Movement initiation reveals a hyperactive direct pathway in a mouse model of dystonia

Dystonia is a movement disorder characterized by involuntary muscle contractions that are often worsened by movement initiation. Theoretical models propose that dystonic movements emerge due to an imbalance of the direct (D1-Medium spiny neurons, MSNs) and indirect (D2-MSNs) basal ganglia pathways. However, dystonia’s pathophysiology remains largely unknown. Thus, we explored the activity of genetically identified MSNs during self-paced movement in a mouse model of inherited dystonia.Adult DYT-TOR1AΔGAG knock-in (DYT) mice and wild-type (WT) expressing Cre recombinase under the control of the dopamine D1 or A2A receptors (for D2 populations) were used. Mice underwent a right-side sciatic nerve crush (SNC) – a procedure that induces dystonic-like movements (DLMs). In a sham group, the sciatic nerve was exposed but not crushed. The tail suspension test was used to evoke DLMs that were later quantified using markerless pose estimation.DYT mice, but not WT or sham, showed severe and persistent DLMs on the lesioned hindlimb. Additionally, we used in vivo calcium imaging to monitor D1- and D2-MSNs activity during open field (OF) behavior, before and up to 9 weeks after the SNC (w9). In the OF, the three groups traveled comparable distances and had similar acceleration at movement initiation. Interestingly, upon movement initiation, the activity of D1-MSNs significantly increased in DYT mice when compared to WT and sham. Conversely, the activity of movement-modulated D2-MSNs of DYT and WT mice was comparable at w9.Our results are evidence for a circuit dysfunction in dystonia, revealing a hyperactive direct pathway at movement initiation.