Impact of electrical stimuli on Medial Vestibular Nucleus neurons, in vitro

Abstract

Vestibular/balance dysfunction increases with age and results in increased risk of falling, with potentially severe consequences. Galvanic Vestibular Stimulation (GVS) has been shown to improve vestibular function via activation of the primary vestibular afferents. For example, in vivo experiments have observed GVS to increase the sensitivity of primary vestibular afferents and receptor hair cells, and therefore enhances the ability of mechanoreceptors to detect and respond to incoming signals. Further, in vitro immunohistochemical experiments have identified the activation of several brainstem nuclei in response to GVS, in particular the Medial Vestibular Nucleus (MVN), which is the major focus of this thesis. The mechanism of action of GVS is thought to involve Stochastic Resonance (SR), which is defined as the improvement of signal detection within a linear system in response to low-level noise. However, despite this, the precise biophysical basis remains unclear. Similarly, it is unclear how GVS impacts the central vestibular nuclei despite evidence of activation of these neuronal pathways in response to GVS. Using in vitro patch clamp electrophysiology, this work sought to characterise the effects of GVS-like stimuli on MVN neurons in mice. This thesis describes how electrical stimuli such as GVS directly impact the discharge of MVN neurons. Chapter 1 introduces the vestibular system as a whole and demonstrates how GVS and other vestibular stimuli impact the vestibular system. Chapter 2 systematically reviews the GVS literature and shows that GVS of all stimulus types (i.e., stochastic, Gaussian white noise, sinusoidal) improves vestibular function in healthy cohorts. However, optimal GVS parameters (frequency range and stimulus type) remain unclear. Chapter 3 describes the general electrophysiological methods used to obtain data from MVN neurons in C57BL/6 mice. Chapter 4 details the impact of sinusoidal and stochastic electrical stimuli on MVN neuronal discharge, where the heterogeneous MVN neuronal population determines the impact of these stimuli on neuronal gain. Chapter 5 is an extension of Chapter 4 and considers the impacts of electrical stimuli on MVN neurons in male and female mice, where type A MVN neurons are most susceptible to gain changes in female mice. Chapter 6 discusses how the experiments and findings outlined in this thesis fit into the current GVS and MVN literature, as well as outline future experiments that would further the findings presented throughout this thesis. Finally, this chapter concludes that GVS is able to consistently improve vestibular function, and electrical stimuli specifically target type A MVN neurons in female mice which may elucidate the increased prevalence of vestibular disorders and reduced vestibular performance observed in females.