Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia
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| Title: | Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia |
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| Authors: | Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA ( host institution ), DeSimone, Jesse C. ( UF author ), Pappas, Samuel S. ( author ), Febo, Marcelo ( UF author ), Burciu, Roxana G. ( UF author ), Shukla, Priyank ( UF author ), Colon-Perez, Luis M. ( UF author ), Dauer, William T. ( author ), Vaillancourt, David E. ( UF author ) |
| Source: | Neurobiology of Disease, Vol 106, Iss, Pp 124-132 (2017) |
| Publisher Information: | Elsevier BV, 2017. |
| Publication Year: | 2017 |
| Subject Terms: | Male, 0301 basic medicine, Rest, Dystonia Musculorum Deformans, Neurosciences. Biological psychiatry. Neuropsychiatry, Mice, Transgenic, Multimodal Imaging, Diffusion MRI, Mouse model, Functional connectivity, 03 medical and health sciences, Prosencephalon, 0302 clinical medicine, Body Water, Neural Pathways, Animals, GABAergic Neurons, 10. No inequality, Functional MRI, Brain Mapping, DYT1 dystonia, Free-water, 16. Peace & justice, Magnetic Resonance Imaging, Cholinergic Neurons, Corpus Striatum, Disease Models, Animal, Female, RC321-571, Molecular Chaperones |
| Description: | Multiple lines of evidence implicate striatal dysfunction in the pathogenesis of dystonia, including in DYT1, a common inherited form of the disease. The impact of striatal dysfunction on connected motor circuits and their interaction with other brain regions is poorly understood. Conditional knock-out (cKO) of the DYT1 protein torsinA from forebrain cholinergic and GABAergic neurons creates a symptomatic model that recapitulates many characteristics of DYT1 dystonia, including the developmental onset of overt twisting movements that are responsive to antimuscarinic drugs. We performed diffusion MRI and resting-state functional MRI on cKO mice of either sex to define abnormalities of diffusivity and functional connectivity in cortical, subcortical, and cerebellar networks. The striatum was the only region to exhibit an abnormality of diffusivity, indicating a selective microstructural deficit in cKO mice. The striatum of cKO mice exhibited widespread increases in functional connectivity with somatosensory cortex, thalamus, vermis, cerebellar cortex and nuclei, and brainstem. The current study provides the first in vivo support that direct pathological insult to forebrain torsinA in a symptomatic mouse model of DYT1 dystonia can engage genetically normal hindbrain regions into an aberrant connectivity network. These findings have important implications for the assignment of a causative region in CNS disease. |
| Document Type: | Article |
| Language: | English |
| ISSN: | 0969-9961 |
| DOI: | 10.1016/j.nbd.2017.06.015 |
| Access URL: | https://europepmc.org/articles/pmc5555738?pdf=render https://pubmed.ncbi.nlm.nih.gov/28673740 https://doaj.org/article/5b8a86faa2674516b32288e44eaf54d3 http://www.sciencedirect.com/science/article/pii/S0969996117301420 https://utsouthwestern.pure.elsevier.com/en/publications/forebrain-knock-out-of-torsina-reduces-striatal-free-water-and-im https://www.sciencedirect.com/science/article/pii/S0969996117301420 http://europepmc.org/articles/PMC5555738 https://www.ncbi.nlm.nih.gov/pubmed/28673740 |
| Rights: | Elsevier TDM CC BY NC ND |
| Accession Number: | edsair.doi.dedup.....172c783eadba81d5f34862922e98c5dc |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Multiple lines of evidence implicate striatal dysfunction in the pathogenesis of dystonia, including in DYT1, a common inherited form of the disease. The impact of striatal dysfunction on connected motor circuits and their interaction with other brain regions is poorly understood. Conditional knock-out (cKO) of the DYT1 protein torsinA from forebrain cholinergic and GABAergic neurons creates a symptomatic model that recapitulates many characteristics of DYT1 dystonia, including the developmental onset of overt twisting movements that are responsive to antimuscarinic drugs. We performed diffusion MRI and resting-state functional MRI on cKO mice of either sex to define abnormalities of diffusivity and functional connectivity in cortical, subcortical, and cerebellar networks. The striatum was the only region to exhibit an abnormality of diffusivity, indicating a selective microstructural deficit in cKO mice. The striatum of cKO mice exhibited widespread increases in functional connectivity with somatosensory cortex, thalamus, vermis, cerebellar cortex and nuclei, and brainstem. The current study provides the first in vivo support that direct pathological insult to forebrain torsinA in a symptomatic mouse model of DYT1 dystonia can engage genetically normal hindbrain regions into an aberrant connectivity network. These findings have important implications for the assignment of a causative region in CNS disease. |
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| ISSN: | 09699961 |
| DOI: | 10.1016/j.nbd.2017.06.015 |