MECHANICAL CHANGES IN THE DEVELOPING BRAIN

描述（由申请人提供）：我们的目标是测量雪貂大脑皮层折叠过程中机械特性的空间、时间和方向变化。折叠的扰动会产生严重而持久的后果，但其机制尚不清楚。货车埃森（1997）假设轴突中的机械张力驱动皮质折叠。根据这一假说，大脑皮层中相互联系紧密的区域之间的张力会将这些区域拉到一起，产生一个向外的褶皱（脑回）;连接较弱的区域最终会被一个向内的褶皱（脑沟）分开。这种假设的机制鼓励紧凑的布线（货车埃森，1997）。为了评估这种理论模型，需要精确测量发育中大脑的残余应力、刚度和各向异性。方法：将在新生雪貂中进行研究。雪貂有一个回脑，在出生后的第一个月里经历折叠。力学性能将从实验数据结合有限元建模中找到。通过测量局部切割后的变形来估计残余应力。大脑的硬度特性将从剪切波速度和压痕分析来测量。扩散张量成像（DTI）将提供组织各向异性的数据，并将对运动蛋白（动力蛋白、驱动蛋白、肌球蛋白II、肌球蛋白V）的区域分布进行组织学评估。预计刚度和残余应力在空间上、时间上以及作为方向的函数而变化。这种变异在大脑形态发生中至关重要。具体目标：在新生雪貂脑中（1）测量不同位置和方向的局部残余应力;（2）成像不同方向的剪切波传播，以估计小变形的局部刚度和各向异性。(3)测量组织压痕过程中的力-位移关系;使用局部变形的逆建模来开发大应变的本构关系。(4)在折叠过程中进行DTI [和组织学]研究，以表征解剖学、显微结构和细胞变化。比较扩散和机械性质的空间、方向和发育变化。意义：这是建立包括生长在内的皮质折叠严格生物力学模型的第一步。需要这样的模型来理解病理的因果途径（例如，无脑回畸形、多小脑回畸形）导致精神残疾和疾病（发育迟缓、癫痫发作）。公共卫生相关性：大脑发育过程中皮质折叠的紊乱会产生严重而持久的后果，但其机制尚不清楚。该项目是发展包括生长在内的皮质折叠的严格生物力学模型的第一步。需要这样的模型来理解病理的因果途径（例如，无脑回畸形、多小脑回畸形）导致精神残疾和疾病（如发育迟缓、癫痫发作）。

DESCRIPTION (provided by applicant): Our objective is to measure spatial, temporal, and directional variations in mechanical properties of the ferret brain during cortical folding. Disturbances of folding have serious and lasting consequences, but the mechanism is not understood. Van Essen (1997) hypothesized that mechanical tension in axons drives cortical folding. According to this hypothesis, tension between strongly interconnected regions of the cortex pulls these regions together, generating an outward fold (gyrus); weakly-connected regions end up separated by an inward fold (sulcus). This hypothesized mechanism encourages compact wiring (Van Essen, 1997). To evaluate such theoretical models, accurate measurements of residual stress, stiffness, and anisotropy in the developing brain are needed. Approach: Studies will be performed in the neonatal ferret. The ferret has a gyrencephalic brain which undergoes folding during the first post-natal month. Mechanical properties will be found from experimental data combined with finite element modeling. Residual stress will be estimated by measuring deformation after local cuts. Stiffness properties of the brain will be measured from shear wave speed and analysis of indentation. Diffusion tensor imaging (DTI) will provide data on tissue anisotropy, and regional distribution of motor proteins (dynein, kinesin, myosin II, myosin V) will be assessed histologically. Stiffness and residual stress are expected to vary spatially, temporally, and as a function of direction. Such variations would be critically important in brain morphogenesis. Specific aims: In the neonatal ferret brain (1) Measure local residual stress in different locations and directions; (2) Image shear wave propagation in different directions to estimate local stiffness and anisotropy for small deformations. (3) Measure force-displacement relationships during indentation of tissue; use inverse modeling of local deformation to develop constitutive relationships for large strain. (4) Perform DTI [and histological] studies during folding to characterize anatomical, microstructural, and cellular changes. Compare spatial, directional, and developmental variations in diffusion and mechanical properties. Significance: This is the first step toward development of a rigorous biomechanical model of cortical folding, including growth. Such models are needed to understand the causal pathways of pathologies (e.g., lissencephaly, polymicrogyria) responsible for mental disability and disease (retardation, seizure). PUBLIC HEALTH RELEVANCE: Disturbances of cortical folding in brain development have serious and lasting consequences, but the mechanism is not well understood. This project is the first step toward development of a rigorous biomechanical model of cortical folding, including growth. Such models are needed to understand the causal pathways of pathologies (e.g., lissencephaly, polymicrogyria) responsible for mental disability and disease (such as retardation, seizure).