Werner Graf - US grants

Flatfish constitute a natural paradigm for investigating adaptive changes in the central nervous system, because their vestibular and oculomotor coordinate systems undergo a 90 degrees relative displacement during metamorphosis. This displacement requires the introduction of a new conversion factor for the transmission of signals coded in vestibular coordinates into motor commands coded in eye muscle coordinates. Our previous studies revealed a dramatic rewiring at the level of secondary vestibular neurons connected to the horizontal canal system, exhibiting an extensive termination pattern in vertical oculomotor neuron pools via connections which are absent in all other vertebrates studied so far. Experiments are planned to give a full description of the pre- and postmetamorphic vestibulo-ocular reflex (VOR) system in the flatfish. These include, first, extracellular and intercellular HRP applications at the level of primary and secondary vestibular afferents of both labyrinths including a quantitative analysis of the peripheral nerves supplying vestibular end-organs in order to demonstrate symmetry of the labyrinthine connections as well as double intracellular recordings to ascertain the excitatory or inhibitory nature of the identified secondary vestibular neurons within the push-pull system of the VOR system. Secondly, extracellular recordings during optokinetic stimulation will provide information about the organization of the visual space of these animals. Thirdly, experiments in the alert behaving flatfish will reveal the structure-function relationship of the morphologically described connections to the actual eye movements of the fish. Fourth, experiments in premetamorphic and metamorphosing animals and in fish which are locked in certain stages of the metamorphosis will reveal the nature of the occurrance of these newly formed connections, whether they originate from newly born neurons or from synaptic connections which have been there previously. These experiments involve the creation of hyperdimensional larvae by environmental and pharmacological manipulations, as well as the usage of autoradiographic techniques. The proposed experiments would not only be a comprehensive way to describe the VOR system in the adult flatfish, but also give information about the mechanisms involved in an adpating brain, especially in the context of adaptive plasticity during experimental perturbation.

Eye and head movements that occur in three-dimensional space are commonly described by the extrinsic orthoganal x,y,z axes (Cartesian) coordinate system. However, for weak coordinated motor commands, especially those resulting from multisensory integration, biological systems are likely to utilize intrinsic reference frames that are geometrically different from Cartesian systems. Our prior studies in the accessory optic system and cerebellum indicated that the coordinate axis for the orientation frames of the vestibulo-oculo motor and visual climbing fibers were geometrically closely related. The planes were three-dimensional, non-orthogonal, oblique and axially symmetric to the midline and in fact, these results suggested that the vestibular coordinate system may form the basic geometric architecture. Accordingly, experiments are proposed to test the coordinates of the geometric space leading to visual modulation of identified secord order vestibular neurons including a broader morphological study of neuronal network underlying vertical vestibulo-ocular reflexes. In addition, both the signals and patterning of extraocular motoneuron and muscle activity leading to compensatory eye movement in lateral- and frontal-eyed animals will be studied. Rabbits and cats, respectively, will be used to determine if the orientation planes of identified vestibular neurons are indeed similar in the two species. Vestibular stimulation will be provided by a three-dimensional turntable and visual stimulation by a three-axis planetarium projector producing a full field constant pattern. The neuronal network underlying the vertical vestibular ocular reflexes will be studied with intracellular HRP methods. Standard neurophysiological techniques and eye movement measurement will be employed. Data analysis will be accomplished by on- and off-line computer compilation. The immediate objective of the project is to describe exactly how the semi-circular canal sensory planes are related to the instrinsic framework for other sensory and motor coordinate systems. This goal will be achieved by studying how different classes of information coded in each individual coordinates interact with each other and, more specifically, how this relationship is visualized in respect to central neuronal connectivity. The long term objective of the proposal is to test the hypothesis that the intrinsic coordinate system may be common for all vertebrate species, cat, rabbit, goldfish.

The overall goal of the proposed experiments is to demonstrate that neuronal operations can be meaningfully interpreted within the concept of intrinsic reference frames. To this effect, the realization of reference frames in the eye and head movement system of vertebrates will be studied in a behavioral context, as will their phylogenetic and ontogenetic development. The first specific aim will be to determine the process of sensory-motor transformation in the vestibulo-ocular reflex system and the involved neuronal circuits. The second project will establish the structure-function relationship of vestibular neurons to compensatory and voluntary eye movements in all three dimensions of physical space. The third specific aim will be to describe the ontogenesis of the optokinetic reference frame within the retino-cerebello-vestibulo-oculomotor loop, using dark-reared animals. The fourth specific aim targets the phylogenetic development of the vertebrate vestibulo-oculomotor system, in particular the acquisition of a horizontal semicircular canal by gnathostomes and the prototypical bony fish and elasmobranch oculomotor organization. The fifth specific aim will be to investigate further the biomechanics of the vertebrate head-neck ensemble, extending this study to the human head movement system. Completion of this particular project may yield useful data in regard to orthopedic and neuronal disorders involving the cervical vertebral column. Experimental techniques utilized in this research include acute and chronic animal preparations, three-dimensional visual and vestibular stimuli with extraand intracellular recordings, extra- and intrdcellular horseradish peroxidase (HRP) histochemistry, three-dimensional eye movement recordings with the magnetic search coil technique, cineradiography, and selective lesions of labyrinthine endorgans. As a long-term goal, the proposed experiments should demonstrate that the brain utilizes intrinsic reference frames to reduce the degrees of freedom of sensory-motor systems, thus simplifying neuronal operations, as well as economizing brain function in light of a narrow window of optimal brain-to-body ratio.

This action is to help support the travel costs of fourteen U.S. scientists so that they may present scientific papers at an international conference which focuses on neural mechanisms of head and neck movements. The meeting will be held in Paris, France and will be attended by leading scientists in the fields of eye movement physiology, biomechanics, rototics, embryology, evolution, and comparative aspects of the head.neck movement systems. By bringing together this diverse group of scientists, more opportunities will be available for cross.fertilization of scientific fields. This planned gathering should enlarge the pool of scientists interested in head movement control and establish a conceptual and collaborative umbrella.

Rauschecker 0730255

PIRE: International Research Program in Cognitive and Computational Neuroscience

In this Partnership for International Research and Education award, Georgetown University and Howard University will develop a multi-lateral international neuroscience collaboration involving several German and French institutions. The U.S. researchers and students involved will work with teams at the Technical University of Munich led by Arthur Konnerth, at the Ludwig-Maximilians-University in Munich led by Benedikt Grothe, at the Max Planck Institute for Biological Cybernetics in Tubingen led by Nikos Logothetis, at the Eberhard-Karls-University in Tubingen led by Peter Thier, at the Laboratory for Molecular and Cellular Neurobiology in Gif-sur-Yvette led by Gabriella Ugolini, and at the Brain and Cognition Research Center in Toulouse led by Simon Thorpe. They will form a focused, integrated, and complementary collaboration to lead neuroscience research and education on the international stage. Research topics include the neuronal functions of the cerebral cortex associated with auditory object processing, motion processing and contextual motor behavior, and the interaction of stimulus processing and category processing to produce object recognition.

This award will help to train the next generation of globally engaged scientists and engineers, as approximately twenty undergraduate students, fourteen graduate students, and five postdoctoral researchers will be funded to conduct research abroad with the German and French partners over the five-year course of the award. In addition, this award will allow Georgetown and Howard Universities to pursue their plans of developing a joint doctoral program with the Technical University of Munich and will leverage funds already received by the Technical University of Munich from the German Research Foundation, which encourage U.S. / German collaboration by allowing German doctoral students to conduct research at Georgetown via the International Research Training Group program. This award will enhance an already-existing neuroscience collaboration between Howard University and Georgetown University and will broaden participation by taking advantage of Howard University's ability to recruit under-represented minority students. The project overall is designed to broaden students' perspectives through an active international collaboration and participation in jointly organized international summer academies. The award includes funding for an outside evaluator to determine how well the project reaches its goals.

This award receives support from NSF's Office of International Science and Engineering and Division of Behavioral and Cognitive Sciences.

DESCRIPTION (provided by applicant): This renewal of the Specialized Neuroscience Research Program (SNRP) is based on commitments made by Howard University and the College of Medicine which guarantee long-term support toward the goal of developing talented minority neuroscientists. During SNRP-1 we developed an extensive research infrastructure, established multiple inter-departmental and inter-institutional research collaborations, and accomplished significant goals in interdisciplinary research. These achievements were crucial to the process by which we were able to attract three new project leaders to participate in the renewal of this program, (SNRP-2). In phase one of the SNRP, we focused on neuronal networks regulating breathing and the airway functions that are coupled to systems involved in behavioral state control. The current three interrelated projects seek to better understand how structural, functional, or genetic alterations in neuronal networks affect cardiovascular functions, aging, and cognition. Dr. Davila-Garcia's Project will use ultrastructural, electrocardiographic, echocardiographic, and physiological methods in the cat to define selected intrinsic cardiac neural mechanisms mediating parasympathetic control of ventricular functions. These novel studies will provide the first detailed analyses of the functional roles and neuroanatomical circuits of ventricular ganglia which mediate vagal effects on either or both ventricles of the heart. The resulting data will have important implications for understanding diseases such as congestive heart failure and pulmonary hypertension. The overall goal of Dr. Duttaroy's Project is to use the Drosophila model to understand the mechanistic basis of an oxidative damage protection system and how it is devoted towards maintaining the integrity of the nervous system, cognition, and neuromuscular ability as a function of age. Dr. Manaye's Project will utilize a well established mouse model of oxidative stress, the double transgenic expression of toxic beta-amyloid (Abeta), in combination with state-of the-art neurostereological techniques, to characterize age- and gender-related alterations in noradrenergic pathways innervating the amygdala, hippocampus, and frontal cortex. These studies will test the hypothesis that the age-related accumulation of toxic proteins related to Alzheimer's disease cause a cascade of neuroinflammatory responses leading to progressive degeneration of noradrenergic pathways responsible for cognitive and affective neurological functions. Administrative Core (Core A) will maintain centralized financial record keeping, prepare financial and scientific reports, facilitate the use of common resources, and monitor scientific progress. Neurobiology Core will provide central facilities, facilitate standardization of anatomical, neurochemical, molecular, physiological, and pharmacological methods, and assure uniform criteria for data analysis. Each project in this proposal for renewal arises directly from on-going work in our laboratories at Howard University. The overall program will provide new knowledge on plasticity of neuronal networks that regulate autonomic functions, behavioral state control, and cognition.

This Integrative Graduate Education and Research Training (IGERT) award focuses on the evolution of the human brain, cognition, and related behavioral responses to environmental change. The program integrates cross-disciplinary research training in a unique mix of disciplines, namely archeology, biomechanics and engineering, cognitive science, comparative and experimental functional morphology, ecology, evolutionary and developmental biology, genetics, geochemistry, morphometrics, life history, molecular biology, neuroscience, and paleoclimatology. Innovative educational and training aspects include an emphasis on collaboration via group problem-based learning approaches, required laboratory rotations in two different disciplines, and seminars in ethics and professional conduct. The program combines George Washington University?s PhD program in Hominid Paleobiology with the Howard University PhD in Physiology and Biophysics, together with faculty from the Smithsonian Institution and Johns Hopkins University?s Center for Functional Anatomy and Evolution, The collaboration with Howard University (an HBCU) and existing and planned internship programs for undergraduates will increase the recruitment of underrepresented minorities. Outreach activities include a required internship in the public understanding of science, in conjunction with area institutions such as the National Geographic Society, USA Today, NPR, the National Academy of Sciences, American Anthropological Association, local schools and others. The program offers research-training opportunities at major international institutions in Europe (e.g., Max Planck Institut für evolutionäre Anthropologie (MPIEA); Swedish Museum of Natural History; Università degli Studi di Firenze?s Laboratori di Antropologia; University of Bordeaux), China and Africa. 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.