Subthalamic neurons interact with nigral dopaminergic neurons to regulate movement in mice

Abstract

Aim: This study aims to address the role of the interaction between subthalamic (STN) neurons and substantia nigra pars compacta (SNc) dopaminergic (DA) neurons in movement control.

Methods: Fiber photometry and optogenetic/chemogenetic techniques were utilized to monitor and manipulate neuronal activity, respectively. Locomotion in mice was recorded in an open field arena and on a head-fixed apparatus. A hemiparkinsonian mouse model was established by unilateral injection of 6-OHDA in the medial forebrain bundle. Whole-cell patch-clamp techniques were applied to record electrophysiological signals in STN neurons and SNc DA neurons. c-Fos-immunostaining was used to label activated neurons. A rabies virus-based retrograde tracing system was used to visualize STN neurons projecting to SNc DA neurons.

Results: The activity of STN neurons was enhanced upon locomotion in an open field arena and on a head-fixed apparatus, and the enhancement was significantly attenuated in parkinsonian mice. Optogenetic stimulation of STN neurons enhanced locomotion, increased activity of SNc DA neurons, meanwhile, reduced latency to movement initiation. Combining optogenetics with patch-clamp recordings, we confirmed that STN neurons innervated SNc DA neurons through glutamatergic monosynaptic connections. Moreover, STN neurons projecting to SNc DA neurons were evenly distributed in the STN. Either 6-OHDA-lesion or chemogenetic inhibition of SNc DA neurons attenuated the enhancement of locomotion by STN stimulation.

Conclusion: SNc DA neurons not only affect the response of STN neurons to movement, but also contribute to the enhancement of movement by STN stimulation. This study demonstrates the role of STN-SNc interaction in movement control.

Keywords: Parkinson's disease; dopaminergic neurons; movement; substantia nigra pars compacta; subthalamic nucleus.