Role of basal ganglia and cerebellar inputs to motor thalamus in gait

PROJECT SUMMARY/ABSTRACT
Walking gait is an essential function of the nervous system that depends on the precise coordination of
multiple brain circuits. Gait disturbances are among the most disabling motor symptoms across a range of
disorders typically affecting the basal ganglia, such as Parkinson’s disease (PD), or the cerebellum, such as
spinocerebellar ataxia. While much is known about the alterations within the basal ganglia and cerebellum in
these disorders, their effects on downstream gait circuits have not been studied. The motor thalamus is a key
hub that integrates basal ganglia and cerebellar inputs and regulates gait via its projections to the motor cortex.
Altered motor thalamus function has been linked to gait disturbances both in Parkinson’s disease and ataxia.
However, despite its clinical relevance, the functional roles of basal ganglia and cerebellar inputs to motor
thalamus in gait and their role in gait disturbances remain largely unknown.
The goal of this work is to define the function of motor thalamus and its inputs from basal ganglia
and cerebellum in the control of gait and to determine whether alterations in this circuit drive
parkinsonian gait disturbances. These goals will be addressed using a newly-developed gait analysis pipeline
that combines high-speed video recordings and machine learning-assisted mouse tracking, allowing quantitative
measurement of kinematic and coordination aspects of gait in freely walking mice. With recent development of
small high-density probes, optogenetics and chemogenetics, the activity in these circuits can be easily measured
and manipulated during behavior. Thus, I will record thalamic single-unit firing during gait with optogenetic
identification of basal ganglia- and cerebellar-recipient thalamic neurons in order to understand their different
and overlapping gait-tuning properties. Moreover, chemogenetic and optogenetic perturbations will help define
the causal role of each input in shaping gait. Finally, these studies will be complemented by examining the role
of this circuit in the context of a Parkinson’s disease mouse model, to determine how their altered function
contributes to parkinsonian gait, which will be supported by ex vivo electrophysiology studies to determine the
underlying synaptic and cellular mechanisms.
My long-term career goal is to combine cellular and system neuroscience approaches to study the circuits
governing gait, and determine how these circuits are disrupted in diseases with gait disturbances, such as
Parkinson’s disease or spinocerebellar ataxia. The environment at UCSF provides an opportunity to join these
two subfields of neuroscience, and my mentors and advisory committee are well-positioned to train and evaluate
my progress on this project. I plan to take advantage of the full range of career development opportunities
available to young investigators at UCSF and Gladstone. These include speaking opportunities at internal
retreats, scientific leadership and management courses, and seminars related to grant writing and mentoring
that are specifically tailored for postdoctoral scholars seeking research independence.