Karen A. Mesce - US grants

An important and relatively recent concept has arisen in the neurosciences regarding the functional organization of neural networks and how such systems generate rhythmic behaviors. The salient feature of this concept is that a neural network has the capacity and plasticity to generate various patterned outputs, depending on the specific chemical and/or synaptic inputs the neural network receives. Importantly, the "conservation-modulation" strategy may also be used by the nervous system for the generation of increasingly complex behaviors expressed at later developmental stages. It is thought that the development of adult-specific locomotor behaviors in vertebrates may be based on such a strategy. The proposed research will examine the developing central nervous system of the holometabolus insect, Manduca sexta, where developmental construction of adult behavior appears to be based on the neuromodulation of neural circuitry present at earlier developmental stages. The proposed research will examine the cellular and developmental aspects of neural elements underlying adult ecdysis, a hormonally activated rhythmic behavior that enables the insect to escape from its old cuticle. Previous experiments indicate that the larval ecdysis motor pattern can be un-masked in the adult. Its retention in the adult is thought to contribute to the novel adult-specific ecdysis pattern. By the influence of descending neural activity, in some unknown way, the conserved larval ecdysis pattern-generating circuitry is acted upon to produce adult ecdysis behavior. Preliminary studies indicate that within a group of approximately 15 pairs of descending thoracic neurons, there are modifying interneurons that are necessary for the transformation of the larval ecdysis motor program into the adult-specific one. I propose to: (1) examine the functional role that individual descending interneurons play in the transformation of the larval ecdysis pattern to that of the adult pattern, and (2) examine the developmental history of descending thoracic interneurons, and the anatomical connections these neurons make with the conserved larval circuitry in the adult. Intra- and extracellular electrophysiological methods will be used to study the actions of the descending interneurons on identified ecdysis out-put motoneurons and possibly other interneurons. Various cell tracers will be used to study the anatomy of the descending thoracic interneurons, especially during metamorphic development. This is the first invertebrate model system developed where it is possible to study, at the cellular level, how adult behavior arises from the apparent modulation of a motor program expressed earlier in development.

LAY ABSTRACT Principal Investigator: Mesce, Karen Proposal Number: IBN-9813995 The brain and nervous systems of all animals, including our own, can be greatly altered by various types of neuroactive substances. This is a familiar concept if one thinks of the effects of 'street' drugs on the brain, or the way one feels in response to a jolt of adrenaline. Both adrenaline and serotonin are known as biogenic amines. But, how do brain chemicals work to regulate the production of a particular mood or behavior? What causes specific nerve cells to release their chemicals for the production of appropriate behavior, and what are the neural targets for such chemicals? At the level of individual nerve cells, answers to such questions remain far from complete. The aim of this proposal is to understand better how the biogenic amines work to regulate nervous system function and ultimately the generation of behavior. A simple invertebrate model nervous system has been chosen for study because individual nerve cells (neurons) can be readily studied, especially ones that contain either serotonin or the adrenaline-like compound called octopamine. The electrical activity of amine-containing neurons, and their connections with target nerve cells can be followed in much more detail than is currently possible using more complex vertebrate systems. One important component of this research is based on a recent finding in Dr. Mesce's lab where it was found that the combination of two biogenic amines can result in behaviors not induced by either substance alone. Because the actions of the biogenic amines are fairly conserved across species, including humans, such studies will contribute to an understanding of how single and multiple neural chemicals can orchestrate the release of various kinds of behaviors ranging from the activation or inactivation of locomotion, alteration in motivational state, and possibly, behavioral disorders in humans.

Collaborative Research: Mesce and Fahrbach

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.

Neural mechanisms of hygienic behavior in the honeybee

Lay Summary

Marla Spivak
Karen A. Mesce


The long-term goal of this project is to understand how relatively small genetic differences within a species translate into significant differences in behavior that are based on how neural circuits are 'wired up' versus how neurohormones differentially modify the functioning of similar neural circuits. Honey bees bred for hygienic behavior will be studied and compared to unselected bees that exhibit less hygienic behavior. Hygienic bees detect and remove diseased and parasitized brood from their nest more readily than non-hygienic bees. The honey bee industry is keenly interested in hygienic lines of bees because they are more resistant to diseases and parasitic mites. More significant, however, is the potential that this study will contribute to a better understanding of how a class of compounds, the biogenic amines, contributes to behavioral alterations in humans. The biogenic amines include serotonin, dopamine, and adrenaline-related substances. These neuroactive substances are critically important to human mood disorders, learning and memory, and numerous diseases including Parkinson's disease.
A central hypothesis of this study is that octopamine, a neurohormone related to noradrenaline, contributes to the shaping of the behavioral differences between hygienic and non-hygienic bees. Hygienic bees have increased olfactory sensitivity and responsiveness to diseased brood compared to non-hygienic bees. In essence, it is proposed that neural networks underlying hygienic behavior are 'polymorphic' and thus can be shifted or biased into a mode in which hygienic behavioral expression is activated more or less easily. It is theorized that relatively small genetic differences among animal species may translate into disproportionately large differences in behavior if shared polymorphic neural networks are differentially regulated by octopamine (or dopamine). The specific aims are as follows: 1) determine the relationship between the expression of hygienic behavior and other important honey bee behaviors; 2) Examine the olfactory sensitivity of hygienic and non-hygienic bees, and the role of olfaction in the expression of hygienic behavior; 3) Determine the role of octopamine and dopamine in the expression of hygienic behavior.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

Dopamine (DA) is an important and universal modulator of motor control, but neuroscientists have yet to determine precisely how DA-containing neurons and their targeted circuitry choreograph specific locomotor programs. This has been an especially daunting task in studying the control and initiation of locomotion in higher vertebrate systems. Related to this issue of locomotor regulation is the idea of decision-making, and how one form of locomotion is selected instead of another, for example, the choice between crawling vs. swimming. This collaborative research project is addressing such important questions at the level of single identified neurons; often at times while the intact animal is behaving. The simpler nervous system of the leech, Hirudo medicinalis, was selected for study because it contains relatively large and physiologically accessible neurons and a hierarchical circuit organization, thus facilitating studies of locomotion, body movement and descending control. Specifically, the collaborative research team is characterizing constituents of the pattern-generating network underlying crawling-related behavior, and determining how DA changes the properties of neurons to facilitate their participation in crawling. This approach will lead naturally to an understanding of the neuronal bases of decision-making, because it has been found that whenever DA triggers crawling then swimming is inhibited. The collaborative research team will use a variety of behavioral, electrophysiological, and anatomical methods to study how DA promotes crawling behavior. They will also image neuronal circuits influenced by DA using a state-of-the-art voltage sensitive dye imaging system. Many of the experiments being conducted involve graduate and undergraduate students. Other experiments, with minor modification, incorporate the participation of younger K-12 students. The collaboration with Dr. Crisp at St. Olaf College, an undergraduate-only research institution, provides an additional and valuable exchange of undergraduate training and mentoring opportunities. The projects and technological components of the proposal are inherently integrative, spanning disciplines from Animal Behavior to Cell Biology/Neurobiology, Computational Neuroscience, Physics, and Engineering.

? DESCRIPTION (provided by applicant): Funds are requested to support the 7th Gordon Research Conference and Seminar in Neuroethology, to be held June 27th -July 3rd, 2015 at the Renaissance Tuscany Il Ciocco Resort, Lucca (Barga), Italy. Funds received from the NIH will be used solely to defray the travel and registration costs incurred by US-based students, postdocs, and other invited speakers who are junior, with preference being given to scientists from underrepresented groups. The GRC will be preceded by a two day Graduate Research Seminar organized by graduate students and postdocs for graduate students and postdocs. This innovative program will combine scientific presentations and mentoring to enhance the experience of younger scientists attending their first GRC. The quest to understand the biological principles that exquisitely adapt organisms to their environments and which allow them to solve complex problems, has led to unexpected insights into how similar problems can be solved technologically and are central to the recent BRAIN initiative. Recent cutting-edge advances in neuroethological research are revealing how animals sense their constantly changing environments and use this information neurally to control and steer complex behaviors, such as flight, walking and running, and navigating over great distances. The principles neuroethologists are uncovering showcase the enormous sophistication of natural sensors and actuators, the properties of which will invariably become highly desirable features of future autonomous surgical devices, robots and neural prosthetics that can aid in human movement and sensing due to disease or loss of sensory acuity. The 2015 GRC - whose title is The future is now: Innovative concepts in neuroethology and new technologies - aims to combine cutting-edge fundamental research in Neuroethology with the world's leading research in biomimetics and neuromorphic engineering, allowing an unparalleled forum for biologists and engineers to inspire and learn from each other in a small and collegial environment. Each session of the conference is designed to present the leading research in neuroethology with the latest advances in the fields of biorobotics and biomimetics, with the aim of inspiring the leading researchers in both fields. The program will include sessions on animal and machine locomotion and sensing, olfaction by animals and robots, and animal and machine navigation. In addition there will be several other sessions dealing with the evolution of brains, advances in technology, neural plasticity, emerging sensory modalities and computational neurobiology.