How Peripheral Vestibular Signals Create Vestibular Compound Action Potentials - Project Summary Type I and type II hair cells within sensory epithelia of semi-circular canals and otolith organs transduce head motion into electrical signals used in the coordination of gaze, orientation, and motor movement. These signals are transmitted to the vestibular nuclei, cerebellum, and neural circuits that inform the vestibulo-ocular reflex and the vestibulo-collic reflex. Type I hair cells transmit to chalice like (calyx) terminals of primary afferent neurons through neurotransmitter dependent (quantal) and independent (non-quantal) means. The latter occurs through the modulation of post-synaptic currents via changes in synaptic cleft electrical potential and potassium ion concentration following hair cell stimulation. At present, I study the interaction of quantal and nonquantal transmission in calyx afferents. Next, I aim to connect signal generation in the periphery to in-vivo measures of vestibular activity such as the vestibular compound action potential (VCAP). In-vitro action potential (AP) generation by calyx afferents, in response to hair bundle displacement, is relatively low pass filtered (<100 Hz). However, in-vivo measures indicate that calyx afferents generate AP during high frequency (>100 Hz) air conducted sound (ACS) and bone conducted vibration (BCV) stimulus. The goal of this independent proposal is to reconcile these observations. I will create a representative tile of the vestibular epithelium that contains multiple hair cells and afferents and study how firing of nerve fibers emerging from the tightly packed vestibular epithelium shapes VCAPs in spaces adjacent to the vestibular nerve. This approach will identify the mechanisms underlying the discrepancy between in-vitro, electrophysiological recordings from calyx afferents in semi-intact preparations of vestibular epithelia and in-vivo measurements of VCAPs and scalp recordings during rapid head motion. This research will build fundamental knowledge on how to use the VCAP for diagnosis and treatment of vestibular disorders such as age-related vestibular dysfunction (ARVD) in which a loss of extrastriolar calyceal synapses is reported. The computational, mechanistic, model of how peripheral vestibular signals shape the VCAP will be developed using COMSOL and MATLAB. The proposed model overcomes several challenges involved in simultaneously studying the VCAP and observing peripheral function in-vivo: 1) There is no need to mask for or separate cochlear contributions to the measured electrical signal during ACS or BCV stimulus; 2) The activity and electrical contributions from individual hair cells of differing response polarity and their associated neurons can be tracked; 3) VCAP and vestibular microphonics from regions of the otolith organs or semi-circular canal cristae can be modelled separately without the need to expose vestibular compartments. The outcome will be a model capable of informing vestibular implant stimulation strategies and studying of how vestibular channelopathies and damage may alter VCAPs.
