CENTRAL AND PERIPHERAL CONTROL OF EYE POSITION

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.