Axons Pull on the Brain, But Tension Does Not Drive Cortical Folding

Abstract

During human brain development, the cerebral cortex undergoes substantial folding, leading to its characteristic highly convoluted form. Folding is necessary to accommodate the expansion of the cerbral cortex; abnormal cortical folding is linked to various neurological disorders, including schizophrenia, epilepsy, autism and mental retardation. Although this process requires mechanical forces, the specific force-generating mechanisms that drive folding remain unclear. The two most widely accepted hypotheses are (1) folding is caused by differential growth of the cortex and (2) folding is caused by mechanical tension generated in axons. Direct evidence supporting either theory, however, is lacking. Here we show that axons are indeed under considerable tension in the developing ferret brain, but the patterns of tissue stress are not consistent with a causal role for axonal tension. In particular, microdissection assays reveal that significant tension exists along axons aligned circumferentially in subcortical white matter tracts, as well as those aligned radially inside developing gyri (outward folds). Contrary to previous speculation, however, axonal tension is not directed across developing gyri, suggesting that axon tension does not drive folding. On the other hand, using computational (finite element) models, we show that differential cortical growth accompanied by remodeling of the subplate leads to outward folds and stress fields that are consistent with our microdissection experiments, supporting a mechanism involving differential growth. Local perturbations, such as temporal differences in the initiation of cortical growth, can ensure consistent folding patterns. This study shows that a combination of experimental and computational mechanics can be used to evaluate competing hypotheses of morphogenesis, and illuminate the biomechanics of cortical folding.

The mechanical control of nervous system development

“…In support of this hypothesis, the experimental reduction of proliferation in the outer subventricular zone leads to a reduction in cortical folding (Reillo et al, 2011). The application of finite element models confirmed that differential cortical growth together with remodeling of the subplate might explain cortical folding and the stress patterns found in brain tissue (Xu et al, 2010). Furthermore, it was shown that removal of the cerebral cortex affects the folding pattern of the remaining brain (Welker, 1990).…”

“…Tension exists along axons aligned radially inside the developing gyri and circumferentially in subcortical white matter tracts, but tension is not directed across the developing gyri (Xu et al, 2010). The observed relaxation after cutting was suggested to be attributable to enhanced growth in the gray matter compared with white matter (Xu et al, 2009).…”

“…From the initiation of neurite growth, to the establishment of synaptic connections with a target cell, to the formation of stable neuronal networks, neuronal processes are constantly under tension in vitro (Bray, 1979;Heidemann and Buxbaum, 1994) and in vivo (Gilmour et al, 2004;Siechen et al, 2009;Xu et al, 2010). Tension above or below a certain threshold stimulates neurite extension or retraction, respectively (Fig.…”

“…Thus, tension might serve as a signal for axonal and dendritic survival, and reduced tension might, therefore, contribute to branch pruning (Franze et al, 2009). Accordingly, the orientation of apical dendrites of pyramidal neurons in the cortex and the degree of their dendritic and axonal arborization depends on their location relative to the curvature of the tissue (Welker, 1990), and thus probably on local tension (Xu et al, 2010). Once the neuronal network is connected, the buildup of mechanical tension will lead to a shortening of the involved neuronal processes, thus contributing to the compactness of neural circuitry (Van Essen, 1997).…”

Not just inductive: a crucial mechanical role for the endoderm during heart tube assembly

“…The tensor G changes the zero-stress configuration of each material element (akin to thermal contraction of a passive material), and F* generates mechanical stress by both enforcing geometric compatibility between material elements and accounting for the elastic response of the material to any applied loads. This theory has been used to model several different morphogenetic processes, including head fold formation (Varner et al, 2010) and cardiac c-looping (Voronov et al, 2004;Ramasubramanian et al, 2006) in the chick embryo, cortical folding in the developing ferret brain (Xu et al, 2010), and ventral furrow formation in Drosophila (Muñoz et al, 2007;Muñoz et al, 2010). …”