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.
Highlights
Thalamocortical (TH-C) connections are the major source of subcortical input to the cerebral cortex (Jones et al, 1994), and their development is a major focus of current experimental neurobiological (Ghosh and Shatz, 1993; Molnár et al, 1998a,b, 2012; Del Río et al, 2000; Skaliora et al, 2000; Sestan et al, 2001; O’Leary et al, 2007; Little et al, 2009; Chen et al, 2012; Jabaudon and López Bendito, 2012; Price et al, 2012; Garel and López-Bendito, 2014) and imaging studies of the human brain (Huang et al, 2006, 2009; Rados et al, 2006; Aeby et al, 2009; Metzger et al, 2010; Ball et al, 2012, 2013, 2015; Price et al, 2012; Alcauter et al, 2014; Kostovic et al, 2014; Nevalainen et al, 2014; Wang et al, 2015)
Experimental data show that the processes of initial outgrowth, pathfinding, and target selection of TH-C fibers involve complex cellular and molecular interactions, which include a variety of axonal guidance and signaling molecules regulated by specific sets of genes (Sestan et al, 2001; Polleux et al, 2007; Jabaudon and López Bendito, 2012; Molnár et al, 2012; Price et al, 2012; Frangeul et al, 2016)
The first phase of TH-C axon growth begins in the form of “pioneering” axonal fascicles as early as 7.5 postconceptional weeks (PCW) in the ventrolateral part of the thalamic anlage (Figures 2A,B,C), below the diencephalo-telencephalic sulcus, just across the caudal-basal division of the telencephalic ganglionic eminence
Summary
Experimental data show that the processes of initial outgrowth, pathfinding, and target selection of TH-C fibers involve complex cellular and molecular interactions, which include a variety of axonal guidance and signaling molecules regulated by specific sets of genes (Sestan et al, 2001; Polleux et al, 2007; Jabaudon and López Bendito, 2012; Molnár et al, 2012; Price et al, 2012; Frangeul et al, 2016). The large transient SP compartment is known as a “waiting” compartment for TH-C fibers (Rakic, 1977; Kostovic and Rakic, 1984, 1990; Bystron et al, 2008; Kostovic and Judas, 2010) and plays an important role in cortical circuit formation
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