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Sexual dimorphism of brain developmental trajectories during childhood and adolescence.
Human total brain size is consistently reported to be approximately 8-10% larger in males, although consensus on regionally specific differences is weak. Here, in the largest longitudinal pediatric neuroimaging study reported to date (829 scans from 387 subjects, ages 3 to 27 years), we demonstrate the importance of examining size-by-age trajectories of brain development rather than group averages across broad age ranges when assessing sexual dimorphism. Using magnetic resonance imaging (MRI) we found robust male/female differences in the shapes of trajectories with total cerebral volume peaking at age 10.5 in females and 14.5 in males. White matter increases throughout this 24-year period with males having a steeper rate of increase during adolescence. Both cortical and subcortical gray matter trajectories follow an inverted U shaped path with peak sizes 1 to 2 years earlier in females. These sexually dimorphic trajectories confirm the importance of longitudinal data in studies of brain development and underline the need to consider sex matching in studies of brain development.
Normative brain size variation and brain shape diversity in humans
<jats:p>Brain size variation over primate evolution and human development is associated with shifts in the proportions of different brain regions. Individual brain size can vary almost twofold among typically developing humans, but the consequences of this for brain organization remain poorly understood. Using in vivo neuroimaging data from more than 3000 individuals, we find that larger human brains show greater areal expansion in distributed frontoparietal cortical networks and related subcortical regions than in limbic, sensory, and motor systems. This areal redistribution recapitulates cortical remodeling across evolution, manifests by early childhood in humans, and is linked to multiple markers of heightened metabolic cost and neuronal connectivity. Thus, human brain shape is systematically coupled to naturally occurring variations in brain size through a scaling map that integrates spatiotemporally diverse aspects of neurobiology.</jats:p>
Reduced cortical volume and elevated astrocyte density in rats chronically treated with antipsychotic drugs-linking magnetic resonance imaging findings to cellular pathology.
BACKGROUND: Increasing evidence suggests that antipsychotic drugs (APD) might affect brain structure directly, particularly the cerebral cortex. However, the precise anatomical loci of these effects and their underlying cellular basis remain unclear. METHODS: With ex vivo magnetic resonance imaging in rats treated chronically with APDs, we used automated analysis techniques to map the regions that show maximal impact of chronic (8 weeks) treatment with either haloperidol or olanzapine on the rat cortex. Guided by these imaging findings, we undertook a focused postmortem investigation with stereology. RESULTS: We identified decreases in the volume and thickness of the anterior cingulate cortex (ACC) after chronic APD treatment, regardless of the APD administered. Postmortem analysis confirmed these volumetric findings and demonstrated that chronic APD treatment had no effect on the total number of neurons or S100β+ astrocytes in the ACC. In contrast, an increase in the density of these cells was observed. CONCLUSIONS: This study demonstrates region-specific structural effects of chronic APD treatment on the rat cortex, primarily but not exclusively localized to the ACC. At least in the rat, these changes are not due to a loss of either neurons or astrocytes and are likely to reflect a loss of neuropil. Although caution needs to be exerted when extrapolating results from animals to patients, this study highlights the power of this approach to link magnetic resonance imaging findings to their histopathological origins.
Neuroanatomic Differences Associated With Stress Susceptibility and Resilience.
BACKGROUND: We examined the neurobiological mechanisms underlying stress susceptibility using structural magnetic resonance imaging and diffusion tensor imaging to determine neuroanatomic differences between stress-susceptible and resilient mice. We also examined synchronized anatomic differences between brain regions to gain insight into the plasticity of neural networks underlying stress susceptibility. METHODS: C57BL/6 mice underwent 10 days of social defeat stress and were subsequently tested for social avoidance. For magnetic resonance imaging, brains of stressed (susceptible, n = 11; resilient, n = 8) and control (n = 12) mice were imaged ex vivo at 56 µm resolution using a T2-weighted sequence. We tested for behavior-structure correlations by regressing social avoidance z-scores against local brain volume. For diffusion tensor imaging, brains were scanned with a diffusion-weighted fast spin echo sequence at 78 μm isotropic voxels. Structural covariance was assessed by correlating local volume between brain regions. RESULTS: Social avoidance correlated negatively with local volume of the cingulate cortex, nucleus accumbens, thalamus, raphe nuclei, and bed nucleus of the stria terminals. Social avoidance correlated positively with volume of the ventral tegmental area (VTA), habenula, periaqueductal gray, cerebellum, hypothalamus, and hippocampal CA3. Fractional anisotropy was increased in the hypothalamus and hippocampal CA3. We observed synchronized anatomic differences between the VTA and cingulate cortex, hippocampus and VTA, hippocampus and cingulate cortex, and hippocampus and hypothalamus. These correlations revealed different structural covariance between brain regions in susceptible and resilient mice. CONCLUSIONS: Stress-integrative brain regions shape the neural architecture underlying individual differences in susceptibility and resilience to chronic stress.
Neuroanatomical analysis of the BTBR mouse model of autism using magnetic resonance imaging and diffusion tensor imaging.
Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. Autism-relevant phenotypes in the inbred mouse strain BTBR T+tf/J (BTBR) offer translational tools to discover biological mechanisms underlying unusual mouse behaviors analogous to symptoms of autism. Two of the most consistent findings with BTBR are lack of sociability as measured by the three-chamber social approach task and increased amount of time engaged in self-grooming in an empty cage. Here we evaluated BTBR as compared to two typical inbred strains with high sociability and low self-grooming, C57BL/6J (B6) and FVB/AntJ (FVB), on both the automated three-chambered social approach task and repetitive self-grooming assays. Brains from the behaviorally tested mice were analyzed using magnetic resonance imaging and diffusion tensor imaging to investigate potential neuroanatomical abnormalities throughout the brain; specifically, to discover neuroanatomical mechanisms which could explain the autism-relevant behavioral abnormalities. Significant differences in volume and white matter microstructure were detected in multiple anatomical regions throughout the brain of BTBR compared to B6 and FVB. Further, significant correlations were found between behavioral measures and areas of the brain known to be associated with those behaviors. For example, striatal volume was strongly correlated to time spent in self-grooming across strains. Our findings suggest that neuropathology exists in BTBR beyond the previously reported white matter abnormalities in the corpus callosum and hippocampal commissure and that these brain differences may be related to the behavioral abnormalities seen in BTBR.
Cortical anatomy in human X monosomy.
Turner syndrome (TS) is a model for X chromosome influences on neurodevelopment because it is most commonly caused by absence of one X chromosome and associated with altered brain structure and function. However, all prior in vivo magnetic resonance imaging studies of the brain in TS have either used manual approaches or voxel-based morphometry (VBM) to measure cortical volume (CV). These methods, unlike surface-based morphometry (SBM), cannot measure the two neurobiologically distinct determinants of CV- cortical thickness (CT) and surface area (SA) - which have differing genetic determinants and may be independently altered. Therefore, in 24 adults with X monosomy and 19 healthy female controls, we used SBM to compare (i) lobar CV, CT and SA; (ii) an index of hemispheric gyrification; (iii) CT throughout the cortical sheet; and (iv) CT correlation between cortical regions. Compared to controls, females with TS had (i) significantly increased CT and decreased SA in parietal and occipital lobes (resulting in no significant difference in lobar CV); (ii) reduced hemispheric gyrification bilaterally; (iii) foci of significantly increased CT involving inferior temporal, lateral occipital, intraparietal sulcus (IPS), cingulate and orbitofrontal cortices; and (iv) significantly reduced CT correlation between the left IPS and cortical regions including supramarginal and lateral occipital gyri. Our findings suggest that females with TS have complex, sometimes "opposing", abnormalities in SA/gyrification (decreased) and CT (increased), which can result in no overall detectable differences in CV. Thus, haploinsufficiency of X chromosome genes, may differentially impact the distinct mechanisms shaping SA (e.g. cortical folding) and CT (e.g. dendritic arborization/pruning). CT disruptions are maximal within and between cortical regions previously implicated in the TS cognitive phenotype.
Deep brain stimulation of the ventromedial prefrontal cortex causes reorganization of neuronal processes and vasculature.
BACKGROUND: Chronic high-frequency electrical deep brain stimulation (DBS) of the subcallosal cingulate region is currently being investigated clinically as a therapy for treatment of refractory depression. Experimental DBS of the homologous region, the ventromedial prefrontal cortex (VMPFC), in rodent models has previously demonstrated anti-depressant-like effects. Our goal was to determine if structural remodeling accompanies the alterations of brain function previously observed as a result of chronic DBS. METHODS: Here we applied 6h of high-frequency bilateral VMPFC DBS daily to 8 9-week old C57Bl/6 mice for 5days. We investigated the "micro-lesion" effect by using a sham stimulation group (8 mice) and a control group (8 mice with a hole drilled into the skull only). Whole brain anatomy was investigated post-mortem using high-resolution magnetic resonance imaging and areas demonstrating volumetric expansion were further investigated using histology and immunohistochemistry. RESULTS: The DBS group demonstrated bilateral increases in whole hippocampus and the left thalamus volume compared to both sham and control groups. Local hippocampal and thalamic volume increases were also observed at the voxel-level; however these increases were observed in both DBS and sham groups. Follow-up immunohistochemistry in the hippocampus revealed DBS increased blood vessel size and synaptic density relative to the control group whereas the sham group demonstrated increased astrocyte size. CONCLUSIONS: Our work demonstrates that DBS not only works by altering function with neural circuits, but also by structurally altering circuits at the cellular level. Neuroplastic alterations may play a role in mediating the clinical efficacy of DBS therapy.
Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis.
Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.
Rotarod training in mice is associated with changes in brain structure observable with multimodal MRI.
The brain has been shown to remain structurally plastic even throughout adulthood. However, little is known how motor-skill training affects different MRI modalities in the adult mouse brain. The aim of this study is to investigate whether rotarod training, a simple motor training task taken from the standard test battery, is associated with structural plasticity observable with different MRI modalities in adult C57BL/6 mice. The rotarod is a standard test that taxes motor coordination and balance. We use T2-weighted MRI followed by deformation-based morphometry to assess local volume and fractional anisotropy (FA) derived from diffusion MRI to assess microstructure ex-vivo. Using deformation-based morphometry we found that the hippocampus, frontal cortex and amygdala are larger in rotarod-trained mice compared to untrained controls. Surprisingly, the cerebellum and white matter in the corpus callosum underlying the primary motor cortex are smaller after training. We also found that the volume of the motor cortex is positively correlated with better rotarod performance. Diffusion imaging indicates group differences and behavioral correlations with FA, a measure of microstructure. Trained mice have higher FA in the hippocampus. Better rotarod performance is associated with higher FA in the hippocampus and lower FA in the primary visual cortex. This is the first study to reveal the substantial structural reorganization of the adult mouse brain following only a relatively brief period of motor-skill training by using complementary measures of microstructure and volume.
Longitudinal MEMRI analysis of brain phenotypes in a mouse model of Niemann-Pick Type C disease.
Niemann-Pick Type C (NPC) is a rare genetic disorder characterized by progressive cell death in various tissues, particularly in the cerebellar Purkinje cells, with no known cure. Mouse models for human NPC have been generated and characterized histologically, behaviorally, and using longitudinal magnetic resonance imaging (MRI). Previous imaging studies revealed significant brain volume differences between mutant and wild-type animals, but stopped short of making volumetric comparisons of the cerebellar sub-regions. In this study, we present longitudinal manganese-enhanced MRI (MEMRI) data from cohorts of wild-type, heterozygote carrier, and homozygote mutant NPC mice, as well as deformation-based morphometry (DBM) driven brain volume comparisons across genotypes, including the cerebellar cortex, white matter, and nuclei. We also present the first comparisons of MEMRI signal intensities, reflecting brain and cerebellum sub-regional Mn2+-uptake over time and across genotypes.
Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome.
Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS.
Atrx Deletion in Neurons Leads to Sexually Dimorphic Dysregulation of miR-137 and Spatial Learning and Memory Deficits.
ATRX gene mutations have been identified in syndromic and non-syndromic intellectual disabilities in humans. ATRX is known to maintain genomic stability in neuroprogenitor cells, but its function in differentiated neurons and memory processes remains largely unresolved. Here, we show that the deletion of neuronal Atrx in mice leads to distinct hippocampal structural defects, fewer presynaptic vesicles, and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. We identify male-specific impairments in long-term contextual memory and in synaptic gene expression, linked to altered miR-137 levels. We show that ATRX directly binds to the miR-137 locus and that the enrichment of the suppressive histone mark H3K27me3 is significantly reduced upon the loss of ATRX. We conclude that the ablation of ATRX in excitatory forebrain neurons leads to sexually dimorphic effects on miR-137 expression and on spatial memory, identifying a potential therapeutic target for neurological defects caused by ATRX dysfunction.
MRI analysis of cerebellar and vestibular developmental phenotypes in Gbx2 conditional knockout mice.
PURPOSE: Our aim in this study was to apply three-dimensional MRI methods to analyze early postnatal morphological phenotypes in a Gbx2 conditional knockout (Gbx2-CKO) mouse that has variable midline deletions in the central cerebellum, reminiscent of many human cerebellar hypoplasia syndromes. METHODS: In vivo three-dimensional manganese-enhanced MRI at 100-µm isotropic resolution was used to visualize mouse brains between postnatal days 3 and 11, when cerebellum morphology undergoes dramatic changes. Deformation-based morphometry and volumetric analysis of manganese-enhanced MRI images were used to, respectively, detect and quantify morphological phenotypes in Gbx2-CKO mice. Ex vivo micro-MRI was performed after perfusion-fixation with supplemented gadolinium for higher resolution (50-µm) analysis. RESULTS: In vivo manganese-enhanced MRI and deformation-based morphometry correctly identified known cerebellar defects in Gbx2-CKO mice, and novel phenotypes were discovered in the deep cerebellar nuclei and the vestibulo-cerebellum, both validated using histology. Ex vivo micro-MRI revealed subtle phenotypes in both the vestibulo-cerebellum and the vestibulo-cochlear organ, providing an interesting example of complementary phenotypes in a sensory organ and its associated brain region. CONCLUSION: These results show the potential of three-dimensional MRI for detecting and analyzing developmental defects in mouse models of neurodevelopmental diseases.
4D MEMRI atlas of neonatal FVB/N mouse brain development.
The widespread use of the mouse as a model system to study brain development has created the need for noninvasive neuroimaging methods that can be applied to early postnatal mice. The goal of this study was to optimize in vivo three- (3D) and four-dimensional (4D) manganese (Mn)-enhanced MRI (MEMRI) approaches for acquiring and analyzing data from the developing mouse brain. The combination of custom, stage-dependent holders and self-gated (motion-correcting) 3D MRI sequences enabled the acquisition of high-resolution (100-μm isotropic), motion artifact-free brain images with a high level of contrast due to Mn-enhancement of numerous brain regions and nuclei. We acquired high-quality longitudinal brain images from two groups of FVB/N strain mice, six mice per group, each mouse imaged on alternate odd or even days (6 3D MEMRI images at each day) covering the developmental stages between postnatal days 1 to 11. The effects of Mn-exposure, anesthesia and MRI were assessed, showing small but significant transient effects on body weight and brain volume, which recovered with time and did not result in significant morphological differences when compared to controls. Metrics derived from deformation-based morphometry (DBM) were used for quantitative analysis of changes in volume and position of a number of brain regions. The cerebellum, a brain region undergoing significant changes in size and patterning at early postnatal stages, was analyzed in detail to demonstrate the spatiotemporal characterization made possible by this new atlas of mouse brain development. These results show that MEMRI is a powerful tool for quantitative analysis of mouse brain development, with great potential for in vivo phenotype analysis in mouse models of neurodevelopmental diseases.
Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome.
Mutations in the gene encoding the ATP dependent chromatin-remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital-urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio-temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay.
Spatial gene expression analysis of neuroanatomical differences in mouse models.
MRI is a powerful modality to detect neuroanatomical differences that result from mutations and treatments. Knowing which genes drive these differences is important in understanding etiology, but candidate genes are often difficult to identify. We tested whether spatial gene expression data from the Allen Brain Institute can be used to inform us about genes that cause neuroanatomical differences. For many single-gene-mutation mouse models, we found that affected neuroanatomy was not strongly associated with the spatial expression of the altered gene and there are specific caveats for each model. However, among models with significant neuroanatomical differences from their wildtype controls, the mutated genes had preferential spatial expression in affected neuroanatomy. In mice exposed to environmental enrichment, candidate genes could be identified by a genome-wide search for genes with preferential spatial expression in the altered neuroanatomical regions. These candidates have functions related to learning and plasticity. We demonstrate that spatial gene expression of single-genes is a poor predictor of altered neuroanatomy, but altered neuroanatomy can identify candidate genes responsible for neuroanatomical phenotypes.
Chronic over-expression of TGFβ1 alters hippocampal structure and causes learning deficits.
The cytokine transforming growth factor β1 (TGFβ1) is chronically upregulated in several neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis and multiple sclerosis, and following stroke. Although previous studies have shown that TGFβ1 may be neuroprotective, chronic exposure to elevated levels of this cytokine may contribute to disease pathology on its own. In order to study the effects of chronic exposure to TGFβ1 in isolation, we used transgenic mice that over-express a constitutively active porcine TGFβ1 in astrocytes. We found that TGFβ1 over-expression altered brain structure, with the most pronounced volumetric increases localized to the hippocampus. Within the dentate gyrus (DG) of the hippocampus, increases in granule cell number and astrocyte size were responsible for volumetric expansion, with the increased granule cell number primarily related to a marked reduction in death of new granule cells generated in adulthood. Finally, these cumulative changes in DG microstructure and macrostructure were associated with the age-dependent emergence of spatial learning deficits in TGFβ1 over-expressing mice. Together, our data indicate that chronic upregulation of TGFβ1 negatively impacts hippocampal structure and, even in the absence of disease, impairs hippocampus-dependent learning.
High resolution whole brain imaging of anatomical variation in XO, XX, and XY mice.
The capacity of sex to modify behavior in health and illness may stem from biological differences between males and females. One such difference--fundamental to the biological definition of sex--is inequality of X chromosome dosage. Studies of Turner Syndrome (TS) suggest that X-monosomy profoundly alters mammalian brain development. However, use of TS as a model for X chromosome haploinsufficiency is complicated by karyotypic mosaicism, background genetic heterogeneity and ovarian dysgenesis. Therefore, to better isolate X chromosome effects on brain development and identify how these overlap with normative sex differences, we used whole-brain structural imaging to study X-monosomic mice (free of mosaicism and ovarian dysgenesis) alongside their karyotypical normal male and female littermates. We demonstrate that murine X-monosomy (XO) causes (i) accentuation of XX vs XY differences in a set of sexually dimorphic structures including classical foci of sex-hormone action, such as the bed nucleus of the stria terminal and medial amygdala, (ii) parietal and striatal abnormalities that recapitulate those reported TS, and (iii) abnormal development of brain systems relevant for domains of altered cognition and emotion in both murine and human X-monosomy. Our findings suggest an unexpected role for X-linked genes in shaping sexually dimorphic brain development, and an evolutionarily conserved influence of X-linked genes on both cortical and subcortical development in mammals. Furthermore, our murine findings highlight the bed nucleus of the stria terminalis and periaqueductal gray matter as novel neuroanatomical candidates for closer study in TS. Integration of these data with existing genomic knowledge generates a set of novel, testable hypotheses regarding candidate mechanisms for each observed pattern of anatomical variation across XO, XX and XY groups.