Paul J. May - US grants

Equally necessary for normal visual function are the actions of the pupillary iris that control the amount of light reaching the retina, for both its protection and effective functioning, and the actions of the ciliary muscle that produce accommodation of the lens, bringing the world's objects into sharp focus. Impairment of either of these essential, primarily parasympathetic functions causes visual disorders, yet surprisingly little is known about their central neuronal circuitry. Utilizing a structure-function approach, this gap in our knowledge of the anatomy and physiology of these two systems will be eliminated by correlating intracellular recordings from identified neurons with their morphology as revealed by intracellular staining with horseradish peroxidase. Specifically, identified preganglionic motoneurons of the Edinger-Westphal complex responsible for accommodation or pupillary constriction will be distinguished by physiological criteria and intracellularly injected allowing determination of their morphology and location. Secondly, the afferents to these two motoneuron populations will be identified using intracellular recording and staining techniques. Particular emphasis will be placed on electrophysiological and morphological determination of the synaptic relationship between the motoneurons subserving pupillary constriction and two structures: the pretectum and area 20 of visual cortex. Similarly, the synaptic relationship between the motoneurons subserving lens accommodation and two suprabulbar structures, the interpositus nucleus of the cerebellum and Clare-Bishop area of visual cortex, as well as a presumed midbrain accommodation center, will be ascertained. Third, the circuitry underlying the near reflex will be investigated utilizing the combined intracellular approach to study the connectivity between the midbrain convergence center and preganglionic motoneurons subserving both accommodation and pupillary constriction. Finally, the same techniques will be applied to determine the role of the non-motoneurons in the Edinger-Westphal complex. In conclusion, this correlative structure-function approach will provide a better understanding of the neuronal circuitry that controls lens accommodation and pupillary diameter, making greater insight into disorders of these two functions possible.

? DESCRIPTION (provided by applicant): This project will investigate the inputs and physiology of premotor neurons controlling the near triad actions of vergence, lens accommodation and pupillary constriction; critical actions in the etiology of strabismus and amblyopia. It will: 1. provide the first detailed anatomical demonstration of the circuits underlying vergence functions; 2. characterize the function and connections of a novel set of near triad premotor neurons, and 3. test competing current models of eye movement control. The results will confer a better understanding of the mechanisms for obtaining stereoscopic vision. Two opposing models of eye movement control in 3-D space provide the context. One traces its lineage to Hering, who believed that conjugate and vergence eye movement signals were added together at the level of the motoneuron. The other traces its heritage to Helmhotz, who believed that the movement of each eye is independently controlled, and that conjugate and vergence movements represent learned patterns of volitional coordination. We will characterize the physiological responses and determine the inputs to two populations of neurons: perioculomotor vergence cells believed to lie in the supraoculomotor area (SOA) and a newly discovered set of premotor neurons located in the central mesencephalic reticular formation (cMRF). These two populations contact the preganglionic motoneurons in the Edinger-Westphal nucleus (EWpg) that control the lens and pupil, and medial rectus motoneurons active in vergence, indicating a function in near triad control. The study will determine whether the perioculomotor vergence cells and/or premotor cMRF neurons are targeted by the caudal, saccade-related component of the colliculus, the rostral colliculus, which contains cells active during fixation and vergence, or the frontal eye fields (FEF) vergence zone. The 5 inter-related aims carried out in macaque monkeys utilize physiological recording in awake behaving animals, conventional neuronal tracers and transneuronal transport of conventional and recombinant viruses. Aim 1 will compare the precise anatomical location of perioculomotor vergence cells and premotor cMRF neurons. Aim 2 will test the Hering and Helmhotz models by using transneuronal tracing to determine whether these two populations or premotor neurons in the pons are anatomically eye- specific. Aim 3 recordings will test the hypothesis that only the premotor cMRF neurons control the near triad during disjunctive saccades. Aim 4 will examine whether the pattern of tectal projections to these two populations supports such a functional division. Aim 5 will combine physiological and anatomical approaches to ask the same question about FEF inputs. The dramatically augmented understanding of eye movement control circuits and cell function afforded by this project will provide a critical basis for improved concepts of eye movement control and coordination in health and disease.

DESCRIPTION (provided by applicant): The oculomotor system is arguably the best understood motor control system due to the combined efforts of scientists in numerous subspecialties who have studied its complex mechanisms. Traditionally, oculomotor researchers have investigated each oculomotor subsystems in isolation, and from a specific technical view point (e.g. neurophysiology), but recently has there been a push to pursue an integrated approach to the system, and to explore how the oculomotor system integrates with systems controlling the head, body and even arms. Moreover, the field has begun to utilize approaches developed to study eye movements as a tool to understand CNS decision making processes. In 2005, we held the first oculomotor Gordon Research Conference (GRC) ever, entitled Oculomotor System Biology. The success of the first meeting resulted in another sponsorship by the GRC in 2007. The emphasis of the 2007 meeting was on the extraocular periphery, integration of oculomotor and vestibular subsystems, cognitive processes, and neuroethology. This conference was extremely productive, providing a forum for dealing with controversial issues in the field, and engendering new collaborations amongst the participants. We hope to capture this same spirit with a third oculomotor Gordon Conference: Eye Movements: The Motor System that Sees the World in 2011. This meeting's themes will include: 1. Eye Movements as a Probe for Attention, Perception, and Decision Making Mechanisms, in which the speaker's will explore how the oculomotor system is now used as a tool to explore the mechanism by which visual sensory information is utilized in the decision making process;2. The Action between Eye Movements, which will explore the characteristics and control mechanisms for the little studied field of microsaccades;3. Central and Peripheral Oculomotor Subsystems in Health and Disease, which will evaluate new findings about the role of peripheral sensory and motor processes in controlling eye orientation, as well as the actions of lower and upper motoneurons within the context of diseases like strabismus;4. Motor Learning, Calibration, Plasticity, and Reward in the Oculomotor System, in which the roles of the cerebellum and basal ganglia in adjusting the performance of, and reinforcing oculomotor behaviors will be explored;and 5. Novel Approaches for Understanding Oculomotor Circuits, which will range from studies using slice preparations and genetic modifications, to studies utilizing non-traditional animal models. Thus, this proposal requests support for a conference, whose objective is to bring together scientists and physicians to take a fresh look at how the diverse components of the oculomotor system interact, and to stimulate increased interdisciplinary research. With the support of NIH we will bring together ideas and investigators that rarely inhabit the same venue in an effort to advance the field in new directions. PUBLIC HEALTH RELEVANCE: Disorders of eye movement systems include strabismus, nystagmus and internuclear ophthalmoplegia. Moreover, oculomotor responses are disturbed in many motor control diseases (Parkinson's, torticollis), sensory syndromes (vertigo), and as a consequence of cognitive deficits (spatial neglect). Other disorders, such as congenital fibrosis, can alter the mechanical properties of the extraocular muscle itself. Consequently, energizing and directing integrated, cutting edge research on how the oculomotor system functions in health and disease, which is the primary goal of this meeting, Eye Movements: The Motor System that Sees the World, is of immense relevance to public health.

? DESCRIPTION (provided by applicant): In humans and other animals with foveate visual systems, eye movement is essential for clear vision, visual information processing, and cognition. The overarching goal of our work is to elucidate the neural mechanisms of eye movement control in order to understand the etiology of oculomotor disorders (e.g., nystagmus, strabismus, etc.) in neurological diseases, and to develop differential diagnoses and effective treatments. The oculomotor system has multiple subsystems performing two basic functions: shifting gaze to acquire a new target of interest and stabilizing gaze on the target against head or target motion. We here propose to study the neural mechanisms of gaze stabilization against self-generated, or active, head movement. The Aims of the proposal are motivated by three recent findings of ours that challenge current models of gaze control. First, we trained monkeys to make active head movements while maintaining stable gaze and found that compensatory eye movement against active head movement is not mediated by the vestibulo-ocular reflex (VOR), which is driven by vestibular sensory signals with a latency of ~7ms. Instead, it is mediated by a previously unrecognized active gaze stabilization (AGS) response, which is driven by corollary discharge of active head motor commands with zero latency with respect to active head rotation. We further showed that adaptive changes in VOR do not transfer to AGS, indicating that AGS is not only independent of the VOR, but also supersedes it during active head rotation. As a novel gaze stabilization mechanism, AGS challenges current models of combined eye-head gaze shifts that treat VOR as the sole gaze stabilizing mechanism interacting with saccades. Second, against the current assumption that active head movement is not explicitly encoded by brainstem neurons, we identified a group of brainstem vestibular-head (VH) neurons that respond to both active and passive head movements. These neurons encode active head velocity commands that supersede vestibular sensory input during active head movement. Third, contrary to the Ocular Plant Hypothesis proposed by Robinson, which assumes a fixed relationship between a motoneuron firing rate and eye movement, we found that following combined eye-head gaze shifts, the abducens neurons firing rate during AGS were much lower than that predicted by their responses during VOR. Taken together, these three results imply that current models of gaze control, developed in head-fixed models using an individual oculomotor subsystem, are insufficient to understand gaze control in natural conditions involving active head movement and multiple oculomotor subsystems. The Aims of the proposal are to elucidate the neural basis of AGS by characterizing the role and connections of VH neurons and the activity of motoneurons of the agonist/antagonist extraocular muscles (EOM) during combined eye-head movements.