TY - JOUR A1 - Knorr, Susanne A1 - Rauschenberger, Lisa A1 - Ramirez Pasos, Uri Eduardo A1 - Friedrich, Maximilian Uwe A1 - Peach, Robert Lucien A1 - Grundmann-Hauser, Kathrin A1 - Ott, Thomas A1 - O'Leary, Aet A1 - Reif, Andreas A1 - Tovote, Philip A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network T2 - Neurobiology of disease N2 - TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism. KW - DYT1 KW - TOR1A KW - Two-hit hypothesis KW - Dopamine KW - LFP Y1 - 2021 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62819 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-628199 SN - 1095-953X N1 - Movie S1. Movie demonstrates DLM categories “focal DLM” and “beginning generalized DLM” in ∆ETorA rats in addition to non-dystonic hindlimb clasping and normal posture of hindlimbs. N1 - Movie S2. Movie demonstrates markerless pose estimation using DLC in a rat without abnormal movements and a rat with DLM during tail suspension. N1 - This work was funded by the German Federal Ministry of Education and Research (BMBF DysTract to C.W.I.), partially by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project-ID 424778381-TRR 295 (A06 to C.W.I.) and under the frame of EJP RD, the European Joint Programme on Rare Diseases and the European Union’s Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP N° 825575 (EurDyscover), by the Nündel Foundation and by the Interdisciplinary Center for Clinical Research (IZKF) at the University of Würzburg (N-362 to C.W.I and P.T.; Z2-CSP3 to L.R.; Z2-CSP13 to M.U.F.). We thank Keali Röhm, Veronika Senger, Heike Menzel and Louisa Frieß for their technical assistance as well as Helga Brünner for the animal care. VL - 154 IS - art. 105337 SP - 1 EP - 13 PB - Academic Press CY - Orlando, Fla. ER -