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.
Individuals affected by many different neurodevelopmental disorders of widely varying, or even unknown cause, often exhibit abnormal patterns of brain folding. In principle, the folding pattern could provide information related to the developmental processes responsible for these neurodevelopmental disorders; however to date, little is known about the mechanics of folding. The objective of this proposal is to understand how maturation of brain cells contributes to biomechanical processes that drive folding of the cerebral cortex during development, using experimental and computational approaches to investigate folding in a controlled animal model system.
