Spinocerebellar ataxias (SCAs) are progressive, debilitating and fatally inherited neurodegenerative diseases. Most cerebellar ataxias result from the unstable expansions of CAG repeats. Spinocerebellar ataxia type 1 (SCA1) is an inherited neurological disorder (autosomal dominant, repeat expansion) that affects the brainstem, spinocerebellar tracts and particularly the Purkinje cells in the cerebellar cortex. Currently, there are no therapies available to target disease progression. Our goal is to understand the link between brain structure, e.g., the cerebello-thalamo-cortical circuitry (CTC), brain function and gait performance in SCA1. In this proposal, we begin with querying single-unit spiking activity and local field potentials simultaneously from CTC areas and electrically neuromodulate each area in awake behaving mice transgenic models of SCA1. To do so, we will interrogate the CTC circuit in two different mice models of SCA1 in aim 1 and neuromodulate the CTC circuit in these animals to improve or aggravate gait function in aim 2. Altogether, we hypothesize that monitoring single-unit spiking activity and local field potentials simultaneously from cerebello-thalamo-cortical (CTC) areas and electrically neuromodulating each area in SCA1 awake behaving mice will reveal the neurophysiological underpinnings of SCA1 gait ataxia. Ultimately, findings from this innovative and novel study will pave the way for applying neuromodulatory therapies to SCAs.
Debilitating conditions such as cerebellar ataxia currently have no available pharmacological therapies and patients remain highly disabled despite receiving the best medical treatment available. The cerebellum is emerging as an attractive and promising target for neuromodulation in many neurological disorders. Due to the intimate connections between cerebellar areas and several important cortical and thalamic structures, neuromodulation of these different neuronal networks likely would enable the treatment of pathologic neuronal oscillations and subsequently influence motor and sensory integration. This proposal aims to identify the role that the different nodes of the cerebello-thalamo-cortical network play in spinocerebellar ataxia and develop a neuromodulatory approach to drive gait benefit to ultimately translate to a therapy.
