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.

抽象的在受许多神经发育影响的个体的大脑皮层中观察到的折叠模式疾病与典型发育的“对照”个体的疾病不同。人类大脑皮层折叠起来从妊娠中期到产后头几个月的时期。尽管人们知道很多大脑在这段时间内如何发育，包括增殖活动、许多细胞的形态成熟细胞类型、突触连接的建立、皮质电路的发育、宏观生长和大脑系统级的生理变化，但人们对这些变化之间的关系知之甚少成熟时产生正常或异常的折叠图案。我们认识上的缺陷细胞水平发育事件与宏观行为（生长和发育）之间的关系组织的生物力学特性）限制了我们解释给定折叠异常的能力神经发育来源，或对于特定的重要潜在病因而言神经发育障碍。该应用提出了一系列研究来链接高精度实验通过计算模拟来测量大脑生长和机械特性，以推进我们的研究了解影响大脑皮层折叠的生物力学因素。本次联合实验理论方法将用于分析雪貂大脑皮层的折叠。与人脑一样，雪貂的大脑在成熟时拥有脑回和脑沟，但与人类不同的是，这些褶皱是在出生后出现的雪貂。具体重点将放在初级视觉皮层内的枕颞沟 (OTS)，与其他脑沟相比，其折叠相对较晚，直到 P35 结束。最近，我们发现OTS 在经历过双边性手术的雪貂中，OTS 的形成受到严重影响（或者根本不形成 OTS）。 P7 去核。因此，生长和机械性能将通过视力控制（SC）来表征并在 P8 至 P38 的 6 个时间点对 P7 (BEP7) 雪貂进行双侧去核。该数据将是与大脑生长的多尺度理论和计算模型的发展相结合。在目标 1 中，将通过体内 MRI 在宏观尺度上表征生长，并通过测量如何在细胞水平上表征生长 P7 摘除会影响增殖动力学并改变细胞体和神经纤维体积。皮质折叠。在目标 2 中，将在同一年龄范围内量化组织的机械特性。剪切皮质灰质和发育白质的模量将使用原子力显微镜测定。将通过观察切口后的组织变形来测量组织应力。组织应力较小空间尺度将从原子核的形状和细胞的方向分布推断出来流程。在目标 3 中，目标 1 和 2 的实验数据将整合到组织生长模型中和变形，并且模型的有效性将通过观察其重演的能力来评估 SC 和 BEP7 雪貂之间折叠模式的差异。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Longitudinal MRI of the developing ferret brain reveals regional variations in timing and rate of growth.

发育中的雪貂大脑的纵向 MRI 显示了生长时间和速度的区域差异。

DOI：
发表时间：
2024-04-01
期刊：
影响因子：
0
作者：
Garcia, Kara E;Wang, Xiaojie;Santiago, Sarah E;Bakshi, Stuti;Barnes, Anthony P;Kroenke, Christopher D
通讯作者：
Kroenke, Christopher D