Connecting the mechanobiology of tissue and cells in cerebral cortical folding

摘要 受多种神经发育影响的个体大脑皮层的折叠模式 精神障碍不同于典型发展中的“对照”个体。人类的大脑皮层折叠起来 从怀孕中期到出生后的头几个月的时期。尽管很多人都知道 大脑在这段时间内是如何发育的，包括增殖活动，许多 细胞类型，突触连接的建立，皮质回路的发展，宏观生长，以及 大脑中系统水平的生理变化，对这些变化如何联系的了解相对较少 成熟时产生正常的或不正常的折叠图案。我们对……认识上的缺陷 细胞水平的发育事件与宏观行为之间的关系(生长和 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，或就潜在的致病因素而言，对特定的 神经发育障碍。这项申请提出了一系列研究，以联系高精度的实验 通过计算模拟测量大脑生长和力学特性，以提高我们的 了解影响大脑皮质折叠的生物力学因素。这项联合实验 并将理论方法用于分析雪貂大脑皮层的折叠。就像人脑一样， 雪貂的大脑在成熟时拥有脑回和脑沟，但与人类不同的是，这些皱折是在出生后 雪貂。具体的焦点将放在初级视觉皮质内的枕叶颞沟(OTS)上， 与其他脑沟相比，它的折叠相对较晚，到第35页结束。最近，我们发现OTS 在经历了双侧手术的雪貂中，形成受到严重影响(或者根本没有形成OTS) 术后第7天摘除眼球。因此，生长和机械性能将在目视对照(SC)中表征 在P7(BEP7)雪貂上从P8到P38的6个时间点进行双侧去核。该数据将是 与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， 生长将通过体内核磁共振在宏观尺度上进行表征，并通过测量如何在细胞水平上进行 P7核摘除影响细胞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，组织的机械性能将在相同的年龄范围内被量化。剪切 皮质灰质和发育中的白质的模数将使用原子力显微镜来确定。 组织应力将通过观察切开后的组织变形来测量。组织上的应力较小 空间尺度将从原子核的形状和细胞的取向分布中推断出来 流程。在目标3中，来自目标1和目标2的实验数据将被整合到组织生长模型中 和变形，并将通过观察其概括能力来评估模型的有效性 SC雪貂和BEP7雪貂折叠模式的差异。

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.