Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1

Golden, Carla E. M.; Yee, Yohan; Wang, Victoria X.; Harony‐Nicolas, Hala; Hof, Patrick R.; Lerch, Jason P.; Buxbaum, Joseph D.

doi:10.1038/s41398-020-00943-x

Cited by 6 publications

(5 citation statements)

References 43 publications

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“…An abnormal increase of WM maturation was observed in an adolescent model of compulsive checking behavior [ 76 ], in selectively bred ASD/ADHD-like behavior rats [ 77 ], and in animals with repetitive traumatic brain injury (TBI) that showed impulsivity [ 78 ]. In line with our result, some studies have shown an increase in CC in an adolescent model of compulsive checking behavior [ 76 ], in selectively bred ASD/ADHD-like behavior rats [ 77 ], and in a female rat model of Fragile X syndrome characterized by autistic behaviors [ 79 ]. Moreover, OCD-like behavior mice exhibited increased c-fos expression in the AC ([ 80 ].…”

Section: Discussionsupporting

confidence: 91%

Mapping the neuroanatomical abnormalities in a phenotype of male compulsive rats

Martín-González,

Prados-Pardo,

Sawiak

et al. 2023

Behav Brain Funct

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Compulsivity is considered a transdiagnostic dimension in obsessive–compulsive and related disorders, characterized by heterogeneous cognitive and behavioral phenotypes associated with abnormalities in cortico-striatal-thalamic-cortical circuitry. The present study investigated the structural morphology of white and gray matter in rats selected for low- (LD) and high- (HD) compulsive drinking behavior on a schedule-induced polydipsia (SIP) task. Regional brain morphology was assessed using ex-vivo high-resolution magnetic resonance imaging (MRI). Voxel-based morphometry of segmented MRI images revealed larger white matter volumes in anterior commissure and corpus callosum of HD rats compared with LD rats. HD rats also showed significantly larger regional volumes of dorsolateral orbitofrontal cortex, striatum, amygdala, hippocampus, midbrain, sub-thalamic nucleus, and cerebellum. By contrast, the medial prefrontal cortex was significantly smaller in HD rats compared with LD rats with no significant group differences in whole brain, ventricular, or cerebrospinal fluid volumes. These findings show that limbic cortico-basal ganglia structures implicated in impulse control disorders are distinct in rats that are vulnerable to develop compulsive behavior. Such abnormalities may be relevant to the etiology of compulsive disorders in humans.

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Section: Discussionsupporting

confidence: 91%

Mapping the neuroanatomical abnormalities in a phenotype of male compulsive rats

Martín-González,

Prados-Pardo,

Sawiak

et al. 2023

Behav Brain Funct

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“…Nevertheless, axons with larger diameter show a detectable contrast according to our simulations, see Supplementary Materials . Despite this limitation, since large axons are found preferentially in specific pathways, their absence in the expected pathways, or abnormal presence in unexpected pathways can disclose the neural basis of specific neurological or psychiatric pathologies (DeLuca et al, 2004 ; Zikopoulos and Barbas, 2013 ; Huang et al, 2016 ; Judson et al, 2017 ; Golden et al, 2020 ) and, possibly, of individual skills (de Manzano and Ullén, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

Bundle-Specific Axon Diameter Index as a New Contrast to Differentiate White Matter Tracts

et al. 2021

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In the central nervous system of primates, several pathways are characterized by different spectra of axon diameters. In vivo methods, based on diffusion-weighted magnetic resonance imaging, can provide axon diameter index estimates non-invasively. However, such methods report voxel-wise estimates, which vary from voxel-to-voxel for the same white matter bundle due to partial volume contributions from other pathways having different microstructure properties. Here, we propose a novel microstructure-informed tractography approach, COMMITAxSize, to resolve axon diameter index estimates at the streamline level, thus making the estimates invariant along trajectories. Compared to previously proposed voxel-wise methods, our formulation allows the estimation of a distinct axon diameter index value for each streamline, directly, furnishing a complementary measure to the existing calculation of the mean value along the bundle. We demonstrate the favourable performance of our approach comparing our estimates with existing histologically-derived measurements performed in the corpus callosum and the posterior limb of the internal capsule. Overall, our method provides a more robust estimation of the axon diameter index of pathways by jointly estimating the microstructure properties of the tissue and the macroscopic organisation of the white matter connectivity.

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“…Three of the regions that were reduced in volume, the superior and inferior colliculi and the thalamus, are involved in sensory processing, suggesting a potential locus for the sensory deficits often documented in PMS and the rat model (De Rubeis et al, 2018 ; Droogmans et al, 2020 ; Engineer et al, 2018 ). Interestingly, we recently reported similar structural alterations in another rat model of a monogenic cause of ASD, Fragile X syndrome, using the same imaging techniques and parameters (Golden et al, 2020 ), establishing the potential for commonality across syndromes. The relationship between the structure of these regions and their functional consequences should be further investigated in rodent models of ASD.…”

Section: Discussionmentioning

confidence: 56%

Reduced brain volume and white matter alterations in Shank3‐deficient rats

et al. 2021

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Mutations and deletions in the SHANK3 gene cause the major neurodevelopmental features of Phelan–McDermid syndrome (PMS), which is characterized by intellectual disability, autism spectrum disorder, and sensory hyporeactivity. SHANK3 encodes a key structural component of excitatory synapses important for synaptogenesis. Clinical assessments and limited brain imaging studies of patients with PMS have uncovered regional volume reductions and white matter thinning. While these impairments have been replicated ex vivo in pups of a rat model, brain structure has not been assessed in rats in vivo or in adults. We assessed the brain structure of heterozygous and homozygous adult Shank3‐deficient male rats in comparison to wild‐type littermates with magnetic resonance imaging using both anatomical assessments and diffusion tensor imaging (DTI). Shank3‐deficient rats showed a reduction in overall brain size and the absolute volume of the neocortex, piriform cortex, thalamus, forebrain, inferior and superior colliculi, internal capsule, and anterior commissure. The superior colliculus was decreased in relative volume. DTI revealed that axial diffusion and fractional anisotropy were reduced in the external capsule and mean diffusion was increased in the fornix, suggesting that restriction of diffusion perpendicular to the axis of the axonal fibers was impaired in these white matter tracts. Therefore, Shank3‐deficient rats replicate the reduced brain volume and altered white matter phenotypes present in PMS. Our results indicate that the loss of a glutamatergic synaptic protein, Shank3, has structural consequences at the level of the whole brain. The brain regions that were altered represent potential cross‐species structural biomarkers that warrant further study.

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Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1

Cited by 6 publications

References 43 publications

Mapping the neuroanatomical abnormalities in a phenotype of male compulsive rats

Mapping the neuroanatomical abnormalities in a phenotype of male compulsive rats

Bundle-Specific Axon Diameter Index as a New Contrast to Differentiate White Matter Tracts

Reduced brain volume and white matter alterations in Shank3‐deficient rats

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