The direct and indirect pathways of the angular vestibulo-ocular reflex (aVOR) constitute principal nervous system mechanisms for the maintenance of gaze, of normal posture, balance, and coordination, and of spatial orientation during angular locomotion. The long-term goal of this research program is to identify anatomical and neurochemical constituents of defined neuronal circuits of the central vestibular system. The objective of this current research proposal is to visualize glycinergic neurons and terminals in the vestibular nuclei, in order to further elucidate the cellular bases for inhibitory control of the velocity storage component of the aVOR. This objective will be accomplished using qualitative and quantitative immunocytochemical approaches to identify the neurotransmitter-defined neurons by light microscopy and to characterize and quantify the synaptic interactions involving these cells at the ultrastructural level. The first specific aim is to characterize the regional distribution, morphology, ultrastructural features and synaptology of glycine- immunoreactive neurons and terminals in the vestibular nuclei of normal animals. Using multiple electron-dense labels, the synaptic interactions between glycinergic and GABAergic neurons, the possible co-existence of the two inhibitory amino acids in individual vestibular cells, and the somatodendritic distribution of glutamatergic synaptic inputs to glycinergic cells will be identified and quantitated. The second specific aim is to visualize and quantify degenerating and non-degenerating glycine- immunoreactive neurons and terminals in the vestibular nuclear complex (VNC) of monkeys after midline medullary section of vestibular commissural fibers. Since the midline medullary lesion interrupts the indirect, but not the direct pathway, the degenerating elements are likely to be the neurons responsible for the production and/or maintenance of velocity storage. The third specific aim is to identify and quantify the ultrastructural features and synaptology of the central terminals of primary vestibular afferent fibers using colloidal gold-tagged lectin transport molecules. Immunocytochemical studies of this tissue will demonstrate the direct or indirect nature of the synaptic input from primary afferents to glycinergic and/or GABAergic cells in the VNC. These studies will help to specify the role of glycinergic inhibition in the aVOR, in the organization of the velocity storage mechanism, in the mediation of vestibular commissural inhibition, and in the modulation of primary vestibular afferent activity. The information generated by this research is necessary for understanding how vestibular compensation is mediated, for clarifying the neuronal substrate(s) for brainstem lesions that lead to balance disorders, and for the rational development of pharmacotherapeutics for central vestibular deficits.
