The Peripheral Vestibular System in Congenital Vestibular Disorders

ABSTRACT In the US, an estimated 3.3 million children experience dizziness and balance problems (19). Children with congenital vestibular disorders (CVDs) show delayed motor development and challenges in maintaining posture and balance, indicating that the vestibular neural circuitry is affected. Computed tomography (CT) shows that children with CVDs most commonly form a sac-like inner ear with the semicircular canals missing or truncated. It is not known how their vestibular connectivity is altered. We hypothesize that formation of a sac-like inner ear during early gestation results in a reduced number of vestibular ganglion cells forming fewer primary vestibular synapses on hair cells peripherally and on vestibular nuclei neurons centrally, leading to underconnectivity in the vestibular system. We further hypothesize that the sac-like inner ear pathology results in abnormal convergence of canal and otolith fibers onto vestibular nuclei neurons, or anomalous connectivity, contributing to abnormal signal processing in these neurons. The proposed work will establish a framework to test the overarching hypothesis that formation of a congenitally-malformed, sac-like inner ear alters the peripheral and central vestibular neural circuitry. To address these questions, our laboratory has implemented and validated a new chick embryo model. We can produce a reproducible animal model in 85% of cases by surgically rotating the developing inner ear or “otocyst” 180° on one side in two-day old chick embryos (E2). Since the procedure involves Anterior-posterior axis Rotation of the Otocyst to produce a Sac-like inner ear, the model is called the ARO/s chick. The sac-like inner ear of ARO/s chicks resembles the sac-like inner ear in children with CVDs. After hatching (H), ARO/s chicks experience challenges in maintaining balance and walking. As a first step in understanding the consequences of the sac-like inner ear on the developing vestibular neural circuitry, in Specific Aim 1 we will further analyze the vestibular epithelium and quantify vestibular ganglion cells to determine to what extent primary vestibular afferent synapses are decreased in ARO/s chicks. In Specific Aim 2, we will combine imaging and electrophysiological approaches to determine whether a structurally-uniform class of vestibular nuclei neurons, the principal cells of the tangential nucleus (TN), acquire the orderly inputs from canal and otolith fibers, passive and active membrane properties, and synaptic transmission found in normal chicks. In Specific Aim 3, we will perform ethological tests to characterize posture and balance in H5 ARO/s chicks, followed by the horizontal vestibuloocular reflex (hVOR) using Earth vertical axis rotation (EVAR) to test canal function and the static tilting platform test to evaluate otolith function. The experimental outcomes will provide a foundation to better understand the pathological changes occurring in the vestibular neural circuitry of CVD patients, and modify our thinking on how to treat these disorders.