The long-range goal of this research is to understand the cellular and molecular mechanisms that mediate the normal performance and adaptive plasticity of the vestibulo-ocular reflex (VOR). The VOR prevents blurred vision during self-motion by producing eye movements that precisely compensate for motion of the head. Neuronal mechanisms of plasticity enable the VOR to perform accurately in the face of development, trauma, and disease. Although the roles of particular classes of neurons to signal transformations and plasticity have been identified, little is understood about how cellular mechanisms contribute to the day-to-day performance and adaptive capabilities of the VOR. The objective of the proposed research is to elucidate how cerebellar activity influences signalling and plasticity in distinct classes of vestibular nucleus neurons. The central hypothesis is that central vestibular and cerebellar synapses onto vestibular nucleus neurons exhibit activity-dependent plasticity. The proposed research will use a brainstem slice preparation to examine the short and long term synaptic dynamics onto cerebellar target neurons, which mediate cerebellar influences on signaling and plasticity in the VOR. Distinct classes of cerebellar target neurons will be identified by their axonal projections and patterns of cerebellar synaptic cell terminals. The influence of vestibular nerve, commissural, and cerebellar synaptic activity will be examined in cerebellar target neurons and in other identified vestibular nucleus neurons. These studies will provide foundations for targeted investigations of the molecular mechanisms that underlie vestibulo-ocular reflex plasticity as well as for pharmacological treatments of cerebellar disorders and of oculomotor disorders that cause nystagmus.

Public Health Relevance

The goal of this project is to identify cellular mechanisms of eye movement performance and plasticity, with a particular focus on cerebellar influence over the vestibulo-ocular reflex, which is critical for stabilizing images on the retina during self-motion. Cellular mechanistic analyses of vestibular and cerebellar control of eye movements are essential for developing therapeutic treatments both for cerebellar disorders including ataxias and neurodegenerative diseases as well as for devastating disorders of eye movements including nystagmus and consequent oscillopsia.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011027-16
Application #
8233300
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Araj, Houmam H
Project Start
1994-09-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
16
Fiscal Year
2012
Total Cost
$428,625
Indirect Cost
$203,625
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kolkman, Kristine E; McElvain, Lauren E; du Lac, Sascha (2011) Diverse precerebellar neurons share similar intrinsic excitability. J Neurosci 31:16665-74
Shin, Minyoung; Moghadam, Setareh H; Sekirnjak, Chris et al. (2011) Multiple types of cerebellar target neurons and their circuitry in the vestibulo-ocular reflex. J Neurosci 31:10776-86
van Welie, Ingrid; du Lac, Sascha (2011) Bidirectional control of BK channel open probability by CAMKII and PKC in medial vestibular nucleus neurons. J Neurophysiol 105:1651-9
Kolkman, Kristine E; Moghadam, Setareh H; du Lac, Sascha (2011) Intrinsic physiology of identified neurons in the prepositus hypoglossi and medial vestibular nuclei. J Vestib Res 21:33-47
Gittis, Aryn H; Moghadam, Setareh H; du Lac, Sascha (2010) Mechanisms of sustained high firing rates in two classes of vestibular nucleus neurons: differential contributions of resurgent Na, Kv3, and BK currents. J Neurophysiol 104:1625-34
McElvain, Lauren E; Bagnall, Martha W; Sakatos, Alexandra et al. (2010) Bidirectional plasticity gated by hyperpolarization controls the gain of postsynaptic firing responses at central vestibular nerve synapses. Neuron 68:763-75
Bagnall, Martha W; Zingg, Brian; Sakatos, Alexandra et al. (2009) Glycinergic projection neurons of the cerebellum. J Neurosci 29:10104-10
Bagnall, Martha W; McElvain, Lauren E; Faulstich, Michael et al. (2008) Frequency-independent synaptic transmission supports a linear vestibular behavior. Neuron 60:343-52
Gittis, Aryn H; du Lac, Sascha (2008) Similar properties of transient, persistent, and resurgent Na currents in GABAergic and non-GABAergic vestibular nucleus neurons. J Neurophysiol 99:2060-5
Bagnall, Martha W; Stevens, Renna J; du Lac, Sascha (2007) Transgenic mouse lines subdivide medial vestibular nucleus neurons into discrete, neurochemically distinct populations. J Neurosci 27:2318-30

Showing the most recent 10 out of 22 publications