Semi-automated registration-based anatomical labelling, voxel based morphometry and cortical thickness mapping of the mouse brain

Pagani, Maria Pia; Damiano, Mario; Galbusera, Alberto; Tsaftaris, Sotirios A.; Gozzi, Alessandro

doi:10.1016/j.jneumeth.2016.04.007

Cited by 58 publications

(50 citation statements)

References 60 publications

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“…BTBR mice have decreased brain volume compared to controls [96]. MRI studies have revealed decreased gray matter volume in the dorsofrontal, cingulate, retrosplenial, occipital and parietal cortex, as well as in subcortical areas including lateral and posterior thalamus, posterior hypothalamus and ventral hippocampus, but increased volume in the olfactory bulbs, medial prefrontal and insular cortex, amygdala and dorsal hippocampus [87, 270]. These findings agree with the reduction of gray matter volume over time in ASD, which is associated with increased severity of symptoms [143].…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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“…BTBR structural MRI data was also recently used for the development of semi-automated registration-based procedures for voxel based morphometry, and cortical thickness estimation (Pagani et al 2016). The latter was found generally reduced in BTBR mice, with no particular cell population affected more than others (Fenlon et al 2015).…”

Section: Neuroanatomy Of the Btbr Mouse: Impaired Axon Guidance Anmentioning

confidence: 99%

The BTBR mouse model of idiopathic autism – Current view on mechanisms

Meyza

Blanchard

2017

Neuroscience & Biobehavioral Reviews

129

109

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Autism spectrum disorder (ASD) is the most commonly diagnosed neurodevelopmental disorder, with current estimates of more than 1% of affected children across nations. The patients form a highly heterogeneous group with only the behavioral phenotype in common. The genetic heterogeneity is reflected in a plethora of animal models representing multiple mutations found in families of affected children. Despite many years of scientific effort, for the majority of cases the genetic cause remains elusive. It is therefore crucial to include well-validated models of idiopathic autism in studies searching for potential therapeutic agents. One of these models is the BTBR T+Itpr3tf/J mouse. The current review summarizes data gathered in recent research on potential molecular mechanisms responsible for the autism-like behavioral phenotype of this strain.

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“…To identify putative gray matter reorganization coincident with functional hypo-connectivity in the cortex of Shank3B -/mice, we carried out post-mortem Voxel-Based Morphometry (VBM) (Pagani et al, 2016b). Images were acquired on ex-vivo in paraformaldehyde fixed specimens, a procedure employed to obtain high-resolution images with negligible confounding contributions from physiological or motion artefacts.…”

Section: Structural Mrimentioning

confidence: 99%

“…Inter-group morpho-anatomical differences in local GM volumes were mapped using a registrationbased VBM procedure (Pagani et al, 2016a;Pagani et al, 2016b). Briefly, high-resolution T2-weighted images were corrected for intensity non-uniformity, skull stripped and spatially normalized to a study-based template using affine and diffeomorphic registrations.…”

Section: Voxel-based Morphometry (Vbm) Of Gray Matter (Gm) Volumementioning

confidence: 99%

“…For statistical analysis, voxel-wise intergroup differences in regional GM volume differences between Shank3B -/mice and controls were mapped using a 2-tailed Student's t-test (|t| > 2, p < 0.05) and FWE cluster-corrected using a cluster threshold of p = 0.01 (Worsley et al, 1992) as implemented in FSL (Jenkinson et al, 2012). To quantify volumetric changes identified with VBM, we employed preprocessed images to independently calculate the size of neuroanatomical areas via volumetric anatomical labelling (Pagani et al, 2016b).…”

Section: Voxel-based Morphometry (Vbm) Of Gray Matter (Gm) Volumementioning

confidence: 99%

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Deletion of autism risk gene Shank3 disrupts prefrontal connectivity

Pagani

Bertero

Liska

et al. 2018

Preprint

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Mutations in the synaptic scaffolding protein Shank3 are a major cause of autism, and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher order socio-communicative functions remain unclear. Using highresolution functional and structural MRI in mice, here we show that loss of Shank3 (Shank3B −/− ) results in disrupted local and long-range prefrontal functional connectivity, as well as fronto-striatal decoupling. We document that prefrontal hypo-connectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity.

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Semi-automated registration-based anatomical labelling, voxel based morphometry and cortical thickness mapping of the mouse brain

Abstract: The detailed operational workflows described here are expected to help the implementation of rodent morphoanatomical methods by non-expert users, and ultimately promote the use of these tools across the preclinical neuroimaging community.

Cited by 58 publications

References 60 publications

Autism spectrum disorder: neuropathology and animal models

Autism spectrum disorder: neuropathology and animal models

The BTBR mouse model of idiopathic autism – Current view on mechanisms

Deletion of autism risk gene Shank3 disrupts prefrontal connectivity

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