Title: “In vivo voltage imaging of striatal neuron activity during movement”
Xue Han, PhD – BME (Advisor, Chair)
John White, PhD – BME
Jerome Mertz, PhD – BME
Michael Hasselmo, PhD – Psychological and Brain Sciences
The basal ganglia circuit has long been recognized as an important regulator for movement in the brain1,2. Dysfunction of this circuit can result in motor disorders such as Parkinson’s and Huntington’s disease. The striatum, the largest nucleus of the basal ganglia, is critical for normal motor control and is implicated in the pathology of various movement disorders. The vast majority (~95%) of striatal neurons are inhibitory medium spiny projection neurons (MSNs), which are often classified into two groups based on their dopamine receptor expression (D1-MSNs and D2-MSNs). The remaining 5% are GABAergic and cholinergic interneurons, thought to modulate striatal function by regulating the output projecting MSNs. Recently, it has been reported that both striatal MSNs and interneurons are modulated during movement and that cholinergic interneurons (ChIs) in particular promote movement termination by synchronizing MSN activities. ChIs are also thought to contribute to oscillatory dynamics in normal and pathological striatal circuits, with ChI stimulation resulting in increased beta frequency (~15-30Hz) oscillations in striatal local field potential (LFP) recordings, as well as decreased locomotion akin to deficits observed in Parkinson’s disease. Current techniques fall short of demonstrating how ChIs can coordinate their activity to influence MSNs and subsequent motor output, due to the inability to record both spiking and subthreshold activity from multiple cells simultaneously during movement. The goal of the proposed research is to develop the use of a novel genetically-encoded voltage sensor to probe the spiking and subthreshold activity of striatal neurons during locomotion. At the conclusion of this study, we hope to better understand how striatal neurons, particularly ChIs, coordinate motor activity. Such an understanding could provide valuable insight into the basis of cholinergic signaling in the brain, as well as strategies for intervention in basal ganglia circuit disorders. Additionally, I expect the novel voltage imaging techniques deployed here to have a broad impact on systems neuroscience, motivating future voltage imaging analysis of a variety of neural circuits involved in behavioral and pathological paradigms.