The role of unipolar brush cells in vestibular circuit processing and in balance

The role of unipolar brush cells in vestibular circuit processing and in balance The role of unipolar brush cells in vestibular circuit processing and in balance The vestibular cerebellum integrates signals that convey head, body and eye movements to coordinate balance. When this neural processing is disrupted by central or peripheral vestibular disorders, profound instability, vertigo, and balance errors result. We lack a basic understanding of the circuitry and physiology of the first vestibular processing region in the cerebellum, the granule cell layer. This lack of knowledge is a major roadblock to the development of therapies that could ameliorate peripheral disorders such as Menieres disease. Vestibular sensory signals are conveyed directly from the inner ear to the cerebellum, where they are processed by unipolar brush cells (UBCs), an understudied cell-type that is numerous in vestibular cerebellar lobes. UBCs transform signals in remarkable ways. The UBCs elaborate dendritic brush slows the diffusion of glutamate and amplifies synaptic input by extending its duration profoundly. There are two subtypes of UBC, ON UBCs that respond to an increase in presynaptic input with a prolonged increase in firing, and OFF UBCs that invert the presynaptic input to a prolonged pause in firing. UBCs have branching axons that diverge to numerous postsynaptic granule cells and other UBCs. Because UBCs extend and amplify the signals they recieve, their activity will dramatically affect downstream neurons in the circuit. However, a major roadblock to understanding how vestibular signals are processed is our lack of knowledge regarding the postsynaptic effects of UBC activity. This proposal aims to (1) determine the projection patterns of ON and OFF UBCs, (2) test synaptic transmission between UBCs and their targets, and (3) identify contribution of UBCs to balance in vivo. Pathological changes in vestibular sensory input, such as occurs in Menieres disease, will impact the signals that UBCs receive and disrupt processing that is essential for balance. By exploring how UBCs contribute to sensory processing we will identify central causes of vestibular dysfunction. Additionally, with a more complete understanding of the circuitry and physiology of the vestibular cerebellum it may be possible to develop therapies for vestibular dysfunction caused by peripheral disorders such as Menieres disease. Keywords: unipolar brush cell, vestibular cerebellum, balance Methodology keywords: Electrophysiology, acute brain slice physiology, immunohistochemistry, chemogenetics, rotarod, transgenic mice, super-resolution imaging Research topic area: Menieres disease The role of unipolar brush cells in vestibular circuit processing and in balance