The proposed research has the long-term objective of understanding the functional role of transmitter-specific visual and vestibular olivo-cerebellar pathways. These pathways provide a spatial reference for the control of posture and eye movement and have been implicated in adaptation to unusual motion environments. The proposal has three broad aims: 1) Characterize the afferent pathways to the uvula-nodulus in terms of their encoding properties. Natural visual and vestibular stimulation will be used to evoke activity in single inferior olivary neurons (dorsal cap, beta-nucleus and dorsal medial cell column) in anesthetized rabbits. In addition, microstimulation of the nodulus in the unanesthetized rabbit will be used to. characterize the postural consequences of activating particular regions of this structure whose sensory inputs have already been characterized. The vertical semicircular canals and horizontal optokinetic inputs project topographically onto separate medial-lateral regions of the uvula-nodulus. Both postural and eye movement responses will be recorded during microstimulation of different medial-lateral regions of the uvula-nodulus. The efferent projections of these regions with brainstem regions involved in the control of movement will be studied with orthograde tracer techniques. 2) Examine the Influence of certain transmitters (acetylcholine and GABA) on their target neurons and define receptor subtypes. In the anesthetized rabbit the influence of iontophoretically applied cholinergic and GABAergic antagonists on the discharge of olivary neurons during microstimulation of known nuclear origins of GABAergic and cholinergic pathways will be studied. These experiments will provide a functional description of the specificity of receptor actions on olivary neurons. Immunocytochemical and hybridization histochemical techniques will be used to further characterize the histological and regional distribution of muscarinic receptor subtypes in the cerebellum. 3) Investigate changes in cellular ultrastructure and subcellular proteins caused by long-term (tens of hours) optokinetic stimulation in the unanesthetized rabbit and by shorter-term (tens of minutes) excitatory amino acid-induced depolarization rat cerebellar slices. In rabbits, long-term optokinetic stimulation selectively activates visual olivo-cerebellar pathways. Ultrastructural changes in dorsal cap neurons and their climbing fiber terminals induced by long-term optokinetic stimulation will be characterized. In the rat cerebellar slice, the influence of localized pressure ejections of CRF during depolarization induced by perfusion with excitatory amino acids will be studied immunohistochemically. Stains for different isoforms of protein kinase C and other calcium binding proteins will be examined. These slice experiments are based on a presumed role for CRF in the regulation of Purkinje cell responses to excitatory amino acids. The long-term goal of this proposal is to take advantage of the knowledge concerning the functional specificity of transmitter-specific pathways to formulate pharmacological interventions that can be investigated in intact animals; providing a more rational basis for the treatment of balance disorders, including motion sickness.
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