Biomedical subjects

Glenn D Rosen

Publications and source records attributed to Glenn D Rosen.

At least 19 recordsLinked to original sources

PubMed2007

Disruption of neuronal migration by RNAi of Dyx1c1 results in neocortical and hippocampal malformations.

The brains of individuals with developmental dyslexia have neocortical neuronal migration abnormalities including molecular layer heterotopias, laminar dysplasias, and periventricular nodular heterotopias (PNH). RNA interference (RNAi) of Dyx1c1, a candidate dyslexia susceptibility gene, disrupts neuronal migration in developing embryonic neocortex. Using in utero electroporation, we cotransfected cells in the rat neocortical ventricular zone (VZ) at E14/15 with short hairpin RNA vectors targeting Dyx1c1 along with either plasmids encoding enhanced green fluorescent protein or plasmids encoding monomeric red fluorescent protein only. RNAi of Dyx1c1 resulted in pockets of unmigrated neurons resembling PNH. The pattern of migration of transfected neurons was bimodal, with approximately 20% of the neurons migrating a short distance from the VZ and another 40% that migrated past their expected lamina. Approximately 25% of the transfected brains had hippocampal pyramidal cell migration anomalies. Molecular layer ectopias, which were not related to injection site artifacts, were also seen in 25% of the animals. These results support the hypothesis that targeted disruption of the candidate dyslexia susceptibility gene, Dyx1c1, results in neuronal migration disorders similar to those seen in the brains of dyslexics.

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PubMed2006

Developmental timeframes for induction of microgyria and rapid auditory processing deficits in the rat.

Induction of a focal freeze lesion to the skullcap of a 1-day-old rat pup leads to the formation of microgyria similar to those identified postmortem in human dyslexics. Rats with microgyria exhibit rapid auditory processing deficits similar to those seen in language-impaired (LI) children, and infants at risk for LI and these effects are particularly marked in juvenile as compared to adult subjects. In the current study, a startle response paradigm was used to investigate gap detection in juvenile and adult rats that received bilateral freezing lesions or sham surgery on postnatal day (P) 1, 3 or 5. Microgyria were confirmed in P1 and 3 lesion rats, but not in the P5 lesion group. We found a significant reduction in brain weight and neocortical volume in P1 and 3 lesioned brains relative to shams. Juvenile (P27-39) behavioral data indicated significant rapid auditory processing deficits in all three lesion groups as compared to sham subjects, while adult (P60+) data revealed a persistent disparity only between P1-lesioned rats and shams. Combined results suggest that generalized pathology affecting neocortical development is responsible for the presence of rapid auditory processing deficits, rather than factors specific to the formation of microgyria per se. Finally, results show that the window for the induction of rapid auditory processing deficits through disruption of neurodevelopment appears to extend beyond the endpoint for cortical neuronal migration, although, the persistent deficits exhibited by P1 lesion subjects suggest a secondary neurodevelopmental window at the time of cortical neuromigration representing a peak period of vulnerability.

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PubMed2006

How replicable are mRNA expression QTL?

Applying quantitative trait analysis methods to genome-wide microarray-derived mRNA expression phenotypes in segregating populations is a valuable tool in the attempt to link high-level traits to their molecular causes. The massive multiple-testing issues involved in analyzing these data make the correct level of confidence to place in mRNA abundance quantitative trait loci (QTL) a difficult problem. We use a unique resource to directly test mRNA abundance QTL replicability in mice: paired recombinant inbred (RI) and F(2) data sets derived from C57BL/6J (B6) and DBA/2J (D2) inbred strains and phenotyped using the same Affymetrix arrays. We have one forebrain and one striatum data set pair. We describe QTL replication at varying stringencies in these data. For instance, 78% of mRNA expression QTL (eQTL) with genome-wide adjusted p < or = 0.0001 in RI data replicate at a genome-wide adjusted p < 0.05 or better. Replicated QTL are disproportionately putatively cis-acting, and approximately 75% have higher apparent expression levels associated with B6 genotypes, which may be partly due to probe set generation using B6 sequence. Finally, we note that while trans-acting QTL do not replicate well between data sets in general, at least one cluster of trans-acting QTL on distal Chr 1 is notably preserved between data sets.

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PubMed2006

Rapid auditory processing and learning deficits in rats with P1 versus P7 neonatal hypoxic-ischemic injury.

Hypoxia-ischemia (HI) is associated with premature birth, and injury during term birth. Many infants experiencing HI later show disruptions of language, with research suggesting that rapid auditory processing (RAP) deficits (i.e., impairment in the ability to discriminate rapidly changing acoustic signals), play a causal role in language problems. We recently bridged these lines of research by showing RAP deficits in rats with unilateral-HI injury induced on postnatal days 1, 7, or 10 (P1, P7, or P10. While robust RAP deficits were found in HI animals, it was suggested that our within-age sample size did not provide sufficient power to detect age-at-injury differences within the pooled HI group. The current study sought to examine differences in neuropathology and behavior following unilateral-HI injury on P1 versus P7 in rats. Ages chosen for HI induction reflect differential stages of neurodevelopmental maturity, and subsequent regional differences in vulnerability to reduced blood flow/oxygen (modeling age-related differences in premature/term HI injury). Results showed that during the juvenile period, both P1 and P7 HI groups exhibited significant RAP deficits, but deficits in the P1 HI group resolved with repeated testing (compared to shams), while P7 HI animals showed lasting deficits in RAP and spatial learning/memory through adulthood. The current findings are in accord with evidence that HI injury during different stages of developmental maturity (age-at-injury) leads to differential neuropathologies, and provide the novel observation that in rats, P1 versus P7 induced pathologies are associated with different patterns of auditory processing and learning/memory deficits across the lifespan.

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PubMed2006

From genes to behavior in developmental dyslexia.

All four genes thus far linked to developmental dyslexia participate in brain development, and abnormalities in brain development are increasingly reported in dyslexia. Comparable abnormalities induced in young rodent brains cause auditory and cognitive deficits, underscoring the potential relevance of these brain changes to dyslexia. Our perspective on dyslexia is that some of the brain changes cause phonological processing abnormalities as well as auditory processing abnormalities; the latter, we speculate, resolve in a proportion of individuals during development, but contribute early on to the phonological disorder in dyslexia. Thus, we propose a tentative pathway between a genetic effect, developmental brain changes, and perceptual and cognitive deficits associated with dyslexia.

Animals↗

PubMed2006

Independent quantitative trait loci influence ventral and dorsal hippocampal volume in recombinant inbred strains of mice.

Anatomical and functional studies support segregation of the hippocampus into ventral and dorsal components along its septotemporal axis. However, it is unknown whether the development of these two components of the hippocampus is influenced by common or separate genetic factors. In this study, we used recombinant inbred strains of mice to determine whether the same or different quantitative trait loci (QTL) influence ventral and dorsal hippocampal volume. Using two sets of strains of recombinant inbred mice (BXD and AXB/BXA), we identified separate QTLs for ventral and dorsal hippocampal volume. In BXD mice, suggestive QTLs for ventral hippocampus were identified on chromosomes 2, 8 and 13, and a significant QTL for dorsal hippocampal volume was identified on chromosome 15. There was also a suggestive QTL for dorsal hippocampal volume on chromosome 13. In AXB/BXA mice, there were no significant or suggestive QTLs for ventral hippocampal volume, but a significant QTL for dorsal hippocampus was identified on chromosome 5. These findings suggest that the development of the ventral and dorsal components of the hippocampus is influenced by separate genetic loci.

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PubMed2005

Purkinje cell loss accompanies motor impairment in rats developing at altered gravity.

We have previously reported that the developmental exposure of rats to altered gravity (1.65 g) from gestational day 8 to postnatal day 21 impacts motor functions and cerebellar structure. The present study examined whether the decrease in cerebellar mass accompanied by impaired performance on a rotorod in hypergravity-exposed rats was related to a decrease in Purkinje cell number. The total number of Purkinje cells was determined on postnatal day 21 using a stereological analysis applied to paraformaldehyde-fixed cerebellar samples subsequently embedded in celloidin. Total Purkinje cell number was decreased by 17.7-25.3%. These results imply that exposure to altered gravity during Purkinje cell birth may affect their proliferation, resulting in a decrease in Purkinje cell number, which, in turn, leads to motor impairment.

Animals↗

PubMed2005

Auditory processing deficits in unilaterally and bilaterally injured hypoxic-ischemic rats.

Hypoxic-ischemic represents a common cause of damage to the prenatal brain and can co-occur with prematurity. Prematurity is associated with emergent language impairments, and it has been suggested that rapid auditory processing deficits play a causal role in language difficulties. We previously demonstrated rapid auditory processing deficits in juvenile rats receiving neonatal unilateral hypoxic-ischemic injury, but these deficits appeared to resolve by adulthood. The current study compared unilaterally and bilaterally injured hypoxic-ischemic rats on auditory tasks, to assess whether rapid auditory processing recovery in adulthood is related to this aspect of injury. Current results indicate that while neonatal unilateral and bilateral hypoxic-ischemic injury both lead to rapid auditory processing deficits in the juvenile period, only rats with bilateral hypoxic-ischemic injury exhibit deficits that persist into adulthood.

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PubMed2005

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

Pulmonary 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.

Aged↗

PubMed2005

Auditory processing deficits in rats with neonatal hypoxic-ischemic injury.

Hypoxia-ischemia (HI) refers to reduced blood oxygenation and/or a diminished amount of blood perfusing the brain, and is associated with premature birth/very low birth weight (VLBW). HI represents a common cause of injury to the perinatal brain. Indeed, a significant number of premature/VLBW infants go on to demonstrate cognitive/behavioral deficits, with particularly high incidence of disruptions in language development. Auditory processing deficits, in turn, have been suggested to play a causal role in the development of language impairments. Specifically, the inability to identify fast elements in speech is purported to exert cascading detrimental effects on phonological discrimination, processing, and identification. Based on this convergent evidence, the current studies address auditory processing evaluation in a rodent model of HI injury induced on postnatal days 1, 7, or 10 (which in turn is well accepted as modeling HI-related injury to the perinatal human). Induced injuries were followed by a battery of auditory testing, and a spatial maze assessment, performed both during juvenile and adult periods. Results indicate that rats suffering from these early HI insults performed significantly worse than shams on tasks requiring rapid auditory processing, and on a test of spatial learning (Morris water maze (MWM)), although these effects were not seen on simpler versions of auditory tasks or on a water escape assessment (thus ruling out hearing/motor impairments). Correlations were found between performance on rapid auditory and spatial behavioral tasks and neuroanatomical measures for HI animals such as: the volume of the hippocampus, cerebral cortex, ventricles, and/or the area of the corpus callosum. Cumulative findings suggest that perinatal HI injury in the rat may lead to neurodevelopmental damage associated, in turn, with auditory processing and/or learning and memory impairments. As such, the current model may have critical implications for the study of neurophysiological underpinnings of cognitive deficits in premature/VLBW infants.

Aging↗

PubMed2004

Impaired gap detection in juvenile microgyric rats.

Previous research with adult animal models links the presence of cortical neuromigrational anomalies (i.e., microgyria similar to that found in brains of dyslexics) with rapid auditory processing (RAP) impairments. RAP impairments are in turn found in children with specific language impairment (SLI) and also in individuals with dyslexia. Gap detection, a simple measure of auditory temporal acuity, appears to be impaired in children with SLI but not in dyslexic adults, even though both groups exhibit impaired processing on more complex, rapid auditory tasks. In the current study, juvenile rats with bilateral microgyria, but not their adult counterparts, exhibited impaired detection of short duration silent gaps in white noise when compared to age-matched sham littermates. Results lend further support to: (1) an association between neuromigrational anomalies and RAP impairments; and (2) the validity of an animal model of RAP impairments associated with language disturbances in humans. Current results also support the view that auditory processing disturbances associated with cortical malformations may be evident early in development at a relatively "low" level (e.g., simple gap detection), but may require "higher-order" auditory discrimination tasks (e.g., tone sequences, phonemic discriminations) to be elicited later in life.

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PubMed2004

Severity of focal microgyria and associated rapid auditory processing deficits.

Data from rodent models of induced microgyria suggest that bilateral damage leads to more severe rapid auditory processing deficits than unilateral damage. It is unclear whether this reflects the degree, or bilateral/unilateral nature, of damage. The current study evaluates the effects of microgyric severity by assessing rats with single- vs double-pair bilateral focal microgyric lesions, using auditory discrimination and MGN measures. Behavioral data show a significant auditory processing deficit on rapid processing tasks for microgyric as compared to control subjects, and also reveal more severe deficits for double- than for single-pair bilateral microgyrics. Greater disruptions are also seen in the MGN of double-pair compared to single-pair bilateral microgyric subjects.

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PubMed2004

Sex differences in rapid auditory processing deficits in microgyric rats.

Early neocortical injury has been associated with rate-specific auditory processing deficits using rodent models. In the few cases where females were studied, they appeared less vulnerable than males to the behavioral consequences of early neocortical injury. In the current study, male rats with neocortical microgyria were found to exhibit significant impairments in detecting tone sequences at short but not long inter-stimulus intervals (ISI) as compared to sham-operated male littermates. Microgyric females, however, performed similarly to sham-operated female littermates on this task at all durations. Current findings support an association between focal cortical malformations and impaired rapid auditory processing in males, and less vulnerability in females to the behavioral consequences of these malformations on a task eliminating confounds of motivation, experience, and estrus.

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PubMed2004

The Collaborative Cross, a community resource for the genetic analysis of complex traits.

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

Animals↗

PubMed2004

Surface alignment of an elastic body using a multiresolution wavelet representation.

An algorithm for nonlinear registration of an elastic body is developed. Surfaces (outlines) of known anatomic structures are used to align all other (internal) points. The deformation field is represented with a multiresolution wavelet expansion and is modeled by the partial differential equations of linear elasticity. A hierarchical approach that reduces algorithm complexity is adopted. The performance of the algorithm is evaluated by two-dimensional alignment of sections from mouse brains located in the olfactory bulbs. The registration algorithm was guided by manually delineated contours of a subset of brain structures and validated based on another subset of brain structures. The wavelet alignment algorithm produced a twofold to fivefold improvement in accuracy over an affine (linear) alignment algorithm.

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PubMed2003

Genetic control of interconnected neuronal populations in the mouse primary visual system.

Proliferation and survival of different cell types is thought to be modulated by cell interactions during development that achieve numerical and functional balance. We tested the precision of coregulation of numbers of neurons, glial cells, and endothelial cells in the dorsal lateral geniculate nucleus (LGN) in 58 isogenic strains of mice. We acquired matched counts of retinal ganglion cells (RGCs) in these strains and tested the precision of numerical matching between retina and LGN. Cells were counted using unbiased counting protocols and tissue from the Mouse Brain Library (www.mbl.org). Classification criteria were assessed using immunohistochemical criteria. The LGN contains an average of 17,000 neurons, 12,000 glial cells, and 10,000 endothelial cells. Variation around these means is typically twofold, and cell ratios vary widely. Strain differences in LGN volume correlate moderately well with glial cell number (r = 0.69) and less well with RGC number (r = 0.35) and with LGN neuron number (r = 0.32). Populations of LGN neurons and glial cells correlate only modestly (r = 0.44; p < 0.01). The single most surprising and unequivocal finding was the lack of any detectable correlation between populations of LGN neurons and RGCs, a correlation of merely 0.01 across 56 strains. In contrast, RGC number correlates significantly with LGN glial cell number, a surprising twist on the numerical matching hypothesis (r = 0.33; p < 0.01). We conclude that numbers of these two functionally coupled neuron populations are modulated over a wide range by independent genetic and developmental mechanisms.

Age Factors↗

PubMed2003

Quantitative trait loci modulate ventricular size in the mouse brain.

Cerebral ventricular size in humans varies significantly. Abnormal enlargement of the ventricles has been associated with schizophrenia, and hydrocephalus can lead to serious cognitive and motor deficiencies in humans and animals. In this study, we mapped quantitative trait loci (QTLs) modulating cerebroventricular size in mice. We hypothesized that genes underlying hydrocephalus might also modulate normal variation in ventricular size. By using digital images of mouse brain sections and stereological techniques, we estimated the volume of the combined lateral and third ventricles, as well as the volume of the entire brain, in 228 AXB and BXA recombinant inbred mice and their parent strains (A/J and C57BL/6J). Ventricle size, expressed as percentage of brain volume, is a heritable trait (h(2) = 0.32). We detected a major QTL controlling variance in volume on chromosome (Chr) 8 near the markers D8Mit94 and D8Mit189. We also detected a strong epistatic interaction affecting ventricular volume between loci on Chr 4 (near D4Mit237 and D4Mit214) and on Chr 7 (D7Mit178 and D7Mit191). These three QTLs, labeled Vent8a, Vent4b, and Vent7c, are close to genes that have been previously implicated in hydrocephalus.

Animals↗

PubMed2003

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.

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