Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia

NEUROBIOLOGY OF DISEASE

卷:106

Article

DeSimone, Jesse C.¹  Pappas, Samuel S.²  Febo, Marcelo³  Burciu, Roxana G.¹  Shukla, Priyank¹  Colon-Perez, Luis M.³  Dauer, William T.^2,4,5  Vaillancourt, David E.^1,6,7 

[1] Univ Florida, Dept Appl Physiol & Kinesiol, 1864 Stadium Rd,100 FL Gym, Gainesville, FL 32611 USA

[2] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA

[3] Univ Florida, Coll Med, Dept Psychiat, Gainesville, FL 32611 USA

[4] Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Vet Affairs Ann Arbor Healthcare Syst, Ann Arbor, MI 48105 USA

[6] Univ Florida, Coll Med, Dept Neurol, Gainesville, FL 32610 USA

[7] Univ Florida, Dept Biomed Engn, Gainesville, FL 32611 USA

关键词: Diffusion MRI;    DYT1 dystonia;    Free-water;    Functional connectivity;    Functional MRI;    Mouse model;   

DOI  :  10.1016/j.nbd.2017.06.015

来源: Elsevier

【 摘 要 】

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. (C) 2017 Elsevier Inc. All rights reserved.

【 授权许可】

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