iyer, Ravishankar; Jongeneel, Cornelis Victor; Robinson, Gene E.; Sinha, Saurabh
Institution: University of Illinois - Urbana-Champaign
Title: MRI/Dev.: Novel Computing Instrument for Big Data
Project Proposed:
This project, developing CompGen, an instrument that adopts a hardware-software co-design approach, aims to provide a
- Vehicle for biologists and computer scientists to collaborate and develop new algorithms that are significantly faster and more accurate at a scale essential for handling the data deluge;
- Software framework and tool set for algorithm development that support diverse data analysis and visualization;
- Framework for developing accelerators and mapping to heterogeneous computational resources and hierarchical database storage.
Promising technologies include emerging die-stacked and non-volatile memory technologies as well as accelerators (GPUs, FPGAs, APUs).
The project brings together a multidisciplinary team of geneticists, bioinformatics specialists, computer and algorithms designers, and data mining experts. The research to be enabled includes a wide and eclectic variety of problems with direct impact on health and social issues. Some directions include understanding the impact of climate change on gene expression and ecosystems, bringing genetic analysis into medical clinics, identifying effective antibiotics, and exploring socio-genomics relations between stress, depression, and genetics among low-income African-American mothers.
CompGen provides an environment that enables managing and processing genomic information and developing new algorithms. The instrument brings disruptive computing architectures and algorithmic techniques to facilitate analysis of genomic data while providing high accuracy results, resilience to errors, and scalability with growing volumes of data. It enables addressing the challenges of scale and diversity in genomic data through the development of new algorithms, models, and statistical methods. The instrument development focuses on reduction of data volume, optimization of storage hierarchy, identification and implementation of computational primitives, data visualization, mathematical toolkit optimization, and performance and reliability assessment. These developments are expected to lead to new computational structures and hardware/software architectures that can be incorporated into hierarchical databases as well as heterogeneous processors for data analysis, compression, and optimization.
Broader Impacts:
In addition to serving many areas, CompGen will serve as a tool for educating students and professionals in efficient ways to process and analyze genomic data and for handling big data in general. The instrument will serve multidisciplinary classes in which students gain hands-on research experience and introductory classes that expose students to applications and tools. Existing outreach and education programs will be utilized to expose the instrument. Plans include Open House events attracting thousands of visitors, Coursera courses, and minority outreach workshops. A mentoring tool, Mytri, will be used for networking among female students. Moreover, the CompGen design will be made available to others by fundamentally changing the methods by which big datasets are handled in genomics research. To this effect, an R&D consortium of hospitals, companies, and universities has been established to help identify needs, provide sources of data, act as early adopters, and ensure that new technologies are transferred smoothly into widespread use.

A key challenge in biology is to understand the link between brain function and behavior. Knowledge of brain functional dynamics is especially important for understanding how experience shapes the brain. This project couples state-of-the-art techniques to measure and mathematically model brain metabolic activity, using the honey bee as a model system and aggression as the focal behavior. Experiments will determine whether experimentally induced changes in brain metabolism cause changes in aggression, which is what is expected based on previously collected correlative data. Additional experiments will determine in which parts of the brain are the aggression-related changes in metabolic activity. This new information will then be used to build a comprehensive model of the bee brain's metabolic network, which will then be validated with experimental work.

This collaborative project will provide integrative training for undergraduate students, graduate students, and post-doctoral associates, and members of the research team will give public presentations on the new insights into brain function gained by this project in a variety of venues for retired people and in K-12 settings. The Institute for Genomic Biology (IGB) at the University of Illinois at Urbana-Champaign will be the facility to store and back up project data, which include mainly RNA bioinformatic sequence-based and metabolomic datasets.

? DESCRIPTION (provided by applicant): Social experiences impact nearly every facet of human behavior, and social adversity can have devastating and long-lasting health effects on mental and emotional health. A comprehensive framework of how social interactions are processed at the molecular, individual behavioral and societal levels is thus essential to fully understand both healthy and impaired social behavior. Plasticity in transcriptional regulatory networks plays a crucial and deeply conserved role in body plan development, and we hypothesize that it also underlies social behavior (another highly plastic property of an organism's biology). To test this hypothesis, we will use an established model of social behavior (the honey bee) to explore the bidirectional flow of information between three levels of biological organization: 1) brain neurogenomic state, 2) individual behavior, and 3) emergent properties of the society. Aim 1 will examine reciprocal feedback between behavioral state and the regulatory functions of two transcription factors (TFs) predicted in previous systems biology studies to play prominent roles in brain gene expression networks regulating social behavior. RNA interference will be used to knock down expression of these TFs and neuroendocrine-mediated manipulation of behavioral state, and to thereby test the hypothesis that social behavior is controlled by context-dependent rewiring of brain transcriptional regulatory networks. Aim 2 will use a novel technology to automatically monitor the social interactions of every bee in the colony, in order to characterize how alterations in the neurogenomic and behavioral state of a set of focal bees (as done in Aim 1) influence the social interactions and brain gene expression of untreated individuals. Aim 3 will then generate novel algorithms to describe the emergent properties of the social network as a whole, and use them to construct a simulation of how the proportion of individuals in a particular behavioral or neurogenomic state influences the global properties of the social network. These analyses will allow us to identify mechanisms of information flow from the transcriptome to the social network, as well as determine how a social network responds to changes in social group composition. The outcome of this research will be a multi-level model of the reciprocal relationships between brain transcriptional regulatory networks, individual behavior, and societal function. This model will provide new insights into how genes influence social behavior and how an individual's neurogenomic and behavioral states influence social groups, with important implications for our understanding of how healthy and pathological behavior influence societal function.

? DESCRIPTION (provided by applicant): Aggressive behavior is a damaging influence in our society, since by definition it is intended to inflict physical or psychological harm. In humans, growing up in a socially adverse environment can strongly influence the development of aggressive tendencies, and genotypic variation can also predispose individuals to aggression. DNA methylation is an epigenetic modification that exists in relatively stable patterns, but can change at specific loci in response to the environment. This stable/dynamic duality potentially places DNA methylation at the regulatory interface between genotypic and environmental influences on behavior. This proposal will investigate whether DNA methylation mediates the influences of genotype and environment on aggression in the honey bee, a model that exhibits well-characterized aggressive behaviors, and unlike the fruit fly, has a fully functional, mammalian-like methylation system. Strains of bees differ in their aggressiveness, and our prior work has shown that the highly aggressive African honey bee (AHB) shows differences in brain gene expression and DNA methylation from the less aggressive European honey bee (EHB). In addition, EHB provoked to aggression by exposure to alarm pheromone show expression changes in some of the same genes. We will test the hypothesis that DNA methylation serves as a stable epigenetic mark regulating inherited differences in aggression, while also acting as a dynamic regulator responding to environmental stimuli that promote aggression. In mammals, DNA methylation patterns can be modulated through active DNA demethylation, which is mediated by ten-eleven translocase (TET) and thymine DNA glycosylase (TDG) enzymes. To determine whether a TET/TDG-dependent DNA demethylation mechanism exists in bees and regulates aggression, TDG will be knocked down in the bee brain using RNA interference (RNAi); preliminary results indicate a ca. 20% knockdown. We will measure DNA demethylation and aggression in the TDG knockdown bees, as well as the accumulation of oxidized 5-methylcytosine derivatives, which are known intermediates of active DNA methylation in other organisms. To explore whether DNA methylation also establishes aggression as a stable trait associated with genotype, we will examine the stability of DNA methylation patterns at aggression-related genes in AHB and EHB. Lastly, we will compare methylation patterns at aggression-related genes between the hereditary and environmentally-induced aggressive contexts. We expect to observe similar methylation patterns between the two, supporting our hypothesis that DNA methylation is a regulator underlying both genotypic and environmental effects on aggression.

The application of genomics across the life sciences industries is currently challenged by an inadequate ability to generate, interpret, and apply genomic data quickly and accurately for a wide variety of applications. Major Innovations in the applicability, timeliness, efficiency, and accuracy of computational genomic methods are needed, and these innovations will develop best when an interdisciplinary team of scientists, engineers, and physicians from academia and industry, spanning computer systems, health care/pharmaceuticals, and life sciences, work together. The University of Illinois at Urbana-Champaign (UIUC) and the Mayo Clinic are building on their longstanding collaboration to form the Center for Computational Biotechnology and Genomic Medicine (CCBGM), which will bring together their excellence in computing, genomic biology, and patient-specific individualized medicine. Working closely with industry, the CCBGM's multidisciplinary teams will use the power of computational genomics to advance pressing societal issues, such as enabling patient-specific cancer treatment, understanding and modifying microbial communities in diverse environments related to human health and agriculture, and supporting humanity's rapidly expanding need for food by improving the efficiency of plant and animal agriculture. The CCBGM will leverage UIUC's long-standing prowess in large-scale parallel systems, big data analytics, and hardware and software system design, to develop new technologies that enable future genomic breakthroughs. A key element of the Center's vision is to advance breakthroughs at the interface of biology and computing to transform health-care delivery while enhancing efforts that focus on the health science needs of underrepresented minorities.


The CCBGM will bring together an interdisciplinary team to address the colossal genomic data challenge. Academia/industry partnerships will enhance research, education, and entrepreneurship while performing important technology transfer. The Center will achieve transformational computing innovations on three fronts. (1) It will innovate computing and data management to deal with issues of scaling to the ever-growing volume, velocity, and variety of genomic data. It will concentrate initially on scaling the computation of epistatic interactions (interactions between two or more genes or DNA variants) in genome-wide association study data, generating lists of genomic features that are maximally predictive of phenotypes, and information-compression algorithms for genomic data storage and transfer. (2) It will revolutionize the generation of actionable intelligence from multimodal structured and unstructured data, to generate knowledge from big data. The emphasis will be on the processing and integration of genomic and multi-omic data, and on the merging of unstructured phenotypic data with information from curated data sources (e.g., electronic medical records, annotation databases). The integration of these diverse data types will improve discovery research, predictive genomics, diagnostics, prognostics, and theranostics. Application areas include targeted cancer therapy, pharmacogenomics, crop improvement, and predictive microbiome analysis. (3) It will achieve systems innovation by designing computer systems specially suited for computational genomics, providing unprecedented speed and energy efficiency while preserving the accuracy of the analytics. The systems will be used to quantify and improve the accuracy of detecting genomic variation and, more generally, to optimize computing architectures for the execution of genome analysis workflows.

Microbes living in their host’s gut perform diverse functions related to nutrition, fighting disease, and behavior. In many cases, the gut microbiome performs necessary functions for its host, such that disruptions in the microbiome result in abnormalities. In other cases, the gut microbiome contributes to variation between individuals, such that differences in microbiomes between individuals drive differences in physiology and behavior. However, it is not known whether gut microbiome function can change over the host’s lifetime. Furthermore, while various studies support the role of gut microbes in mediating host behavior, how they influence host behavior and the factors that mediate this interaction are largely unknown. This project addresses these important questions by studying how the gut microbiome influences behavioral maturation in the honey bee, Apis mellifera, which involves a transition in behavior from caring for larvae inside the hive and performing other in-hive tasks, to foraging for nectar and pollen outside of the hive. This maturation process underlies age-related division of labor, so understanding the role of the gut microbiome in this process promises to illuminate our understanding of honey bee colony function. The results of these studies will also provide novel insights into the dynamics of host-microbe interactions, animal behavior and symbiosis, and gut-brain communication. This project will provide integrative training in behavior, genomics, and microbiology to a diverse set of trainees at various career stages within the home institution, and will serve as the foundation for unique outreach and training activities for local K-12 students.

Understanding how the gut microbiome contributes to the functioning of the gut-brain axis is an emerging area of study in neuroscience, but the mechanisms supporting gut-brain communication remain poorly understood. To address this problem, this project will utilize state-of-the-art behavioral, genomic and genetic tools in the honey bee and its microbiome to determine the role that gut microbes play in honey bee behavioral maturation. Specifically, this project will: 1) Use a combination of several honey bee colony-level manipulations, microbiome sequencing, and behavioral tracking to test the hypothesis that the microbiome influences behavioral maturation in the honey bee; 2) Perform single-microbe inoculations with microbes robustly associated with behavioral maturation, followed by metabolomic and transcriptomic analyses, in order to identify specific microbial factors that influence behavioral maturation and associate them with specific effects on host brain functioning and physiology; 3) Use a recently developed honey bee microbiome genetic toolkit to produce genetically modified microbes in order to functionally assess the role of specific microbial factors in behavioral maturation. Achieving these objectives will provide important new mechanistic insights into the gut-brain axis, and will determine whether and how the microbiome contributes to changes in behavior over the lifetime of an individual.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.