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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.
Systemic inflammation combined with neonatal cerebellar haemorrhage aggravates long-term structural and functional outcomes in a mouse model.
BACKGROUND: Despite the increased recognition of cerebellar injury in survivors of preterm birth, the neurodevelopmental consequences of isolated cerebellar injury have been largely unexplored and our current understanding of the functional deficits requires further attention in order to translate knowledge to best practices. Preterm infants are exposed to multiple stressors during their postnatal development including perinatal cerebellar haemorrhage (CBH) and postnatal infection, two major risk factors for neurodevelopmental impairments. METHODS: We developed a translational mouse model of CBH and/or inflammation to measure the short- and long-term outcomes in cerebellar structure and function. RESULTS: Mice exposed to early combined insults of CBH and early inflammatory state (EIS) have a delay in grasping acquisition, neonatal motor deficits and deficient long-term memory. CBH combined with late inflammatory state (LIS) does not induce neonatal motor problems but leads to poor fine motor function and long-term memory deficits at adulthood. Early combined insults result in poor cerebellar growth from postnatal day 15 until adulthood shown by MRI, which are reflected in diminished volumes of cerebellar structures. There are also decreases in volumes of gray matter and hippocampus. Cerebellar microgliosis appears 24h after the combined insults and persists until postnatal day 15 in the cerebellar molecular layer and cerebellar nuclei in association with a disrupted patterning of myelin deposition, a delay of oligodendrocyte maturation and reduced white matter cerebellar volume. CONCLUSIONS: Together, these findings reveal poor outcomes in developing brains exposed to combined cerebellar perinatal insults in association with cerebellar hypoplasia, persistence of microgliosis and alterations of cerebellar white matter maturation and growth.
Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies.
Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be co-localized with and reciprocal to XO-XX differences in anatomy. These overlaps identify the lateral septum, BNST, ventral group thalamic nuclei and periaqueductal gray matter as regions with replicable sensitivity to X chromosome dose across two SCAs. We then harness anatomical variation across all four karyotype groups in our study--XO, XX, XY and XXY--to create an agnostic data-driven segmentation of the mouse brain into five distributed clusters which (1) recover fundamental properties of brain organization with high spatial precision, (2) define two previously uncharacterized systems of relative volume excess in females vs. males ("forebrain cholinergic" and "cerebelo-pontine-thalamo-cortical"), and (3) adopt stereotyped spatial motifs which delineate ordered gradients of sex chromosome and gonadal influences on volumetric brain development. Taken together, these data provide a new framework for the study of sexually dimorphic influences on brain development in health and disrupted brain development in SCA.
Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood.
CONTEXT: Volumetric studies have reported relatively decreased cortical thickness and gray matter volumes in adults with attention-deficit/hyperactivity disorder (ADHD) whose childhood status was retrospectively recalled. We present, to our knowledge, the first prospective study combining cortical thickness and voxel-based morphometry in adults diagnosed as having ADHD in childhood. OBJECTIVES: To test whether adults with combined-type childhood ADHD exhibit cortical thinning and decreased gray matter in regions hypothesized to be related to ADHD and to test whether anatomic differences are associated with a current ADHD diagnosis, including persistent vs remitting ADHD. DESIGN: Cross-sectional analysis embedded in a 33-year prospective follow-up at a mean age of 41.2 years. SETTING: Research outpatient center. PARTICIPANTS: We recruited probands with ADHD from a cohort of 207 white boys aged 6 to 12 years. Male comparison participants (n = 178) were free of ADHD in childhood. We obtained magnetic resonance images in 59 probands and 80 comparison participants (28.5% and 44.9% of the original samples, respectively). MAIN OUTCOME MEASURES: Whole-brain voxel-based morphometry and vertexwise cortical thickness analyses. RESULTS: The cortex was significantly thinner in ADHD probands than in comparison participants in the dorsal attentional network and limbic areas (false discovery rate < 0.05, corrected). In addition, gray matter was significantly decreased in probands in the right caudate, right thalamus, and bilateral cerebellar hemispheres. Probands with persistent ADHD (n = 17) did not differ significantly from those with remitting ADHD (n = 26) (false discovery rate < 0.05). At uncorrected P < .05, individuals with remitting ADHD had thicker cortex relative to those with persistent ADHD in the medial occipital cortex, insula, parahippocampus, and prefrontal regions. CONCLUSIONS: Anatomic gray matter reductions are observable in adults with childhood ADHD, regardless of the current diagnosis. The most affected regions underpin top-down control of attention and regulation of emotion and motivation. Exploratory analyses suggest that diagnostic remission may result from compensatory maturation of prefrontal, cerebellar, and thalamic circuitry.
Spatial patterns of cortical thinning in mild cognitive impairment and Alzheimer's disease.
Cortical thickness is a more reliable measure of atrophy than volume due to the low variability in the cytoarchitectural structure of the grey matter. However, this more desirable measure of disease-related alterations is not fully evaluated in early dementia. The study presented here is the first to report the spatial patterns of cortical thickness in the pre-clinical stages of Alzheimer's disease, namely mild cognitive impairment (MCI). Cortical thickness measurements for 34 healthy elderly, 62 MCI and 42 Alzheimer's disease subjects were made using fully automated magnetic resonance imaging-based analysis techniques in order to determine the pattern of cortical thinning as a function of disease progression. The thickness of the cortex decreased significantly when the healthy elderly brains were compared to those with MCI, mainly in the medial temporal lobe region and in some regions of the frontal and the parietal cortices. With the progression of disease from MCI to Alzheimer's disease, a general thinning of the entire cortex with significant extension into the lateral temporal lobe was found. In all cases, the results were more pronounced in the left hemisphere. In conclusion, we have shown that there is a specific pattern in the thinning of the cortical ribbon which is in agreement with the previous histological reports. These novel findings support the notion of increased isocortical involvement with the progression of disease.
Brain imaging in drug R&D.
Magnetic resonance imaging (MRI), used as a clinical diagnostic tool since the early 1980s, is rapidly gaining traction as an integral part of the drug development process. Brain imaging research spans a wide area, covering both structure and function, and ranging from the physics and physiology associated with novel acquisition techniques, to the development of sophisticated image processing algorithms. This paper briefly describes two methods on either end of this spectrum: the "pipeline" framework for the fully automated morphometric analysis of brain imaging data, and molecular MRI, which holds promise for the non-invasive detection of molecular targets of new pharmacological compounds. The potential use of these technologies is illustrated by examples of their applications in multiple sclerosis, Alzheimer's disease, and oncology.
Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.
Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a β-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the β-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism.