Thalamic projections to the subthalamic nucleus contribute to movement initiation and rescue of parkinsonian symptoms

Abstract

The parafascicular nucleus (Pf) of the thalamus provides major projections to the basal ganglia, a set of subcortical nuclei involved in action initiation. Here, we show that Pf projections to the subthalamic nucleus (STN), but not to the striatum, are responsible for movement initiation. Because the STN is a major target of deep brain stimulation treatments for Parkinson’s disease, we tested the effect of selective stimulation of Pf-STN projections in a mouse model of PD. Bilateral dopamine depletion with 6-OHDA created complete akinesia in mice, but Pf-STN stimulation immediately and markedly restored a variety of natural behaviors. Our results therefore revealed a functionally novel neural pathway for the initiation of movements that can be recruited to rescue movement deficits after dopamine depletion. They not only shed light on the clinical efficacy of conventional STN DBS but also suggest more selective and improved stimulation strategies for the treatment of parkinsonian symptoms.

Optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus controls locomotor movements in a mouse model of Parkinson’s disease

“…PD model. The neurotoxin 6-OHDA was successfully used in mice to ablate DA neurons and evoke locomotor deficits resembling those reported in PD, including decreased number of locomotor initiations (Kravitz et al 2010), increased freezing frequency (Kravitz et al 2010) or akinesia (Watson et al 2021). The mice received 30 min prior to 6-OHDA (or vehicle) injection, a systemic injection of desipramine to protect the noradrenergic and serotoninergic systems (25 mg/kg, 300 µL i.p.)…”

“…The scalp incision was sutured, and antibiotics were applied locally. The animals were tested 3 days after 6-OHDA injection, when the DA cells have degenerated, and locomotor deficits are observed (Kravitz et al 2010, Watson et al 2021 The positions of the joints and toe tip were detected using DeepLabCut. A moving average of the MTP speed was used to determine the stance and swing Sections were then treated during 2 h at 40°C in the oven with an RNA hybridization antisense probe against ZsGreen-C1 (ACD, 461251, lot 20296A) and another against mouse Slc17a6-C4 (i.e.…”

“…We induced parkinsonian conditions in mice by bilaterally injecting in the striatum the neurotoxin 6-hydroxydopamine (6-OHDA), which is well known to damage the nigrostriatal DA pathway and to induce a dramatic decrease in locomotor activity (e.g. Kravitz et al 2010, Watson et al 2021. Using in vivo optogenetics in mice expressing channelrhodopsin in a Cre-dependent 8/51 manner in Vglut2-positive neurons (Vglut2-ChR2-EYFP mice), we show that photostimulation of glutamatergic neurons in the CnF robustly initiated locomotion, reduced immobility, increased the time spent in locomotion, and precisely controlled locomotor speed.…”

“…We induced parkinsonian conditions in mice by bilaterally injecting in the striatum the neurotoxin 6-hydroxydopamine (6-OHDA), which is well known to damage the nigrostriatal DA pathway and to induce a dramatic decrease in locomotor activity (e.g. Kravitz et al 2010, Watson et al 2021. Using in vivo optogenetics in mice expressing channelrhodopsin in a Cre-dependent .…”

“…The scalp incision was sutured, and antibiotics were applied locally. The animals were tested 3 days after 6-OHDA injection, when the DA cells have degenerated, and locomotor deficits are observed (Kravitz et al 2010, Watson et al 2021).…”