Sagittally oriented fiber systems of the early fetal cerebral wall are the main constituents of the IZ, defined as cerebral fibrillar compartments (Angevine et al.
1970); (Kostović et al.
2002a; Bystron et al.
2008; Kostović and Judaš
2015). This fibrillar cerebral compartment/zone actually forms sagittally and tangentially oriented “corridors” for bundles of projection axons destined for remote polar portions of the cerebral hemispheres. Within these “corridors”, axonal bundles show stratification (Zecevic and Verney
1995; Del Río et al.
2000; Kostović et al.
2002a), which is probably a result of the combined influence of sequential, time-scheduled growth of different classes of axonal pathways (Kostović and Judaš
2007,
2015; Kostović et al.
2014b), the maintenance of axonal fasciculation through different internal molecular mechanisms and externally available guidance molecules (Tessier-Lavigne
1992; Judaš et al.
2003; Charron
2005). Cellular and molecular mechanisms governing growth through sagittal “corridors” of the IZ are largely unexplored in the human brain. However, our current data show that borders (walls) of “corridors” for axonal growth contain characteristically aligned cells (“corridor” cells), which express some of the glial markers and may provide structural and molecular support for axonal growth through the axonal SS towards target polar areas. In addition, our data indicate that there is a structural, spatial (“compartmental”) framework for axonal growth, in addition to the molecular mechanisms described in the previous experimental literature (Tessier-Lavigne
1992), which exists from the early life and determines the laminar position of the main afferent system in IZ; thalamic afferents occupy intermediate and deep positions in the IZ (Kostović and Goldman-Rakić
1983; Kostović and Rakić
1984; Vasung et al.
2010,
2017; Krsnik et al.
2017), while basal forebrain afferents form (more superficial) the ESS which is in the continuity with the external capsule (Kostović and Rakić
1984; Kostović
1986; Kostović et al.
2002a). This presumably cholinergic projection was also previously identified and visualized in the adult human brain (Selden
1998). In the present study, we further confirm the advantages of using transient AChE histochemical staining to study the growth of thalamocortical and basal forebrain fibers (Kostović and Goldman-Rakić
1983; Kostović and Rakić
1984; Kostović
1986; Kostović and Judaš
2010). However, in the present study, we also study other transient chemical features of the fiber-rich IZ, such as the early immunostaining for SNAP25 and synaptophysin. Synaptophysin was detected in the fibers of the IZ, which is devoid of synapses (Molliver et al.
1973; Kostović and Rakić
1990), indicating that synaptophysin reactivity in the IZ and the SVZ is not, at that specific time, related to synaptic distribution (not shown). Transient staining of fibrillar zones using synaptic markers was also described in human fetal material by Bayatti et al. (
2008) and Sarnat (
2013). Such histochemical and immunocytochemical techniques cannot, however, detect cortical long-efferent projection pathways, which also develop during comparative phases of fetal development (Eyre et al.
2000; Eyre
2003; Staudt
2007), after the first pioneer projection (Meyer et al.
2000) has already established. The continuity of sagittally running (projection, commissural, and associative) fibers within the common fibrillar “corridor” raises the question of developmental sequence and time overlap in respect of the growth of different fiber systems. The sequential ingrowth of afferent fiber systems, observed in the present study, is in accordance with the previous studies of the developing human brain (Marin-Padilla
1970; Nobin and Björklund
1973; Olson et al.
1973; Mrzljak et al.
1988; Zecevic and Verney
1995; Kostović et al.
2002a; Judaš et al.
2005; Kostović and Judaš
2007). The first efferent pioneer projection originating from calretinin-reactive cells of the pioneer neurons (Meyer et al.
2000) also takes a course within the IZ. However, the first robust fiber system constituting the IZ and the SS is projection fibers from the thalamus (Molliver et al.
1973; Kostović and Goldman-Rakić
1983; Kostović and Rakić
1984; Kostović and Judaš
2010; Krsnik et al.
2017) and efferent cortical fibers (Eyre et al.
2000; Vasung et al.
2010,
2011), as well as projection fibers from the basal forebrain (Kostović
1986). The early development of thalamocortical fibers is consistent with our observation relating to the early dispersion of the SVZ. Within the thalamocortical projection system, the early development of primary visual projection from the lateral geniculate body was first demonstrated by Hevner (
2000) and more recently by Vasung et al. (
2017), and projection from pulvinar was documented by Kostović and Rakić (
1984). The callosal system (Ren et al.
2006) runs periventriculary in the PVFZ (Kostović et al.
2002a; Vasung et al.
2011). The fiber system within the deep SVZ was also described as inner fibrillar layer (IFL) by Smart et al.
2002, using histological sections prepared from the primate brain, although not specifically attributed to the CC, and it was marked correctly on sections from the Yakovlev collection (Rakić and Yakovlev 1968; Bayer and Altman
1991; Wang et al.
2015). According to the anatomical description of the adult human brain presented in the classical literature, callosal fibers, which form forceps in both an anterior and posterior direction, run for a considerable distance around the ventricles in sagittal directions, to form the tapetum in the occipital lobe (Sachs
1892; Déjerine
1895; Von Monakow
1905; Polyak
1957; Hosoya et al.
1998; Schmahmann and Pandya
2006). In the present study, we found that sagittally running callosal fibers markedly delineate the ISS on the medial side of the occipital lobe, gradually invading the PVFZ and SVZ around 15 PCW. More precisely, callosal fibers split the deepest portion of the SVZ, adjacent to the VZ. The occipital extension of the CC in PVFZ appears to be more pronounced in the human brain compared to other species and seems to be absent in the rodent brain (Smart et al.
2002).
There is a general agreement that long associative pathways for the lateral aspect of hemispheres develop relatively late in fetal life (Catani et al.
2003; Huang et al.
2006; Kostović and Jovanov-Milošević
2006; Kasprian et al.
2008; Vasung et al.
2010,
2017; Takahashi et al.
2012). However, evidence from a previous MR tractographic study supports the idea that the main trajectory of all long associative pathways is visible by birth (Kasprian et al.
2008; Vasung et al.
2017). Of all associative pathways, the inferior frontoocciptal fascicle (iFOF) shows the closest association with the SS. Other associative pathways are lateral or more ventral from the SS. Indeed, the iFOF develops in the lower (ventral) extension of the EC, and has been described as an associative pathway (Takahashi et al.
2012; Huang and Vasung
2014; Mitter et al.
2015). We have clearly demonstrated that the main portion of the EC, and its radiation, contains projection fibers from the cholinergic basal forebrain (Kostović
1986) and develops at least two months earlier than the associative pathways. Within the ESS, the associative iFOF develops later within the EC showing the same fan-like radiation as the primordial EC.