QTL mapping of cell number in the mouse CNS
Informatics Center for Mouse Genomics
Animal Models of Learning Disabilities
Early H-I Brain injury and behavioral outcome in rats
Funded Projects of the Rosen Lab
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QTL mapping of cell number in the mouse CNS |
Informatics Center for Mouse Genomics |
Animal Models of Learning Disabilities |
Early H-I Brain injury and behavioral outcome in rats |
The cerebral cortex plays an essential role in the integration of higher cognitive functions, while the striatum is intimately involved in the coordination of movement and executive function. A variety of developmental disorders have been associated with perturbations of these anatomic regions, including developmental dyslexia, autism, schizophrenia, Tourette's syndrome, and bipolar disorders to name but a few. This proposal seeks to map quantitative trait loci (QTL) that modulate absolute and relative magnitudes of glial and neuronal cell numbers and regional volume in both the neocortex and striatum of the mouse. Using a genetic reference population, classic QTL mapping techniques, bioinformatic haplotype mapping, and microarray analysis of gene expression profiles, a small but important set of genes that are responsible for some of the remarkable quantitative differences seen among inbred strains of mice will be mapped. The following questions will be addressed:
To answer these questions, highly accurate, unbiased, and efficient estimates of cell number and volume will be assessed by stereology. These traits will be mapped using GeneNetwork, a public online resource for the investigation of systems genetics. The QTL intervals thus defined will be narrowed using haplotype maps derived from sequence databases of the two parent strains, and by the creation of a database of gene expression levels of the BXD recombinant inbred set at different stages of development. All data gathered from these experiments will be added to GeneNetwork and will be publicly accessible. The questions addressed in the proposal have important implications for a number of disease states, including a variety of developmental disorders. The extension of current transcriptome databases to encompass gene expression analysis at various stages of development will enable a systems genetic approach to understanding fundamental aspects of brain development.
The purpose of this Human Brain Project is to develop and enhance a suite of Web accessible resources and analytic tools that are being used to study the underlying genetic bases for molecular, structural, and functional variation of the CNS. Our resources include extensive digital image repositories, massive transcriptome data sets, and two decades worth of legacy phenotype data that are completely open to the research community through web sites at nervenet.org, mbl.org, www.webqtl.org, and www.neuroterrain.org. The Informatics Center for Mouse Neurogenetics provides a unique research environment for exploring and synthesizing complex data sets across scales—from SNP polymorphisms and variation in gene expression, through to neuroanatomical, cellular, physiological, and behavioral traits. We rely on an essentially immortal reference panel that consists of 80 BXD recombinant inbred strains generated by crossing mouse strains that have both been sequenced. We will extend four significant resources and technologies:
The Mouse Brain Library (MBL) consists of a large digital library of images suitable for online structural and stereological analysis of the CNS. Images can be rapidly searched, sorted, and downloaded at a resolution of 0.2–5.0 microns per pixel using an intuitive and powerful Web interface. This project is the responsibility of the Rosen Lab.Achieving the aims of these four projects will catalyze a new approach to studying the nervous system and will lead to novel lines of research on the development, normal function, and disease mechanisms that affect the human brain.
The aim of the proposed research is to deepen our understanding of some of the biological substrates of developmental dyslexia. It concerns both the difficulties many dyslexics and other language-impaired individuals have with processing rapidly changing sounds, and the cognitive difficulties they experience. Over the past 15 years, we have developed an animal model that allows us to address both of these issues.
The dyslexic cerebral cortex is characterized by focal cortical malformations the likes of which can be induced in rats. These induced malformations are associated with anatomic, physiologic, and behavioral defects similar to those seen in dyslexics. We hypothesize that these malformations alter the developmental molecular milieu, which in turn leads to changes in neuronal growth and survival. They cause abnormal differentiation of NMDA and GABA receptors, changes in trophic activity, and disruption of developmentally regulated plasticity. They corrupt functional auditory maps and cortico-cortical and thalamo-cortical circuits, which in turn leads to disorders of perceptual and cognitive auditory processing. Some of these effects are sexually dimorphic.
We propose a deeply interactive, cross-level approach linking structure, systems and cell physiology, and behavior to investigate these hypotheses. Following early injury to the cortical plate we will look at the changes in types, locations, and numbers of cortical and thalamic neurons, receptors, and connections. We will examine the effects of pharmacologic manipulation on these structural parameters, as well as on physiology and behavior. We will study the effect of microgyria on the normal patterns of, and experience-dependent changes in, synaptic plasticity. We will determine the mechanisms underlying changes in neocortical synaptic plasticity. We will develop rapid and robust techniques for assessing temporal receptive field abnormalities in altered animals, and will determine how temporal spectral properties are represented in individual auditory cortical neurons. We will delineate the anatomical pathways mediating the auditory processing deficits in microgyric animals. We will elaborate on acoustic stimulus and task parameters that elicit processing deficits in the microgyric rats and will examine the factors known to affect expression of the behavioral deficits. Finally, we will assess the neural mechanisms underlying the association between microgyria and processing deficits, via exogenous experimental manipulations; and, we will begin to examine the visual temporal processing deficits in the animal model.
Neurological impairment due to oxygen deprivation (hypoxia/ischemia or HI) is a common mechanism of damage to the premature and/or very low birth-weight (VLBW) infant brain. Such injuries contribute to a significant increase in the incidence of long-term behavioral and cognitive deficits (such as language and learning disabilities) among premature/VLBW populations. However, many factors impede a direct assessment of neurodevelopmental trends in this population. For example, precise details on timing, extent, and location of brain damage are often difficult to obtain in neonates, limiting the ability to statistically assess relationships between HI injury and long term outcome. Fortunately related research has shown that neonatal induction of HI injuries in rodents produces a neuropathology strikingly similar to that seen in human premature/VLBW neonates. Several reports show a decrement in learning and cognitive skill for rats with neonatal HI injuries, but no research of which we are aware has examined the impact of experimental manipulations of injury on long term outcome using a variety of functional assessments -- the central aim of this proposal. Specifically, the studies proposed here will assess the consequences of timing and severity of an induced neonatal HI injury (measured by age at injury and duration of hypoxia) on cognitive/behavioral outcome in a rat model. We will also assess interactions between HI injury and sex, based on clinical evidence of gender differences in response to HI injury, as well as potential ameliorative effects of a neuroprotective agent on long-term behavioral outcome and neuropathology. Dependent variables will include behavioral measures (sensory processing indices, and spatial and non-spatial learning indices, from juveniles and adults), electrophysiological indices, and post mortem anatomical indices. Convergent data will allow for a comprehensive statistical assessment of the impact of experimental variables on functional and anatomical outcome, as well as correlations between function and anatomy. Our findings will contribute general information to the field of neurodevelopmental assessment, with specific implications for clinical treatment of premature/VLBW infants. Future applications may include improvements in cognitive outcome predictions following HI injury, as well as increased insight on amelioration treatment and therapy for infants suffering early HI injuries.