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Dendritic amplification mechanisms for action initiation in the normal and Parkinsonian primary motor cortex

Our goal is providing a novel cellular mechanism for a long-standing system’s level question of basal ganglia-mediated action initiation, and defining its role in the pathogenesis of Parkinson's disease (PD). Timely initiation of movements is a key process required for executing smooth efficient movements, and is severely disrupted in PD. We will focus on Basal ganglia-cortical loops, which play a pivotal role in action initiation in normal brains and pathogenesis of PD. The motor cortex (M1) is the heart of this complex system, conveying output motor commands via the pyramidal tract (PT) neurons. Basal ganglia-cortical loops carried by thalamo-cortical afferents are one of the main input sources to M1, showing exquisite localization to distal tuft dendrites of PT neurons. Because of their distal dendritic termination, they are expected to contribute negligibly to the output of PT neurons, posing a major problem in our understanding of the strong effect of basalganglia

on action initiation via M1. We propose dendritic amplification mechanisms and local

dendritic spikes play a pivotal role in increasing the gain of basal ganglia-loop inputs in tuft dendrites, and disruption of these mechanisms fundamentally contributes to motor disability of PD. Toward this end, we will use behavioral motor paradigms in mice, combined with two-photon imaging of network and dendritic activity in-vivo as well as opto- and chemo-genetic manipulations of neuronal activity.

Ultimately, understanding what mechanisms drive activity in normal and Parkinsonian PT neurons will serve as a foundation for developing novel neuro-stimulation paradigms to treat PD in the future.

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