Wu Zhou - US grants

[unreadable] DESCRIPTION (provided by applicant) The vestibulo-ocular reflex (VOR) stabilizes gaze and hence foveal images during head movements. Deficits in the VOR resulting from disease or changes in development can severely impair vision. Neural adaptation in the VOR is essential to overcome these deficits. Over the past several decades, the investigation of the VOR and its adaptation has been focused on the contributions of brainstem and cerebellar pathways. The contributions of cerebral cortex in the VOR, however, remain largely unexplored. Recent studies have demonstrated that the frontal eye field (FEF) has direct projections to brainstem VOR pathways and neurons in the subregion of the FEF linked to smooth eye movements (FEFsem) exhibit activity related to both eye movements and head movements, suggesting an important role for the FEFsem in the VOR. The objective of the proposed research is to employ single unit recording and chemical lesion approaches to study the contributions of the FEFsem in the generation and adaptation of the VOR. The first aim is to use single unit recording techniques to quantitatively analyze how the FEFsem neurons encode head motion in monkeys. Recently, we have developed a paradigm that induces robust short-term and long-term plasticity in the VOR that compensates for translational head movements (TVOR). A novel feature of the paradigm is that these behavioral changes are not guided by visual information but by the spatial context of the task, i.e. whether the target is stationary in space or fixed relative to the head. The second aim is to take advantage of this paradigm to study the role of the FEFsem neurons in the generation of the TVOR. This experiment will provide greater understanding of the FEFsem in the information processing related to the task context and in the voluntary control and adaptation of the TVOR. The third aim is to assess the functional significance of the FEFsem by reversibly inactivating the FEFsem and studying its effect on the generation and adaptation of the TVOR. This research will provide important knowledge for understanding the fundamental vestibular and oculomotor neurophysiology and improving the diagnosis and treatment of vestibular disorders in humans.

[unreadable] DESCRIPTION (provided by applicant): The long-term objective of the application is to understand the neural mechanisms of sensorimotor transformation in the vestibular system. Over the past several decades, the investigation of the VOR has established that the VOR response to a given head movement is not fixed, but is under the modulation of behavioral contexts (i.e., viewing distance). Deficits in the context-dependent VOR gain modulation resulting from disease or environmental changes can severely impair vision. The neural mechanisms underlying this important VOR function, however, remain to be explored. Our recent studies demonstrate that the interaction of vestibular and eye position signals in the direct VOR pathways is multiplicative, rather than additive as presently assumed. Our modeling analysis further suggests a novel neural mechanism that implements the VOR gain modulation by viewing distance. The specific aims of the application are to employ single unit recording and computational modeling approaches to further study the interaction of vestibular and eye position signals in the key components of the direct VOR circuits. A unique strength of the proposal is that we take advantage of the acoustic activation of vestibular system and employ click to evoke impulse responses of the VOR to a unilateral vestibular stimulation. This paradigm permits us examine the neural substrate and signal processing underlying VOR gain modulation. The first aim is to use single unit recording techniques to quantitatively analyze the interaction of vestibular and eye position signals in identified motoneurons that innervate the medial or lateral rectus muscles. These experiments will identify whether the multiplicative computation is performed in the motoneuron pools of the VOR pathway. The second aim is to use single unit recording techniques to quantitatively analyze the interaction of vestibular and eye position signals in three groups of VOR premotor neurons. These experiments will identify whether these VOR interneurons are the sites for multiplicative computation. Computational model simulation will examine the cellular mechanisms underlying the multiplicative interaction in both premotor and motoneurons. This application will provide important knowledge for understanding the fundamental vestibular and oculomotor neurophysiology and improving the diagnosis and treatment of vestibular disorders in humans. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): In humans and other foveate animals eye movement is essential both for clear vision and for visual information processing and cognition. The overarching goal of our research is to elucidate the neural mechanisms of eye movement control for understanding etiology of oculomotor disorders (e.g., nystagmus, strabismus, etc.) in neurological diseases and developing discriminative diagnoses and effective treatments. In this R21 proposal, we are going to simultaneously measure eye position, muscle tension (MT) and motoneuron activity of the medial and lateral recti during combined eye- head gaze shifts. The proposal meets the objectives of the R21 program in two ways: [1] This will be the first time that MT of an agonist/antagonist pair will be measured during combined eye-head gaze shifts and related to eye movement and motoneuron activity; [2] We are going to test the hypothesis that innervation of the medial and lateral recti can become non-reciprocal in the presence of interactions between saccadic gaze shifting response and gaze stabilizing response. If correct, this hypothesis would cause a paradigm shift away from the gaze control models pioneered four decades ago by DA Robinson (1968, 1975, 1978), which are the basis of most current oculomotor basic science and clinical intervention. This application will provide important knowledge not only for understanding the fundamental vestibular and oculomotor neurophysiology, but also for improving the diagnosis and treatment of vestibular and oculomotor disorders in humans.

? 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.

Project Summary The overarching goal of the project is to elucidate the mechanisms underlying the vestibular deficits due to exposure to blast overpressure waves, such as that produced by explosive devices. The project addresses an urgent need of the societies as nearly half of the service members who have experienced blast exposure showed vestibular signs and symptoms, e.g. dizziness, imbalance and vertigo, which increase fall risk and result in impaired performance during deployment and daily living. Lack of an understanding on the underlying mechanisms represents a critical knowledge gap in developing effective prevention, diagnosis and treatment programs of blast overpressure-induced vestibular deficits. The aim of the proposal is to fill the knowledge gap by developing a rodent model of blast- induced vestibular injuries and identifying the biomarkers of the underlying injuries. Different from current blast animal models in which blast overpressure waves are delivered over the whole head or the whole animal, a unique feature of our model is that we deliver precisely controlled blast overpressure waves (0~100psi) primarily into the external ear canal, therefore, avoiding impacting other air-filled organs. The present application will take advantage of the animal model to longitudinally assess acute-through-chronic anatomical, physiological and behavioral biomarkers of the vestibular deficits caused by blast exposure. Aim 1a is to examine the effects of blast exposure on vestibular hair cell morphology and Aim 1b is to study responses of vestibular afferents to head rotation and translation in rats. Aim 1c is to examine the effects of blast exposure on the central vestibular system, including brain stem vestibular nuclei and cerebellum. Expression of biomarkers for inflammation, neuronal/axonal damage, and blood-brain-barrier (BBB) disruptions will be examined. Aim 1d is to examine the effects of blast exposure on the vestibular ocular reflex (VOR) using sinusoidal and transient head rotation/translation. These aims will lay the foundation for understanding blast-induced peripheral and central vestibular injuries and contribute to addressing the clinical vestibular signs and symptoms after blast exposure.

Project Summary Primary blast overpressure, such as that produced by explosive devices, has become an increasing cause of injury in both military and civilian populations. Dizziness and imbalance are frequent complaints of blast victims. However, few studies addressed the impact of blast overpressure on the vestibular system, representing an important knowledge gap in developing effective prevention, diagnosis and treatment programs of vestibular deficits in blast victims. To fill the knowledge gap, the goal of the application is to elucidate the mechanisms of blast-induced vestibular injuryin a rat model. The application is built upon our newly developed blast injury device that delivers blast waves directly into the external ear canal of rats. This model allows us investigate impact of primary blast on the vestibular system while avoiding damage to other air-filled organs. The blast-induced vestibular injury model was validated by our preliminary studies that assess vestibular hair cell histology, single vestibular afferent activity and vestibulo-ocular reflex(VOR). Results fromthe preliminary studies suggested that blast-induced vestibular injury is complex in nature and involves a combination of acute and progressive injury at all levels spanning from the periphery to the central vestibular system. The preliminary results lead to our hypothesis that blast exposure triggers degenerative processes in the Type I hair cell mediated pathways and the vestibular function reflects interactions of injury progression and compensatory processes. Current application will take advantage of the novel blast injury model to identify acute-to-chronic morphological, physiological and behavioral biomarkers of the vestibular deficits caused by exposure to blast overpressure waves with different intensities. Aim 1 is to investigate blast-induced structural damage to the vestibular system. We will investigate whether different end organs, types of vestibular hair cells or types of nerve endings exhibit different levels of susceptibility to blast exposure and different recovery over a period of 6 hours to 12 months. We will also investigate injury progression in the vestibular nuclei by analyzing biomarkers of inflammation, axonal damage and apoptosis. In addition, a 3D biomechanical model will be constructed to simulate blast energy propagation through the inner ear to quantify mechanical effects. Aim 2 is to employ single unit recording to assess injury progression in vestibular afferents following blast exposure. Spontaneous discharge and dynamic responses of different subgroups of afferents from the canals and otoliths will be studied. Aim 3 is to assess blast-induced vestibular injury progression by measuring the rotational and translational VORs. Both steady state and transient VORs will be measured to assess integrative outcomes of vestibularinjury progression and compensatory processes and identify the optimal VOR paradigms for diagnosis of blast-induced vestibular injury. Results from the study will elucidate the mechanisms underlying blast-induced vestibular deficits and provide essential information for early diagnosis and targets for intervention.