Understanding the Pathophysiology of Congenital Vestibular Disorders: Current Challenges and Future Directions.

In congenital vestibular disorders (CVDs), children develop an abnormal inner ear before birth and face postnatal challenges to maintain posture, balance, walking, eye-hand coordination, eye tracking, or reading. Only limited information on inner ear pathology is acquired from clinical imaging of the temporal bone or studying histological slides of the temporal bone. A more comprehensive and precise assessment and determination of the underlying mechanisms necessitate analyses of the disorders at the level, which can be achieved using animal models.

Implementing the chick embryo model to study vestibular developmental disorders.

Children with congenital vestibular disorders show delayed motor development and challenges in maintaining posture and balance. Computed tomography images reveal that these children have abnormal inner ears in the form of a sac, with the semicircular canals missing or truncated. Little is known about how this inner ear abnormality affects central vestibular development.

A New Model for Congenital Vestibular Disorders.

Many developmental disorders of the inner ear are manifested clinically as delayed motor development and challenges in maintaining posture and balance, indicating involvement of central vestibular circuits. How the vestibular circuitry is rewired in pediatric cases is poorly understood due to lack of a suitable animal model. Based on this, our lab designed and validated a chick embryo model to study vestibular development in congenital vestibular disorders.

Basic Concepts in Understanding Recovery of Function in Vestibular Reflex Networks during Vestibular Compensation.

Unilateral peripheral vestibular lesions produce a syndrome of oculomotor and postural deficits with the symptoms at rest, the static symptoms, partially or completely normalizing shortly after the lesion due to a process known as vestibular compensation. The symptoms are thought to result from changes in the activity of vestibular sensorimotor reflexes. Since the vestibular nuclei must be intact for recovery to occur, many investigations have focused on studying these neurons after lesions.

Plasticity of spontaneous excitatory and inhibitory synaptic activity in morphologically defined vestibular nuclei neurons during early vestibular compensation.

After unilateral peripheral vestibular lesions, the brain plasticity underlying early recovery from the static symptoms is not fully understood. Principal cells of the chick tangential nucleus offer a subset of morphologically defined vestibular nuclei neurons to study functional changes after vestibular lesions. Chickens show posture and balance deficits immediately after unilateral vestibular ganglionectomy (UVG), but by 3 days most subjects begin to recover, although some remain uncompensated.

Expression of glutamate receptors and potassium channels in vestibular nuclei neurons during development of signal processing.

The principal cells of the chick tangential vestibular nucleus offer a simple neuron model to study signal processing in second-order, vestibular reflex projection neurons. The principal cells represent a relatively uniform population of vestibular nuclei neurons which receive a major input from the primary vestibular fibers and send axons to targets mainly involved in the vestibuloocular reflexes. Here, studies performed on ion channels involved in the emergence and establishment of signal processing in this morphologically-identified subset of vestibular nuclei neurons are reviewed, including the AMPA glutamate receptor subunits GluR1, GluR2, GluR3, and GluR4 and the potassium channel subunits Kv1.

Identification of vestibuloocular projection neurons in the developing chicken medial vestibular nucleus.

Biocytin was injected into the oculomotor, trochlear, or abducens nucleus on one side using isolated chicken brainstem preparations or brain slices to identify the medial vestibular nucleus (MVN) neurons projecting to these targets. Oculomotor nucleus injections produced retrogradely labeled neurons in the contralateral ventrolateral MVN (MVN(VL)), with few labeled neurons in the ipsilateral MVN(VL) and rarely in the dorsomedial MVN on either side. Labeled MVN(VL) neurons were identified as stellate (95%) and elongate (5%) cells.

Presynaptic and postsynaptic ion channel expression in vestibular nuclei neurons after unilateral vestibular deafferentation.

Vestibular compensation refers to the recovery of function occurring after unilateral vestibular deafferentation, but some patients remain uncompensated. Similarly, more than half of the operated chickens compensate three days after unilateral vestibular ganglionectomy (UVG), but the rest remain uncompensated. This review focuses on the studies performed on the principal cells of the chick tangential nucleus after UVG.

Otolith fibers and terminals in chick vestibular nuclei.

The distribution of gravity-sensing, otolith afferent fibers and terminals was studied in the vestibular nuclei of 4-5-day hatchling chicks by using single and double labeling of fibers and terminals with biocytin conjugated to Alexa Fluor and confocal imaging. The vestibular nuclei are represented in a series of five transverse sections of the brainstem immunolabeled with MAP2. Saccular fibers entered the medulla posterior to and at the level of the posterior tangential vestibular nucleus and coursed through ventral parts, producing ascending and descending branches.

Emergence of action potential generation and synaptic transmission in vestibular nucleus neurons.

Principal cells of the chick tangential nucleus are vestibular nucleus neurons in the hindbrain. Although detailed information is available on the morphogenesis of principal cells and synaptogenesis of primary vestibular fibers, this is the first study of their early functional development, when vestibular terminals emerge at embryonic days 10 and 13 (E10 and E13). At E10, 60% of principal cells generated spikes on depolarization, whereas 50% exhibited excitatory postsynaptic currents (EPSCs) on vestibular-nerve stimulation.

Vestibular ganglionectomy and otolith nerve identification in the hatchling chicken.

Unilateral peripheral vestibular lesions are characterized by rapid recovery from the static symptoms, called vestibular compensation, a process likely involving brain plasticity. The hatchling chick offers a promising model for studies of this process. Ganglionectomy is performed, since it provides a reproducible lesion.

AMPA receptor subunit expression in chick vestibular nucleus neurons.

The principal cells of the chick tangential nucleus are vestibular nucleus neurons whose responses on vestibular nerve stimulation are abolished by glutamate receptor antagonists. Using confocal microscopy, we quantified immunolabeling for AMPA receptor subunits GluR1, GluR2, GluR2/3, and GluR4 in principal cells that were identified by the neuronal marker, microtubule-associated protein 2 (MAP2). This work was focused primarily on 9 days after hatching (H9) when the principal cells have acquired some important mature electrophysiologic properties.

Spontaneous synaptic activity is primarily GABAergic in vestibular nucleus neurons of the chick embryo.

The principal cells of the chick tangential nucleus are vestibular nucleus neurons participating in the vestibular reflexes. In 16-day embryos, the application of glutamate receptor antagonists abolished the postsynaptic responses generated on vestibular-nerve stimulation, but spontaneous synaptic activity was largely unaffected. Here, spontaneous synaptic activity was characterized in principal cells from brain slices at E16 using whole cell voltage-clamp recordings.

Developmental change in expression and subcellular localization of two shaker-related potassium channel proteins (Kv1.1 and Kv1.2) in the chick tangential vestibular nucleus.

The chick tangential nucleus is a major avian vestibular nucleus whose principal cells participate in two vestibular reflexes. Intracellular recordings have shown that the principal cells acquire their mature firing pattern gradually during development. At embryonic day 16 (E16), most principal cells fire a single spike, whereas shortly after hatching (H) the vast majority fire repetitively on depolarization.

Differential expression of connexin 43 in the chick tangential vestibular nucleus.

The chick tangential nucleus is a major vestibular nucleus whose principal cells receive convergent inputs from primary vestibular and nonvestibular fibers and participate in the vestibular reflexes. During development, the principal cells gradually acquire the mature firing pattern in part by losing a specific potassium current around hatching (H). Here we focus on characterizing the expression of connexin 43 (Cx43), a gap junction protein found mainly between astrocytes in the mature brain.

Vestibular compensation after ganglionectomy: ultrastructural study of the tangential vestibular nucleus and behavioral study of the hatchling chick.

The tangential nucleus is a major part of the avian vestibular nuclear complex, and its principal cells are structurally distinctive neurons participating in the vestibuloocular and vestibulocollic reflexes. After unilateral peripheral vestibular lesion, a behavioral recovery of function defined as vestibular compensation is observed. Because sprouting and hypertrophy of synapses have been reported in other regions of immature animals after central nervous system injury, we investigated whether this also occurs in the vestibular nuclei during compensation.