The peripheral vestibular system in the inner ear consists of three semicircular canals, utricle and saccule. It plays a key role in transforming head motions into signals to the brain. The vestibular peripheral sensation is modulated by efferent inputs originating in the brain stem. Activation of efferents has been shown to results in altered activity in vestibular afferents. However, the exact nature of the efferent function remain elusive. The vestibular sensation is critical for stabilizing gaze, controlling postural and balane related functions in general. Vestibular disorders, which have high prevalence among adults at age 40 and higher, can severely impact life quality. The bilateral imbalance of afferent activity underlies many vestibular disorders. Interestingly, efferents integrate information from the central nervous system as well as from the vestibular periphery and provide bilateral feedback inputs to the vestibular peripheral organs, hence are ideal for compensating for asymmetry in afferent activity. However, at the cellular level, evidence for such a function is largely missing.A better understanding of efferent inputs to the vestibular periphery at the cellular/synaptic level will not only elucidate important aspects of efferent function, but also help to design better treatments for vestibular disorders. We therefore propose to investigate synaptic mechanisms underlying peripheral efferent modulation. In mammals, the efferents form synapses on calyx-shaped afferent endings that ensheath type I hair cells (HCs), type II HCs, which are by definition contacted by bouton-shaped afferent endings and bouton afferents. We have established methods to perform whole-cell recordings from type II HCs and calyx-afferents in the excised rodent crista, the sensory organ of semicircular canals. We will develop novel methods to investigate properties of different types of efferent inputs and how they are integrated to modify afferent activity.
In Aim 1, for stimulating efferent fibers in excised crist tissue, we propose to develop and refine electrical and optogenetic stimulation methods. Preliminary data show that both methods have advantages and disadvantages.
In Aim 2, we propose to characterize efferent synaptic responses in type II HCs and calyx- afferents. Previous studies and preliminary data suggest that the efferent responses in type II HCs and calyx- afferents are mediated by distinct mechanisms, such as different receptors and transmitter release modes. We will identify the mechanisms underlying differential efferent actions, to provide means to distinguish specific efferent inputs.
In Aim 3, the specific contribution of the efferent to type II HC input on afferent activity is investigated, as type II hir cells feed into afferent activity via glutamatergic signaling. In Summary, the proposed study aims to provide a better understanding of efferent function in the vestibular periphery, at the level of individual synapses as well as the level of peripheral integrating circuitry.
Efferent fibers, originating from the brain stem, project to all of the peripheral vestibular organs, and may play a critical role in modulatin vestibular sensation, both under normal and disease conditions. To understand the mechanisms underlying efferent modulation of peripheral activity, we propose to take a bottom-up approach to investigate synaptic transmission at individual types of efferent peripheral synapses, as well as to explore the integration of those efferent synaptic inputs. We will use electrophysiological approaches and new methodology (optogenetics) to specifically stimulate efferents in excised vestibular peripheral tissue and monitor its effects, to better understand how those synapses work together to adjust the peripheral vestibular signals that enter the brain.
