Dysregulation of External Globus Pallidus-Subthalamic Nucleus Network Dynamics in Parkinsonian Mice During Cortical Slow-Wave Activity and ActivationPublic
The basal ganglia are a remarkably complicated and interconnected tangle of subcortical nuclei whose exact function and composition are hotly debated to this day. What is plainly obvious, however, is that loss of dopaminergic modulation in the basal ganglia, as is the case in Parkinson’s disease (PD) following the progressive degeneration of dopaminergic substantia nigra neurons, leads to catastrophic movement deficits. Further, excessively irregular, temporally offset, and possibly oscillatory activity in the reciprocally connected external globus pallidus (GPe) and subthalamic nucleus (STN) of the indirect pathway of the basal ganglia are tightly linked with motor dysfunction. Precisely which network interactions underlie the emergence, persistence, or amplification of pathologically associated basal ganglia activity following dopamine depletion remain contested. In efforts to address these questions, many formative studies of dopamine depletion leveraged anesthetized preparations to interrogate the transmission of cortically generated activity patterns throughout the basal ganglia but did so without access to cell-class specific manipulations or recording techniques. This dissertation is aimed at extending prior findings in urethane anesthetized rats acquired during slow wave activity (SWA) and activation (ACT) to mice and more rigorously testing several hypotheses regarding the origin or propagation of abnormal basal ganglia activity following dopamine depletion. Here we applied multi-structure extracellular recordings in the unilateral 6-hydroxydopamine mouse model of PD to study network dynamics in the indirect pathway following dopamine depletion. Cell class-specific in vivo optogenetic inhibition was used to both identify neurons and determine their contribution to activity in connected nuclei. We found that following dopamine depletion: D2 dopamine receptor-expressing striatal projection neurons (D2-SPNs), upstream of GPe, were hyperactive during cortical SWA and ACT; prototypic parvalbumin-expressing GPe (PV GPe) neuron activity was excessively suppressed when D2-SPNs were active during cortical SWA and ACT despite elevated autonomous activity; optogenetic suppression of D2-SPN activity largely alleviated abnormal patterning of GPe neurons during SWA; STN firing rates were unaltered during SWA or ACT, but were less entrained to cortical SWA; optogenetic inhibition of PV GPe neuron activity almost entirely eliminated vestigial STN responsiveness to cortical SWA; optogenetic inhibition of STN neurons exacerbated abnormal entrainment of GPe neurons to cortical SWA; excessive oscillatory activity in broad neuronal populations was not detected using traditional methods. Together these findings challenge several theories of basal ganglia dysfunction following dopamine depletion and provide both a framework to test similar hypotheses under awake conditions and a valuable link between the rat and mouse literature with some potentially crucial differences.
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