Genetic, Morphometric, and Behavioral Factors Linked to the Midsagittal Area of the Corpus Callosum

The corpus callosum is the main commissure connecting left and right cerebral hemispheres, and varies widely in size. Differences in the midsagittal area of the corpus callosum (MSACC) have been associated with a number of cognitive and behavioral phenotypes, including obsessive-compulsive disorders, psychopathy, suicidal tendencies, bipolar disorder, schizophrenia, autism, and attention deficit hyperactivity disorder. Although there is evidence to suggest that MSACC is heritable in normal human populations, there is surprisingly little evidence concerning the genetic modulation of this variation. Mice provide a potentially ideal tool to dissect the genetic modulation of MSACC. Here, we use a large genetic reference panel – the BXD recombinant inbred line – to dissect the natural variation of the MSACC. We estimated the MSACC in over 300 individuals from nearly 80 strains. We found a 4-fold difference in MSACC between individual mice, and a 2.5-fold difference among strains. MSACC is a highly heritable trait (h2 = 0.60), and we mapped a suggestive QTL to the distal portion of Chr 14. Using sequence data and neocortical expression databases, we were able to identify eight positional and plausible biological candidate genes within this interval. Finally, we found that MSACC correlated with behavioral traits associated with anxiety and attention

Age at developmental cortical injury differentially Alters corpus callosum volume in the rat

<p>Abstract</p> <p>Background</p> <p>Freezing lesions to developing rat cortex induced between postnatal day (P) one and three (P1 – 3) lead to malformations similar to human microgyria, and further correspond to reductions in brain weight and cortical volume. In contrast, comparable lesions on P5 do not produce microgyric malformations, nor the changes in brain weight seen with microgyria. However, injury occurring at all three ages does lead to rapid auditory processing deficits as measured in the juvenile period. Interestingly, these deficits persist into adulthood only in the P1 lesion case <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. Given prior evidence that early focal cortical lesions induce abnormalities in cortical morphology and connectivity <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr><abbr bid="B4">4</abbr></abbrgrp>, we hypothesized that the differential behavioral effects of focal cortical lesions on P1, P3 or P5 may be associated with underlying neuroanatomical changes that are sensitive to timing of injury. Clinical studies indicate that humans with perinatal brain injury often show regional reductions in corpus callosum size and abnormal symmetry, which frequently correspond to learning impairments <abbrgrp><abbr bid="B5">5</abbr><abbr bid="B6">6</abbr><abbr bid="B7">7</abbr></abbrgrp>. Therefore, in the current study the brains of P1, 3 or 5 lesion rats, previously evaluated for brain weight, and cortical volume changes and auditory processing impairments (P21-90), were further analyzed for changes in corpus callosum volume.</p> <p>Results</p> <p>Results showed a significant main effect of Treatment on corpus callosum volume [F (1,57) = 10.2, P < .01], with lesion subjects showing significantly smaller callosal volumes as compared to shams. An Age at Treatment × Treatment interaction [F(2,57) = 3.2, P < .05], indicated that corpus callosum size decreased as the age of injury decreased from P5 to P1. Simple effects analysis showed significant differences between P1 and P3 [F(1,28) = 8.7, P < .01], and P1 and P5 [F(1,28) = 15.1, P < .001], subjects. Rats with P1 injury resulting in microgyria had the greatest reduction in corpus callosum volume (22% reduction), followed by the P3 group (11% reduction), which showed a significant reduction in corpus callosum volume compared to shams [F(1,31) = 5.9, P < .05]. Finally, the P5 lesion group did not significantly differ from the sham subjects in callosal volume.</p> <p>Conclusion</p> <p>Decrements in corpus callosum volume in the P1 and 3 lesion groups are consistent with the reductions in brain weight and cortical volume previously reported for microgyric rats <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B8">8</abbr></abbrgrp>. Current results suggest that disruption to the cortical plate during early postnatal development may lead to more widely dispersed neurovolumetric anomalies and subsequent behavioral impairments <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>, compared with injury that occurs later in development. Further, these results suggest that in a human clinical setting decreased corpus callosum volume may represent an additional marker for long-term behavioral outcome.</p

The genetic control of neocortex volume and covariation with neocortical gene expression in mice

<p>Abstract</p> <p>Background</p> <p>The size of the cerebral cortex varies widely within human populations, and a large portion of this variance is modulated by genetic factors. The discovery and characterization of these genes and their variants can contribute to an understanding of individual differences in brain development, behavior, and disease susceptibility. Here we use unbiased stereological techniques to map quantitative trait loci (QTLs) that modulate the volume of neocortex.</p> <p>Results</p> <p>We estimated volumes bilaterally in an expanded set of BXD recombinant inbred strains (n = 56 strains and 223 animals) taken from the Mouse Brain Library <url>http://www.mbl.org</url>. We generated matched microarray data for the cerebral cortex in the same large panel of strains and in parental neonates to efficiently nominate and evaluate candidate genes. Volume of the neocortex varies widely, and is a heritable trait. Genome-wide mapping of this trait revealed two QTLs – one on chromosome (Chr) 6 at 88 ± 5 Mb and another at Chr 11 (41 ± 8 Mb). We generated both neonatal and adult neocortical gene expression databases using microarray technology. Using these databases in combination with other bioinformatic tools we have identified positional candidates on these QTL intervals.</p> <p>Conclusion</p> <p>This study is the first to use the expanded set of BXD strains to map neocortical volume, and we found that normal variation of this trait is, at least in part, genetically modulated. These results provide a baseline from which to assess the genetic contribution to regional variation in neocortical volume, as well as other neuroanatomic phenotypes that may contribute to variation in regional volume, such as proliferation, death, and number and packing density of neurons</p

Complex trait analysis of the mouse striatum: independent QTLs modulate volume and neuron number

Abstract Background: The striatum plays a pivotal role in modulating motor activity and higher cognitive function. We analyzed variation in striatal volume and neuron number in mice and initiated a complex trait analysis to discover polymorphic genes that modulate the structure of the basal ganglia

A Comparison of Three Electrophysiological Methods for the Assessment of Disease Status in a Mild Spinal Muscular Atrophy Mouse Model

Objectives: There is a need for better, noninvasive quantitative biomarkers for assessing the rate of progression and possible response to therapy in spinal muscular atrophy (SMA). In this study, we compared three electrophysiological measures: compound muscle action potential (CMAP) amplitude, motor unit number estimate (MUNE), and electrical impedance myography (EIM) 50 kHz phase values in a mild mouse model of spinal muscular atrophy, the Smn1c/c mouse. Methods: Smn1c/c mice (N = 11) and wild type (WT) animals (−/−, N = 13) were measured on average triweekly until approximately 1 year of age. Measurements included CMAP, EIM, and MUNE of the gastrocnemius muscle as well as weight and front paw grip strength. At the time of sacrifice at one year, additional analyses were performed on the animals including serum survival motor neuron (SMN) protein levels and muscle fiber size. Results: Both EIM 50 kHz phase and CMAP showed strong differences between WT and SMA animals (repeated measures 2-way ANOVA, P<0.0001 for both) whereas MUNE did not. Both body weight and EIM showed differences in the trajectory over time (p<0.001 and p = 0.005, respectively). At the time of sacrifice at one year, EIM values correlated to motor neuron counts in the spinal cord and SMN levels across both groups of animals (r = 0.41, p = 0.047 and r = 0.57, p = 0.003, respectively), while CMAP did not. Motor neuron number in Smn1c/c mice was not significantly reduced compared to WT animals. Conclusions: EIM appears sensitive to muscle status in this mild animal model of SMA. The lack of a reduction in MUNE or motor neuron number but reduced EIM and CMAP values support that much of the pathology in these animals is distal to the cell body, likely at the neuromuscular junction or the muscle itself

Brain weight differences associated with induced focal microgyria

BACKGROUND: Disrupting neural migration with bilateral focal freezing necrosis on postnatal day 1 (P1) results in the formation of 4-layered microgyria. This developmental injury triggers a pervasive neural reorganization, which is evident at the electrophysiological, behavioral, and anatomical levels. In this experiment, we investigated changes in brain weight as an index of global disruption of neural systems caused by focal damage to the developing cortical plate. RESULTS: We found a dramatic reduction in overall brain weight in microgyric subjects. This reduction in brain weight among animals with microgyria is reflected in decreased total brain volume, with a disproportionate decrease in neocortical volume. This effect is so robust that it is seen across varied environments, at variable ages, and across the sexes. CONCLUSIONS: This finding supports previous work suggesting that substantial reorganization of the brain is triggered by the induction of bilateral freezing damage. These results have critical implications for the profound re-organizational effects of relatively small focal injuries early in development to distributed systems throughout the brain, and particularly in the cerebral cortex

Recurrence of pulmonary intravascular bronchoalveolar tumor with mediastinal metastasis 20 years later

SummaryPulmonary intravascular bronchoalveolar tumor (IVBAT) also recognized as pulmonary epithelioid hemangioendothelioma, is a rare malignant vascular tumor of unknown etiology. IVBAT is a tumor of multicentric origin and the lungs are rarely involved, with only about 60 cases of pulmonary IVBAT described in the literature. The prognosis is unpredictable, with life expectancy ranging from 1 to 15 years. We report an unusual case of pulmonary IVBAT that recurred in the lung with metastasis to the mediastinum

Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse

<p>Abstract</p> <p>Background</p> <p>Sexual dimorphism in brain gene expression has been recognized in several animal species. However, the relevant regulatory mechanisms remain poorly understood. To investigate whether sex-biased gene expression in mammalian brain is globally regulated or locally regulated in diverse brain structures, and to study the genomic organisation of brain-expressed sex-biased genes, we performed a large scale gene expression analysis of distinct brain regions in adult male and female mice.</p> <p>Results</p> <p>This study revealed spatial specificity in sex-biased transcription in the mouse brain, and identified 173 sex-biased genes in the striatum; 19 in the neocortex; 12 in the hippocampus and 31 in the eye. Genes located on sex chromosomes were consistently over-represented in all brain regions. Analysis on a subset of genes with sex-bias in more than one tissue revealed Y-encoded male-biased transcripts and X-encoded female-biased transcripts known to escape X-inactivation. In addition, we identified novel coding and non-coding X-linked genes with female-biased expression in multiple tissues. Interestingly, the chromosomal positions of all of the female-biased non-coding genes are in close proximity to protein-coding genes that escape X-inactivation. This defines X-chromosome domains each of which contains a coding and a non-coding female-biased gene. Lack of repressive chromatin marks in non-coding transcribed loci supports the possibility that they escape X-inactivation. Moreover, RNA-DNA combined FISH experiments confirmed the biallelic expression of one such novel domain.</p> <p>Conclusion</p> <p>This study demonstrated that the amount of genes with sex-biased expression varies between individual brain regions in mouse. The sex-biased genes identified are localized on many chromosomes. At the same time, sexually dimorphic gene expression that is common to several parts of the brain is mostly restricted to the sex chromosomes. Moreover, the study uncovered multiple female-biased non-coding genes that are non-randomly co-localized on the X-chromosome with protein-coding genes that escape X-inactivation. This raises the possibility that expression of long non-coding RNAs may play a role in modulating gene expression in domains that escape X-inactivation in mouse.</p