Basal ganglia are a highly interconnected group of nuclei involved in motor control. The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. While the prevailing basal ganglia circuit model assumes the GPe as merely a relay, phasic changes in the activity of GPe neurons during movement and their alterations in Parkinson’s disease (PD) argue that the GPe is important in motor control. However, it has been challenging to assign a function to the GPe due to its cellular heterogeneity. Recent studies have shown that PV+ neurons and Npas1+ neurons are the two principal neuron classes in the GPe. The distinct electrophysiological properties and axonal projection patterns argue that these two neuron classes serve different roles in regulating motor output. However, the causal relationship between GPe neuron classes and movement remains to be established. Here, we used in vivo optogenetic approaches and showed that PV+ neurons promoted locomotion and Npas1+ neurons suppressed locomotion in freely moving mice (both males and females). These findings are consistent with their projection patterns, where stimulation of PV+ neuron terminals in the STN and SNr promoted movement and stimulation of Npas1+ neuron terminals in the striatum inhibited movement. The subthalamic nucleus (STN) provides one of the major excitatory inputs to the GPe. This places STN in an important position to regulate GPe activity and its role in movement. Moreover, a hallmark of PD is the emergence of correlated burst spiking in neurons of the GPe and the STN, where eliminating these pathological oscillations within the STN-GPe network can drastically improve motor symptoms in PD patients. Considering the importance of the STN-GPe network in health and disease conditions, there has been a pressing need to redefine the STN-GPe circuit in light of the recent discoveries in the cellular heterogeneity of the GPe in both health and PD. Here, we used ex vivo electrophysiology to show that PV+ neurons and Npas1+ neurons are under different synaptic influences from the STN. Additionally, we found a selective weakening of STN inputs to PV+ neurons in the chronic 6-hydroxydopamine lesion model of PD. This finding reinforces the idea that the reciprocally connected GPe-STN network plays a key role in disease symptomatology and thus provides the basis for future circuit-based therapies.

Creator

• Pamukcu, Arin

DOI

• https://doi.org/10.21985/n2-rchv-ct93

Subject

• Neurosciences

Language

• en

Alternate Identifier

• etdadmin_upload_770344
• http://dissertations.umi.com/northwestern:15325

Date created

• 2020-01-01

Resource type

• Dissertation

Rights statement

• In Copyright