Growth of Thalamocortical Fibers to the Somatosensory Cortex in the Human Fetal Brain

Abstract

Thalamocortical (TH-C) fiber growth begins during the embryonic period and is completed by the third trimester of gestation in humans. Here we determined the timing and trajectories of somatosensory TH-C fibers in the developing human brain. We analyzed the periods of TH-C fiber outgrowth, path-finding, “waiting” in the subplate (SP), target selection, and ingrowth in the cortical plate (CP) using histological sections from post-mortem fetal brain [from 7 to 34 postconceptional weeks (PCW)] that were processed with acetylcholinesterase (AChE) histochemistry and immunohistochemical methods. Images were compared with post mortem diffusion tensor imaging (DTI)-based fiber tractography (code No NO1-HD-4-3368). The results showed TH-C axon outgrowth occurs as early as 7.5 PCW in the ventrolateral part of the thalamic anlage. Between 8 and 9.5 PCW, TH-C axons form massive bundles that traverse the diencephalic-telencephalic boundary. From 9.5 to 11 PCW, thalamocortical axons pass the periventricular area at the pallial-subpallial boundary and enter intermediate zone in radiating fashion. Between 12 and 14 PCW, the TH-C axons, aligned along the fibers from the basal forebrain, continue to grow for a short distance within the deep intermediate zone and enter the deep CP, parallel with SP expansion. Between 14 and 18 PCW, the TH-C interdigitate with callosal fibers, running shortly in the sagittal stratum and spreading through the deep SP (“waiting” phase). From 19 to 22 PCW, TH-C axons accumulate in the superficial SP below the somatosensory cortical area; this occurs 2 weeks earlier than in the frontal and occipital cortices. Between 23 and 24 PCW, AChE-reactive TH-C axons penetrate the CP concomitantly with its initial lamination. Between 25 and 34 PCW, AChE reactivity of the CP exhibits an uneven pattern suggestive of vertical banding, showing a basic 6-layer pattern. In conclusion, human thalamocortical axons show prolonged growth (4 months), and somatosensory fibers precede the ingrowth of fibers destined for frontal and occipital areas. The major features of growing TH-C somatosensory fiber trajectories are fan-like radiation, short runs in the sagittal strata, and interdigitation with the callosal system. These results support our hypothesis that TH-C axons are early factors in SP and CP morphogenesis and synaptogenesis and may regulate cortical somatosensory system maturation.

Sublaminar organization of the human subplate: developmental changes in the distribution of neurons, glia, growing axons and extracellular matrix

“…AChE fibrillar staining showed predominant activity in the deep SP, which corresponds to the ingrowth of thalamo‐cortical and basal forebrain afferents (Kostović & Goldman Rakić, ; Kostović & Rakić, ; Krsnik et al. ; Žunić Išasegi et al. ).…”

“…; Kostović & Rakić, ; Kostović & Judaš, ; Krsnik et al. ) and may be correlated with the presence of synaptic strata, where the most dense concentration of synapses is found in the superficial third of the SP and where axons actually make more frequent contacts during the ‘waiting period’ (Rakić, ; Kostović & Rakić, ). We refer to the concomitant development of AChE reactivity and synaptic markers in the SP and CP as presented in this study.…”

“…; Krsnik et al. ) and their complex connections during protracted intrauterine development. During growth, afferent fibers may change position within the SP in radial (‘subpial depth’) and tangential direction, and contact postsynaptic elements of SP neurons at different positions (considering layer depth), forming transient or permanent synapses (Molliver et al.…”

Mental development is associated with cortical connectivity of the ventral and nonspecific thalamus of preterm newborns

“…By this time, the first TC fibers have already reached the cortex [Kostovic and M. Judas, 2002;Kostovic and N. Jovanov-Milosevic, 2006], and the brain has progressed to a stage of rapid development, characterized by nonlinear increase in brain volume and an increase in synaptic density. Human thalamocortical axons show prolonged growth (4 months), and somatosensory fibers precede the ingrowth of fibers destined for frontal and occipital areas [Krsnik et al, 2017]. At term-equivalent age, the topography of thalamocortical connections largely resembles that of an adult [Ferradal et al, 2019].…”

Novel imaging techniques to study postmortem human fetal anatomy: a systematic review on microfocus-CT and ultra-high-field MRI

“…The diffusion of water in tissues, probed by diffusion tensor imaging (DTI) offers another source of contrast, particularly suited to characterize tissue with a strong structural alignment such as brain white matter. DTI has proven to be a valuable tool in imaging white matter fibers, allowing the study of the formation and orientation of white matter in fetuses [38][39][40][41].…”