This research program is motivated by two interrelated goals. First, we seek to understand the neural mechanisms by which the brain recovers after loss of vestibular (inner ear balance) sensation on one or both sides. Second, we seek to advance development new treatment approaches to maximize quality of life for individuals disabled by disequilibrium and unsteady vision after loss of vestibular sensation. In the United States alone, about 150,000 people suffer disabling vertigo and unsteadiness each year due to acute unilateral loss of vestibular function, while about 250,000 suffer chronic imbalance and unsteady vision typical of severe bilateral loss that fails to resolve despite existing treatments. Sudden, permanent loss of vestibular nerve input from one labyrinth causes disequilibrium and visual blurring due to disruption of the vestibulo-ocular reflex (VOR), which normally maintains stable vision during head movements. This disruption is usually followed by impressive but incomplete recovery. During the previous funding period, we made excellent progress toward defining the dynamics of VOR compensation and the neural mechanisms upon which it depends. In the proposed research program, we will build upon this solid foundation of progress through three interrelated and synergistic aims. Experiments addressing Aim 1 will characterize the role of floccular target neurons [FTN] during VOR compensation after acute unilateral injury, examining dynamic changes in their sensitivity to vestibular, proprioceptive and efference copy signals. We predict that compensation involves a coordinated sequence of adaptive changes in two largely parallel paths (i.e., FTN and position-vestibular-pause [PVP] neurons), because our recent results show that changes in PVP neurons alone are insufficient to explain VOR recovery.
Aim 2 is to characterize and optimize the pattern of vestibular nerve activity engendered by a multichannel vestibular prosthesis (MVP) we recently created to restore balance sensation to individuals disabled by loss of inner ear function. These experiments are essential for optimizing MVP performance prior to the start of a clinical trial. Finally, studies in Aim 3 will merge the approaches used in Aims 1 &2, using the MVP to realize a previously impossible experimental paradigm that will characterize and correlate central vestibular neuron responses and VOR responses during both loss and restoration of sensory input from the vestibular labyrinth. Combined, these studies will (1) enhance our understanding of how the central nervous system adapts after initially disabling injuries;(2) advance development of a potentially revolutionary tool for replacement of labyrinthine sensation;and (3) clarify how neuronal mechanisms thought to underlie learning at a cellular level can be leveraged to optimize recovery of complex behaviors like the VOR in alert animals and, ultimately, in individuals disabled by loss of vestibular sensation.
After complete loss of vestibular (inner ear balance) sensation on one or both sides, most patients ultimately recover enough to do well, but some fail to compensate and remain disabled by chronic imbalance and inability to see clearly while moving. This research project will define neural mechanisms that underlie how the brain compensates after vestibular injury and advance development of an implantable bionic inner ear device that can replace lost vestibular sensation.
|Straka, Hans; Zwergal, Andreas; Cullen, Kathleen E (2016) Vestibular animal models: contributions to understanding physiology and disease. J Neurol 263 Suppl 1:S10-23|
|Mitchell, Diana E; Della Santina, Charles C; Cullen, Kathleen E (2016) Plasticity within non-cerebellar pathways rapidly shapes motor performance in vivo. Nat Commun 7:11238|
|Jayabal, Sriram; Chang, Hui Ho Vanessa; Cullen, Kathleen E et al. (2016) 4-aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6. Sci Rep 6:29489|
|Eron, Julia N; Davidovics, Natan; Della Santina, Charles C (2015) Contribution of vestibular efferent system alpha-9 nicotinic receptors to vestibulo-oculomotor interaction and short-term vestibular compensation after unilateral labyrinthectomy in mice. Neurosci Lett 602:156-61|
|Sun, Daniel Q; Lehar, Mohamed; Dai, Chenkai et al. (2015) Histopathologic Changes of the Inner ear in Rhesus Monkeys After Intratympanic Gentamicin Injection and Vestibular Prosthesis Electrode Array Implantation. J Assoc Res Otolaryngol 16:373-87|
|Carriot, Jerome; Jamali, Mohsen; Brooks, Jessica X et al. (2015) Integration of canal and otolith inputs by central vestibular neurons is subadditive for both active and passive self-motion: implication for perception. J Neurosci 35:3555-65|
|Cullen, Kathleen E; Brooks, Jessica X (2015) Neural correlates of sensory prediction errors in monkeys: evidence for internal models of voluntary self-motion in the cerebellum. Cerebellum 14:31-4|
|Brooks, Jessica X; Carriot, Jerome; Cullen, Kathleen E (2015) Learning to expect the unexpected: rapid updating in primate cerebellum during voluntary self-motion. Nat Neurosci 18:1310-7|
|Brooks, Jessica X; Cullen, Kathleen E (2014) Early vestibular processing does not discriminate active from passive self-motion if there is a discrepancy between predicted and actual proprioceptive feedback. J Neurophysiol 111:2465-78|
|Oman, Charles M; Cullen, Kathleen E (2014) Brainstem processing of vestibular sensory exafference: implications for motion sickness etiology. Exp Brain Res 232:2483-92|
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