Catherine Emily Carr, PhD - US grants

DESCRIPTION: The objective of this proposal is to understand the mechanisms that control axonal and dendritic differentiation and morphology in granule neurons. To determine how cues intrinsic to the cell, or present in the extracellular environment, direct the differentiation and maturation of granule cell axons and dendrites, the following hypotheses will be tested: 1) The initial site of unipolar process extension is determined by the cytoplasmic location of the Golgi apparatus; after unipolar extension, the GA re-orients within the cytoplasm to support the growth of the second axonal process. To test this hypothesis, time-lapse confocal microscopy will be used to determine the dynamic behavior of the GA during the initial stages of granule clel axon outgrowth in. 2) After initial bipolar parallel fiber (PF) axon outgrowth is completed, diffusible or contact-mediated signals from developing Purkinje cells (PC) and/or granule cells within the molecular layer (ML) cause a down-regulation in expression of the axonal cell adhesion molecule, TAG-1, on granule cells located at the deep external granule layer (EGL)/ML border. To test this hypothesis, it will determined whether granule cell/PC contact in , or conditions that mimic the onset of synaptic activity between granule cells and Pcs, provide an "off-signal" for TAG-1 expression on initial granule cell axons. 3) Exposure of immature granule cells to depolarizing conditions inhibits axonogenesis and promotes dendritic differentiation. To test this hypothesis, immature granule cells will be exposed to depolarizing condition from the time of plating in . 4) Complete granule cell dendritic differentiation, which is characterized by the formation of characteristic claw-like dendrites, proceeds only after direct cell-cell contact with mossy fiber afferents. To test this hypothesis, granule cells will be co-cultured with pontine explants to provide a source of mossy fiber afferent input, to determine whether direct cell-cell contact with mossy fibers 'drives' further dendritic differentiation. Understanding the mechanisms that control the normal differentiation of granule neurons is critical in understanding the etiology of the various cerebellar ataxias and birth defects such as fetal alcohol syndrome.

9720334 Krishnaprasad The goal of this research project is to investigate time coding in the central nervous system, specifically the auditory system of the barn owl, the early development of such codes, the learning of associated maps, and the exploitation of such sound codes and maps in source localization and sound separation. The approach consists of electrophysiological and anatomical study, coupled with mathematical modeling of neural circuitry, the rigorous investigation of the structure and performance of relevant learning algorithms and the creation of an experimental robotic testbed. This testbed, a binaural head, is intended to be capable of orienting itself to sound sources in complex acoustic environments through pure auditory servoing, by utilizing the development of control architectures capable of learning maps of the auditory space of the robot, and drawing upon an evolving understanding of barn owl auditory system. The results of this research will provide insights into the design of novel roles for auditory sensing, interpretation and discrimination in autonomous robotic systems. This research could lead to applications in hands-free human-machine communications in acoustically cluttered environments and in monitoring complex environments such as highly automated manufacturing plants.

DESCRIPTION: (Verbatim from the Applicant's Abstract) The larval lamprey exhibits axonal regeneration and functional recovery following spinal cord lesions. However, the PI has found that by altering the temperature at which animals are maintained, it is possible to produce animals that exhibit either functional or dysfunctional swimming behavior. Thus the lamprey offers the opportunity to study the nature and consequences of dysfunctional regeneration. She has further found anatomical differences between the regenerated systems under the two conditions, specifically in terms of the distribution of serotoninergic axons. Following transections, there is a dramatic increase in serotonin fibers in areas rostral to the lesion, and a dramatic loss in caudal segments. However under conditions that favor recovery, serotonin fibers are more abundant in the caudal segments. She hypothesizes that serotonin fibers are responsible for at least one form of the behavioral differences seen under the different temperature conditions. The PI now proposes to identify the sources of the increased serotonin innervation in rostral segments, and the fate of the lost serotonin in caudal segments. One possibility that will be explored is that the increases in caudal segments is due to collareral sprouting of descending serotonin systems. She will test this hypothesis by evaluating whether the serotonin fibers originate from the brainstem or from dorsal roots. The fate of dopamine fibers will also be evaluated. Other studies will evaluate the functional capabilities of the animals using a sophisticated stochastic phase model to evaluate physiological responses. This technique, which has been developed by the PI, provides a quantitative measure of the degree of coordination between segments. In the same animals, the regenerated fibers will be traced anatomically and using specific markers for GABA and glycine.

[unreadable] DESCRIPTION (provided by applicant): This proposal requests partial support for an international meeting on Neuroethology as part of the Gordon Research Conference series to be held in Magdalen College Oxford August 10-15, 2008, and the preceding Graduate Research Seminar. The broad and long term goal of the conference is to increase our understanding of the evolution of neural circuits. The specific aim of this meeting is to convene 42 speakers that represent critical areas of neuroethology, evolution and development with a total of 135 participants for a five day conference in an isolated academic setting. Since the Gordon Conferences are an excellent forum for bringing together students and leaders in the field to discuss cutting edge problems, the intention of this meeting is to pose provocative questions on subjects that will generate real discussion. Prior to the official Gordon Research Conference, there will be a GRC program called "Graduate Research Seminar: Neuroethology 2050", where graduate students and post-docs will meet to discuss in an informal atmosphere what they think the future of neuroethology holds. The main program will have a keynote address and seven sessions. It will start with two sessions on the fundamentals: First, a session on current views of the origin of nervous systems and second one on homology, homoplasy, and divergence in neural circuits to discuss whether evolution always yields a common solution to similar problems of neural coding. The conference will also concentrate on three other areas with broad interdisciplinary impact. There will be a discussion about the evolution and development (evo-devo) of neural circuits in order to ask how much can be learned about the function of neural circuits from developmental and genetics rules. A session will be devoted to neural circuit properties underlying decision- making in different systems and one to discuss variability and homeostasis. The last two sessions concern future directions for the field. One session will discuss animal models of human characteristics where the questions will be raise about whether researchers are anthropomorphizing or whether there are fundamental common substrates for human traits such as love, dreaming, and social interactions? Our final session is a round table discussion on uncovering general principles in neuroethology. In addition, there will be poster session each evening to permit all participants to contribute. The significance of this application is that the Gordon Research Conference on Neuroethology is a critical component of the yearly series of conferences that propel research in the international community of neurobiologists working on how nervous systems integrate sensory signals within specific environmental contexts to provide behaviors, and how such behaviors, and thus the circuits underlying them, adapt to the natural environment. PUBLIC HEALTH RELEVANCE: The health relatedness of this application is that the discussions will define the questions that require experimental resolution in the studies of neural plasticity, motor control, neural genetics, and modeling. The Gordon Conference on Neuroethology: Behavior, Evolution, and Neurobiology, which will be held August 10-15th at Magdalen College in Oxford England, provides a unique opportunity for researchers from around the world to discuss emerging concepts related to the evolution and function of neural circuits. There will be a special pre-meeting Graduate Research Seminar to enhance the training experience for graduate students. Explicitly examining the evolutionary and comparative aspects of neural circuits will provide insights on the origin and cause of many human neurological and behavioral conditions. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This proposal requests partial support for US young investigators -- graduate students, postdoctoral fellows and assistant professors -- to attend the 10th International Congress of Neuroethology (ICN), to be held on August 5-10, 2012, at the University of Maryland in College Park. Topics to be covered at the meeting include sensory processing and perception, multisensory signaling, locomotion and motor control, behavioral endocrinology, and genetic control of behavior. Some sessions will highlight new technologies, such as automated analysis of complex behaviors emerging in animal groups and optogenetics. The program is designed to incorporate discussion of brain function at different levels of analysis (from biophysics to field behavior) using a wide range of tools and techniques (including those drawn from physics, mathematics, signal processing, molecular biology, genomics, field observations, psychophysics, and neurophysiology) and examined in a diversity of species, both vertebrate and invertebrate. These different approaches are bound together by a common fundamental goal: to uncover neural, computational, and design solutions to natural biological problems that, once identified, can more easily pursued in other species or implemented technologically. PUBLIC HEALTH RELEVANCE: Support of this conference will increase knowledge of neural mechanisms of behavior and will help identify technological solutions to neural and behavioral problems. By providing networking and mentoring activities, the conference will promote education and career development of young investigators. By providing outreach, the conference will increase public understanding of science.

DESCRIPTION (provided by applicant): The broad goal of the proposed research program is to advance our understanding of sound localization. The noteworthy similarities and differences between sound location processing in birds and mammals clearly show that there are many ways of localizing sounds and separating sources from background noise; these different strategies can provide inspiration for the development of new technologies such as cochlear implants. We propose a set of experiments to establish the nature of the interaural time difference (ITD) map, its mechanistic dependence on conduction velocity and afferent convergence, and its emergence during development. We focus on barn owls because they are capable of great accuracy in detecting ITD and are thus a model for studies of sound localization. Sensitivity to ITD first appears in nucleus laminaris (NL), a brainstem auditory nucleus with a similar function to the mammalian medial superior olive. In this application, four aims focus on ITD circuits in NL. We begin with studies of how delay lines create maps of ITD. We will measure conduction delays in NL, and develop a linear model of the delay lines to determine how conduction velocities can account for the map of ITDs. We will then use our investigation of the adult map of ITD to determine how ITD coding develops in young barn owls, animals whose head grows extensively after hatching. In our third aim, we will examine coincidence detection mechanisms that underlie sensitivity to ITDs. Recent intracellular recordings from NL neurons in vivo show that tonal stimuli induce an oscillatory membrane potential in the NL cell. These membrane oscillations must originate from phase-locked synaptic inputs from NM fibers, although how presynaptic, synaptic and postsynaptic properties affect the formation of this potential remains unclear. We will combine morphological and theoretical analyses to test the hypothesis that large numbers of phase locked synaptic inputs are necessary for the formation of the membrane potential oscillations in NL. The fourth and last aim of this application uses a comparative approach to experimentally address the current controversy between map-like place codes in birds vs. rate-based population codes in mammals. In the broader context, understanding the mechanisms and evolution of ITD coding reveals common computational solutions that can guide technological advances.

? DESCRIPTION (provided by applicant): In response to an emerging need for scientists who can bring innovative skills and perspectives to problems in the hearing sciences, we continue to build upon our well established Training Program in Comparative and Evolutionary Biology of Hearing at the University of Maryland, College Park. The 17 Core Faculty in our group bring an extraordinarily broad range of expertise, from cellular and molecular biology to systems neuroscience, while also demonstrating a successful track record in training students. These capabilities allow us to offer a training program that not only emphasizes a comparative and evolutionary perspective to understanding the auditory system, but also does so across different levels of analysis. We propose new approaches to train the next generation of scientists to translate knowledge and methodologies across biomedical sciences, enabling breakthroughs that cannot be achieved through work confined to a single discipline and using a single model system. The next cycle of our training program promotes a focus on translational research, in which we will continue to expand our trainees' appreciation of the biomedical applications of basic research to solving problems concerned with hearing across the human life span, including prevention, diagnosis, and genetics of hearing impairment and relevant therapeutic interventions. Core Faculty are from four departments: biology, psychology, hearing and speech sciences, and electrical and computer engineering. Additional associated faculty from other UMD programs, NIDCD, and other regional institutions, such as the University of Maryland- Baltimore (UMB) and Walter Reed National Military Medical Center, work closely with the Core Faculty and provide further research and training opportunities for pre- and post-doctoral trainees. The Training Program includes support for five predoctoral and three postdoctoral trainees. Predoctoral trainees are generally selected in middle to later training years, when they are primarily engaged in research. In addition to research training, all trainees take courses in the fundamentals of hearing and research ethics, attend seminars/courses in professional development and translational auditory science, as well as participate in all program activities. Emphasis throughout the program is to expose trainees to the breadth of work done in the program's participating labs, and through this exposure, gain a better appreciation for the range of questions being asked and interdisciplinary research methods applied today in the hearing sciences

The goal of the project is to provide a better understanding of what neural processes make up extracellular potentials recorded from brain, like the electroencephalogram (EEG). Although recorded in many settings, these potentials are poorly understood. Yet, they are clinically important; for instance, they are used for diagnosis of epilepsy and early detection of deafness. Development of differential diagnostic tools depends on understanding what brain components contribute to the recorded potentials. The investigators use a combination of quantitative modeling and recordings from the auditory system of the Barn Owl to gain insight into the connection between field potentials and their neuronal generators. In addition to better understanding of a widely used diagnostic tool, a further societally relevant outcome of the project lies in training women in Science, Technology, Engineering, and Mathematics. The U.S. and the German laboratories in this international collaboration have a strong commitment to science education and a well-established track record of training research fellows, as well as high school students and undergraduates from diverse backgrounds.

Extracellular field potentials are typically generated by various neuronal sources, making their interpretation difficult. They are, however, clinically important, with applications ranging from diagnostics to brain-computer interfaces. In the auditory system, for example, the auditory evoked potential, also called the auditory brainstem response (ABR) is widely used for newborn hearing screening but little is known how specific nuclei contribute to it structure. Motivated by clinical relevance and theoretical importance of understanding extracellular field potentials, the international team applies a combined computational and neurophysiological investigation of the extracellular field potential in a bird model system. The targeted neural structure, the Nucleus Laminaris in the Barn Owl, is homogeneous and well organized, and allows direct access to a system with a large extracellular field potential. The investigators' models and experiments delineate the potential contributions of the three possible sources of the extracellular field potentials. The approach tightly integrates theory and experiments, to provide a fundamental understanding of the connection between the extracellular field potentials and their neuronal generators. The results from this collaborative cross-disciplinary effort will provide a basis for the interpretation of the clinically relevant ABR. A companion project is being funded by the German Ministry of Education and Research (BMBF).

PROJECT SUMMARY The broad goal of the proposed research program is to advance our understanding of sound localization. Even when a person has normal hearing, speech perception and learning in noisy reverberant environments may still be compromised due to persistently impaired binaural hearing capabilities. In more profound cases of deafness, bilateral cochlear implant users typically experience poor discrimination of interaural time differences (ITDs), potentially because of early deprivation. This proposal uses an avian model to advance our understanding of binaural development. We have developed this preparation to determine if/when there is a developmental window in which inputs from each ear are synchronized, in order for sensitivity to ITDs to develop. Sensitivity to binaural signals first appears in the brainstem and relies on sub-millisecond precision to detect ITDs. How such extreme precision comes about during development is not fully understood, and these birds provide a well understood model for measurement of precisely timed binaural signals. Our knowledge of this ITD circuit is detailed enough to test the following hypotheses about the physiology and development of sound localization circuits. In the broader context, understanding the mechanisms of sound localization should reveal common computational solutions to guide advances in hearing aid and cochlear implant design. The three overlapping areas to be investigated in this project are: 1. Determine if the representation of ITDs is plastic during development. Detection of ITDs depends on precise coding of delay, with current research on how ITDs change with head growth. We will use a unilateral conductive hearing loss (CHL) model, in which one ear canal is plugged around the onset of hearing, to induce experience dependent plasticity during the period of head growth. These experiments should allow us to determine if maps of ITD are modified by early experience. In Aim 1.2 we will focus on myelin plasticity as a potential mechanism for modification. 2. Address mechanisms underlying the emergence of temporal precision. If delays can be modified by altered experience, it is likely that normal ITD coding also shows developmental refinement. Delay lines encode time with sub-millisecond accuracy. To shed light on the mechanisms underlying ITD map formation, we will combine recordings of the extracellular field potential with intracellular recording from delay line axons to measure the development of ITD coding in the first 2 months posthatch. 3. The role of inhibition in the development of ITD coding. Given the importance of inhibition in regulating auditory brainstem activity, we will examine the nature of the inhibitory input to NL and cochlear nuclei. We will use the unilateral CHL model to induce experience dependent plasticity in map of ITD, and test the competing hypothesis to Aim 1.2, that changes in delay are correlated with changes in inhibition.