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Connecting the mechanobiology of tissue and cells in cerebral cortical folding

连接大脑皮质折叠中组织和细胞的力学生物学

基本信息

批准号：
10619447
负责人：
PHILIP V BAYLY
金额：
$ 50.23万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619447
关键词：
3-Dimensional Affect Age Animal Model Animals Area Atomic Force Microscopy Attention deficit hyperactivity disorder Axon Behavior Bilateral Biological Biological Models Biomechanics Brain Cell Nucleus Cell physiology Cells Cellular biology Cerebral cortex Clinical Management Computer Models Computer Simulation Congenital Disorders Data Dendrites Development Developmental Process Diffusion Magnetic Resonance Imaging Disease Environmental Risk Factor Etiology Event Exhibits Ferrets Fetal Alcohol Spectrum Disorder Fresh Tissue Gene Expression Glial Cell Proliferation Growth Histologic Human Image Individual Knowledge Laws Life Link Magnetic Resonance Imaging Mathematics Measurement Measures Mechanical Stress Mechanics Microgyria Modeling Morphology Neurobiology Neurodevelopmental Disorder Neuroglia Neurologic Neuropil Nuclear Pattern Perinatal Phosphorus 32 Physics Physiological Pregnancy Premature Birth Process Production Proliferating Property Radial Sampling Schizophrenia Series Shapes Source Stress Structure Surface Surgical incisions Synapses System Temporal Sulcus Theoretical model Thick Time Tissue Model Tissues Translating Vision Visual Cortex Williams Syndrome area striata autism spectrum disorder biophysical model brain cell cell cortex cell growth cell type cellular development cohort experimental study gray matter improved in vivo lissencephaly mechanical properties migration multi-scale modeling nerve stem cell neurogenesis neuronal cell body p38 Mitogen Activated Protein Kinase postnatal postnatal development response stress state subventricular zone tissue stress tissue-level behavior white matter

项目摘要

ABSTRACT The folding patterns observed in the cerebral cortex of individuals affected by many neurodevelopmental disorders differ from those in typically-developing "control" individuals. The human cerebral cortex folds over the period from the middle of gestation through the first months of postnatal life. Although much is known about how the brain develops over this time period, including proliferative activity, morphological maturation of many cell types, establishment of synaptic connections, development of cortical circuitry, macroscopic growth, and system-level physiological changes in the brain, relatively little is understood about how these changes relate to the production of a normal, or abnormal, folding pattern at maturity. Shortcomings in our understanding of the relationship between cellular-level developmental events and macroscopic behavior (growth and biomechanical properties of tissue) limit our ability to explain a given folding abnormality in terms of its neurodevelopmental source, or in terms of potential etiological factors important for a specific neurodevelopmental disorder. This application proposes a series of studies to link high-precision experimental measures of brain growth and mechanical properties with computational simulations to advance our understanding of the biomechanical factors that influence cerebral cortical folding. This combined experimental and theoretical approach will be used to analyze folding of the ferret cerebral cortex. As with the human brain, the ferret brain possesses gyri and sulci at maturity, but in contrast to humans, these folds arise postnatally in ferrets. Specific focus will be placed on the occipital temporal sulcus (OTS), within the primary visual cortex, which folds relatively late compared to other sulci, concluding by P35. Recently, we have discovered that OTS formation is severely affected (or that the OTS does not form at all) in ferrets that have undergone bilateral enucleation at P7. Growth and mechanical properties will therefore be characterized in sighted control (SC) and bilaterally enucleated on P7 (BEP7) ferrets at 6 time points ranging from P8 through P38. This data will be integrated with the development of a multiscale theoretical and computational model of brain growth. In Aim 1, growth will be characterized on a macroscopic scale by in vivo MRI, and on a cellular level by measuring how P7 enucleation affects proliferation dynamics and changes cell body and neuropil volumes over the period of cortical folding. In Aim 2, mechanical properties of the tissue will be quantified over the same age range. Shear moduli of cortical gray matter and developing white matter will be determined using atomic force microscopy. Tissue stress will be measured by observing tissue deformations following incisions. Tissue stress on a smaller spatial scale will be inferred from the shapes of nuclei and from the orientation distributions of cellular processes. In Aim 3, the experimental data from Aims 1 and 2 will be integrated into a model of tissue growth and deformation, and the validity of the model will be evaluated by observing its ability to recapitulate differences in folding patterns between SC and BEP7 ferrets.

摘要