In vivo imaging reveals impaired connectivity across cortical and subcortical networks in a mouse model of DYT1 dystonia

DeSimone, Jesse C.; Febo, Marcelo; Shukla, Priyank; Ofori, Edward; Colon-Perez, Luis M.; Li, Yuqing; Vaillancourt, David E.

doi:10.1016/j.nbd.2016.07.005

Cited by 29 publications

(22 citation statements)

References 79 publications

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“…In cKO mice studied here, forebrain eradication of torsinA from cholinergic and GABAergic neurons resulted in significantly increased striatal FC with the primary somatosensory cortex and thalamus. This is compatible with previous work using an exploratory-based independent component analysis (ICA) (DeSimone et al, 2016) showing increased FC in the striatum, thalamus, and somatosensory cortex in overtly asymptomatic DYT1 KI mice, which emulate the human DYT1 genotype (Dang et al, 2005). Additionally, this finding is consistent with positron emission tomography (PET) studies reporting sensorimotor hyperexcitability in symptomatically penetrant DYT1 patients compared to non-manifesting DYT1 carriers (Carbon et al, 2010).…”

Section: Discussionsupporting

confidence: 92%

“…Increased FC across multiple cerebellar and brainstem regions in cKO mice in the absence of a cerebellar molecular lesion indicates the ability of forebrain-specific torsinA suppression to cause a whole-brain network-level FC impairment. Consistent with our previous work (DeSimone et al, 2016), we again find FW to be a sensitive measure of microstructural integrity in mouse models of DYT1 dystonia.…”

Section: Discussionsupporting

confidence: 92%

“…Studies in models of other forms of dystonia have also emphasized dysfunction of the cerebellar nuclei and Purkinje cells to be involved in generalized dystonia (Fremont et al, 2017; LeDoux et al, 1993; 1995; 1998; LeDoux and Lorden, 1998; Neychev et al, 2008). Moreover, altered FC was previously demonstrated in the anisiform and paramedian lobules of DYT1 KI mice using exploratory ICA in vivo (DeSimone et al, 2016). …”

Section: Discussionmentioning

confidence: 83%

“…Diffusion MRI pre-processing and analysis was performed using previously described methods and a rodent-modified bi-tensor diffusion analysis pipeline (DeSimone et al, 2016; Pasternak et al, 2009). We used the FMRIB Software Library (FSL: Oxford, UK) and custom designed UNIX shell scripts in Analysis of Functional NeuroImages software (AFNI: Cox, 1996; Version 16.0.19, https://afni.nimh.nih.gov/afni/download/afni/psc_project_view) to correct for eddy current and head motion artifacts, compensation of diffusion gradient rotations in response to these corrections, and manual skull stripping for the removal of non-brain tissue.…”

Section: Methodsmentioning

confidence: 99%

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

DeSimone

Pappas

Febo

et al. 2017

Neurobiology of Disease

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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 GABA-ergic neurons creates a symptomatic model that recapitulates many characteristics of DYT1 dystonia, including the developmental onset of overt twisting movements that are responsive to anti-muscarinic 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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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 83%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

DeSimone

Pappas

Febo

et al. 2017

Neurobiology of Disease

Self Cite

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“…In addition, Dyt1 KI mice, like wild‐type mice, showed increased free‐water in the striatum and cerebellum, while an increase in this index correlated with impaired functional connectivity between the basal ganglia, the cerebellum and the sensorimotor cortex. The in vivo MRI data confirmed the hypothesis that the deletion of the 3‐base (ΔGAG) pair in the Dyt1 gene encoding torsinA affects the level of functional connectivity and the microstructural integrity of the sensorimotor cortex, basal ganglia and cerebellum …”

Section: Dystoniasupporting

confidence: 67%

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

Жунина

Yabbarov

Orekhov

et al. 2019

Int J Experimental Path

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Summary Dystonia associated with Huntington's disease, Parkinson's disease or other neurodegenerative diseases substantially affects patients’ quality of life and is a major health problem worldwide. The above‐mentioned diseases are characterized by neurodegeneration accompanied by motor and cognitive impairment and often have complex aetiology. A frequent feature of these conditions is the abnormal accumulation of protein aggregates within specific neuronal populations in the affected brain regions. Familial neurodegenerative diseases are associated with a number of genetic mutations. Identification of these mutations allowed creation of modern model systems for studying neurodegeneration, either in cultured cells or in model animals. Animal models, especially mouse models, have contributed considerably to improving our understanding of the pathophysiology of neurodegenerative diseases. These models have allowed study of the pathogenic mechanisms and development of new disease‐modifying strategies and therapeutic approaches. However, due to the complex nature of these pathologies and the irreversible damage that they cause to the neural tissue, effective therapies against neurodegeneration remain to be elaborated. In this review, we provide an overview of cellular and animal models developed for studying neurodegenerative diseases, including Huntington's disease and dystonia of different origins.

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In vivo optogenetic inhibition of striatal parvalbumin‐reactive interneurons induced genotype‐specific changes in neuronal activity without dystonic signs in male DYT1 knock‐in mice

Schulz

Richter

2022

J of Neuroscience Research

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The pathophysiology of early‐onset torsion dystonia (TOR1A/DYT1) remains unclear. Like 70% of human mutation carriers, rodent models with ΔGAG mutation such as DYT1 knock‐in (KI) mice do not show overt dystonia but have subtle sensorimotor deficits and pattern of abnormal synaptic plasticity within the striatal microcircuits. There is evidence that dysfunction of striatal parvalbumin‐reactive (Parv+) fast‐spiking interneurons (FSIs) can be involved in dystonic signs. To elucidate the relevance of these GABAergic interneurons in the pathophysiology of DYT1 dystonia, we used in vivo optogenetics to specifically inhibit Parv+ and to detect changes in motor behavior and neuronal activity. Optogenetic fibers were bilaterally implanted into the dorsal striatum of male DYT1 KI mice and wild‐type (WT) littermates expressing halorhodopsin (eNpHR3.0) in Parv+ interneurons. While stimulations with yellow light pulses for up to 60 min at different pulse durations and interval lengths did not induce abnormal movements, such as dystonic signs, immunohistochemical examinations revealed genotype‐dependent differences. In contrast to WT mice, stimulated DYT1 KI showed decreased striatal neuronal activity, that is, less c‐Fos reactive neurons, and increased activation of cholinergic interneurons after optogenetic inhibition of Parv+ interneurons. These findings suggest an involvement of Parv+ interneurons in an impaired striatal network in DYT1 KI mice, but at least short‐term inhibition of these GABAergic interneurons is not sufficient to trigger a dystonic phenotype, similar to previously shown optogenetic activation of cholinergic interneurons.

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In vivo imaging reveals impaired connectivity across cortical and subcortical networks in a mouse model of DYT1 dystonia

Cited by 29 publications

References 79 publications

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

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

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

In vivo optogenetic inhibition of striatal parvalbumin‐reactive interneurons induced genotype‐specific changes in neuronal activity without dystonic signs in male DYT1 knock‐in mice

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