L4) always appear devoid of retrotracing signal ( Dehay et al., 1986 Fame et al., 2011 Innocenti and Clarke, 1983 Innocenti et al., 1977 Meissirel et al., 1991 O'Leary et al., 1981). They found that, although there are more CPNs in young animals, they distribute following adult-like patterns the same areas and layers (e.g. To investigate this, researchers performed retrograde tracer injections in young developing animals. The next challenge was to address how adult CPN distribution arises during development. (E) Diffusion imaging (DI) can be used to visualize callosal tracts in animal models and humans. (D) 3D single neuron reconstructions allow the visualization of neuronal projections within the whole brain. GFP labeling allows the developmental behavior of transient or mature axons to be monitored throughout the midline and contralateral territories. (C) In utero electroporation allows in vivo genetic tracing and manipulation of specific cell types. Adult connectivity is then acquired after selective axonal refinement of these projections. This labeling revealed that most cortical neurons project callosally at early stages independently of their laminar identity. (B) In retrograde callosal injections, the retrograde molecules are injected directly into the CC. It also showed that the layer distribution of CPNs is similar at all developmental stages, and that L4 always appears devoid of retrograde labeling. This approach revealed that the number of CPNs is higher in younger animals (e.g. (A) Retrograde cortical injections can be used to label neurons whose axons are present within the area contralateral to that injected. Methodological approaches for identifying callosal projecting neurons (CPNs) and their axonal behavior. These adult callosal circuits have since been confirmed using various experimental approaches, including genetic tracing, viral injections and electrophysiology ( Tagawa et al., 2008 Rodríguez-Tornos et al., 2016 Petreanu et al., 2007 Wang et al., 2007). They also showed that distributions vary among the functional areas of the cortex: whereas some contain few CPNs, others, like secondary visual areas, have higher proportions ( Fame et al., 2011 Dehay et al., 1988 Innocenti, 1981). These experiments revealed that adult CPNs are predominantly located in L2/3 and L5, with fewer in L6, whereas L4 neurons are mostly devoid of labeling ( Fame et al., 2011 Suarez et al., 2014b). They reported the distribution of labeled somas in the opposite (contralateral) cortex ( Fig. 2A), recording in which of the six cortical layers (L1-6) the labeled cells were found. To identify the neurons that constitute interhemispheric connectivity, pioneering investigators in the 1970s injected axonal retrograde tracer molecules into the cortical plate of one hemisphere of mammalian animal models. As an example, physicians are unable to explain why the CC appears seemingly dispensable in some individuals with complete AgCC, while its loss has dramatic consequences in others. Moreover, the existence of yet to be understood plastic compensatory mechanisms entangles this task further and prevents any accurate prediction of how individuals, even when bearing the same mutations, will perform.
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We also understand very little about the origin of these problems, partly because the extremely broad spectrum of phenotypes complicates causal correlations between genetics and connectivity. Currently, however, researchers and clinicians are unable to predict exactly how structural defects in the CC impact the life and behavior of an individual. Both axonal refinement and myelination are instructed in an activity-dependent manner, demonstrating that CC development is a highly plastic process.ĬC alterations and/or altered patterns of interhemispheric activity appear in many neurodevelopmental disorders, including complete or partial CC agenesis (AgCC), autism spectrum disorders (ASD), schizophrenia, visual cortical impairments and epilepsy ( Aboitiz and Montiel, 2003). Finally, along with increasing myelination, contralateral projections that have invaded the cortical plate branch and remodel even further. Although some developmental callosal projections are maintained, a significant amount are refined.
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These pioneer axons serve to guide the subsequent axons of the bulk of cortical neurons. Then, cortical neurons of the cingulate cortex are the first ones to elongate their axons and cross along this path following specific guidance cues. First, after the fusion of the hemispheres, midline structures generate a route for interhemispheric axons. These studies have revealed that CC development begins at embryonic stages and continues during a protracted period of postnatal life as such, the CC takes longer than other circuits to develop. The development of the CC has mostly been inferred from animal models and from individuals with CC anomalies.