Studies using the magnetic resonance imaging (MRI) technique termed diffusion tensor imaging (DTI) have found that fractional anisotropy (FA) is reduced in cerebral white matter (WM) of mature individuals affected by disorders either of genetic (e.g. Rett syndrome, phenylketonuria), environmental (e.g. fetal alcohol spectrum disorder, premature birth), or multifactorial (e.g. autism, schizophrenia) origin. While these results imply that there are neural structural differences between affected individuals and age-matched controls, the nature of these structural differences at the cellular level remains unknown. We propose to develop an experimental model to investigate the cellular bases of both WM and cerebral cortical changes in FA that are induced by neurodevelopmental disorders. The disorder we chose to study is neonatal bilateral enucleation because this manipulation is known to induce abnormal patterns of neural connections in the visual cortex of altricial species such as rodents and ferrets. We chose ferrets because they have a relatively large cerebral WM to gray matter (GM) ratio, which makes it possible to apply diffusion anisotropy data analysis procedures of relevance to human studies. Based on preliminary observations of changes in both WM and cerebral cortex FA in neonatally enucleated ferrets, we hypothesize that changes in WM FA arise from abnormalities of myelin/glia, or changes in the divergence/convergence of axonal projections, or both. To test this hypothesis, DTI measurements will be performed on post-mortem brains of control and enucleated adult animals. Fractional anisotropy values from visual WM will be compared to Toluidine blue-based measurements of myelination, and to retrograde tracer-based measurements of axonal convergence/divergence. In addition, we hypothesize that changes in cortical GM FA reflect changes in the distribution of axonal and dendritic neuronal processes in the neuropil. This hypothesis stems from an analytical model that we recently developed to relate diffusion anisotropy in the cerebral cortex (expressed as FA) to anisotropy in the distribution of axonal and dendritic neuronal processes in the neuropil (expressed as FAN). We will test this model by comparing FA measurements taken from post-mortem ferret brains at five ages spanning postnatal day (P)6 to P45, to measurements of FAN of dendrites and axons labeled in the same tissue by the application of Golgi and anatomical tracing procedures. We will also characterize the developmental profile of the relationship between FA and FAN following early enucleation. The results are expected to demonstrate that DTI can be used to detect early manifestations of neurodevelopmental disorders in cerebral cortex, potentially prior to the loss of central nervous system plasticity. The proposed experiments will advance our understanding of the cellular changes underlying abnormalities in diffusion anisotropy in both WM and GM. This knowledge will not only facilitate monitoring the integrity of developing neural projections, but also the formulation of therapeutic strategies to counteract deleterious effects that neurodevelopmental disorders on brain development.

Public Health Relevance

Magnetic resonance imaging (MRI) can be used to detect brain anatomical abnormalities in individuals affected by a diverse array of neurodevelopmental disorders, but it is not capable of characterizing these abnormalities in detail. We therefore propose to combine MRI experiments with traditional cellular-anatomical measurements on an animal model of neurodevelopmental disorders to provide a framework for interpreting MRI findings. We will also use this experimental strategy to expand the capabilities of MRI to studies of earlier stages of brain development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS070022-02
Application #
8039920
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Gnadt, James W
Project Start
2010-03-15
Project End
2014-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
2
Fiscal Year
2011
Total Cost
$255,137
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Organized Research Units
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Andelin, Adrian K; Bruning, David J; Felleman, Daniel J et al. (2015) Visual Interhemispheric and Striate-Extrastriate Cortical Connections in the Rabbit: A Multiple Tracer Study. Neurol Res Int 2015:591245
Wang, Xiaojie; Pettersson, David R; Studholme, Colin et al. (2015) Characterization of Laminar Zones in the Mid-Gestation Primate Brain with Magnetic Resonance Imaging and Histological Methods. Front Neuroanat 9:147
Khan, Ahmad Raza; Cornea, Anda; Leigland, Lindsey A et al. (2015) 3D structure tensor analysis of light microscopy data for validating diffusion MRI. Neuroimage 111:192-203
Bayly, P V; Taber, L A; Kroenke, C D (2014) Mechanical forces in cerebral cortical folding: a review of measurements and models. J Mech Behav Biomed Mater 29:568-81
Leigland, Lindsey A; Budde, Matthew D; Cornea, Anda et al. (2013) Diffusion MRI of the developing cerebral cortical gray matter can be used to detect abnormalities in tissue microstructure associated with fetal ethanol exposure. Neuroimage 83:1081-7
Dean, Justin M; McClendon, Evelyn; Hansen, Kelly et al. (2013) Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure through disturbances in neuronal arborization. Sci Transl Med 5:168ra7
Leigland, Lindsey A; Ford, Matthew M; Lerch, Jason P et al. (2013) The influence of fetal ethanol exposure on subsequent development of the cerebral cortex as revealed by magnetic resonance imaging. Alcohol Clin Exp Res 37:924-32
Knutsen, Andrew K; Kroenke, Christopher D; Chang, Yulin V et al. (2013) Spatial and temporal variations of cortical growth during gyrogenesis in the developing ferret brain. Cereb Cortex 23:488-98
Hansen, Mikkel B; Jespersen, Sune N; Leigland, Lindsey A et al. (2013) Using diffusion anisotropy to characterize neuronal morphology in gray matter: the orientation distribution of axons and dendrites in the NeuroMorpho.org database. Front Integr Neurosci 7:31
Jespersen, Sune Norhoj; Leigland, Lindsey A; Cornea, Anda et al. (2012) Determination of axonal and dendritic orientation distributions within the developing cerebral cortex by diffusion tensor imaging. IEEE Trans Med Imaging 31:16-32

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