Effects of external globus pallidus photostimulation on motor behavior in normal and hemi-parkinsonian mice
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COMMabstract
The basal ganglia (BG) are a set of interconnected subcortical nuclei involved in voluntary motor control. External globus pallidus (GPe) is located centrally in the BG, but its precise contribution to BG function is not fully understood. GPe has long been regarded as a simple relay nucleus within the BG, but recent evidence suggest that it may act as an integrative hub for shaping motor and non-motor aspects of behavior. Here, we used an optogenetic approach to investigate the contribution of GPe neurons to motor behavior in normal and Parkinson's disease (PD) mice. Global GPe photostimulation and selective photostimulation of parvalbumin (PV)-expressing neurons were achieved by expressing channelrhodopsin-2 variants using respectively AAV5-HSyn-ChR2(H134R)-eYFP vector in BL6 mice and AAV2-EF1a-DIO-ChR2(E123T/T159C)-eYFP vector in PV-Cre mice. Optical stimulation of GPe with laser-generated green light pulses produced a contralateral circling in normal BL6 mice. Similar locomotor asymmetry was elicited by selective stimulation of PV-expressing neurons. In both cases, the locomotor asymmetry effects were reversible and dependent on the stimulation parameters (light intensity/frequency). We next studied the effects of GPe photostimulation on motor deficits induced by unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra. As expected, hemi-Parkinson mice displayed a range of motor deficits, spontaneous ipsilateral circling, forelimb akinesia and locomotor hypoactivity. GPe stimulations improved the various motor deficits in lesioned mice. These beneficial effects were reversible and observed with stimulation parameters ineffective in sham mice, thus supporting the view that reduced GPe activity contributes to the development of parkinsonian motor impairments. Together, these findings suggest that GPe stimulation may represent a potential therapeutic target for PD.
