Refinement of the Primate Corticospinal Pathway During Prenatal Development.

Perturbation of the developmental refinement of the corticospinal (CS) pathway leads to motor disorders. While non-primate developmental refinement is well documented, in primates invasive investigations of the developing CS pathway have been confined to neonatal and postnatal stages when refinement is relatively modest. Here, we investigated the developmental changes in the distribution of CS projection neurons in cynomolgus monkey (Macaca fascicularis). Injections of retrograde tracer at cervical levels of the spinal cord at embryonic day (E) 95 and E105 show that: (i) areal distribution of back-labeled neurons is more extensive than in the neonate and dense labeling is found in prefrontal, limbic, temporal, and occipital cortex; (ii) distributions of contralateral and ipsilateral projecting CS neurons are comparable in terms of location and numbers of labeled neurons, in contrast to the adult where the contralateral projection is an order of magnitude higher than the ipsilateral projection. Findings from one largely restricted injection suggest a hitherto unsuspected early innervation of the gray matter. In the fetus there was in addition dense labeling in the central nucleus of the amygdala, the hypothalamus, the subthalamic nucleus, and the adjacent region of the zona incerta, subcortical structures with only minor projections in the adult control.

Unique Features of Subcortical Circuits in a Macaque Model of Congenital Blindness.

There is an extensive modification of the functional organization of the brain in the congenital blind human, although there is little understanding of the structural underpinnings of these changes. The visual system of macaque has been extensively characterized both anatomically and functionally. We have taken advantage of this to examine the influence of congenital blindness in a macaque model of developmental anophthalmia. Developmental anophthalmia in macaque effectively removes the normal influence of the thalamus on cortical development leading to an induced "hybrid cortex (HC)" combining features of primary visual and extrastriate cortex. Here we show that retrograde tracers injected in early visual areas, including HC, reveal a drastic reduction of cortical projections of the reduced lateral geniculate nucleus. In addition, there is an important expansion of projections from the pulvinar complex to the HC, compared to the controls. These findings show that the functional consequences of congenital blindness need to be considered in terms of both modifications of the interareal cortical network and the ascending visual pathways.

How Areal Specification Shapes the Local and Interareal Circuits in a Macaque Model of Congenital Blindness.

There is little understanding of the structural underpinnings of the functional reorganization of the cortex in the congenitally blind human. Taking advantage of the extensive characterization of the macaque visual system, we examine in macaque the influence of congenital blindness resulting from the removal of the retina during in utero development. This effectively removes the normal influence of the thalamus on cortical development leading to an induced hybrid cortex (HC) combining features of primary visual and extrastriate cortex. Retrograde tracers injected in HC reveal a local, intrinsic connectivity characteristic of higher order areas and show that the HC receives a uniquely strong, purely feedforward projection from striate cortex but no ectopic inputs, except from subiculum, and entorhinal cortex. Statistical modeling of quantitative connectivity data shows that HC is relatively high in the cortical hierarchy and receives a reinforced input from ventral stream areas while the overall organization of the functional streams are conserved. The directed and weighted anophthalmic cortical graph from the present study can be used to construct dynamic and structural models. These findings show how the sensory periphery governs cortical phenotype and reveal the importance of developmental arealization for understanding the functional reorganization in congenital blindness.

Corticothalamic projections from the rat primary somatosensory cortex.

To study the cells of origin of corticothalamic inputs to the ventral posterior and posterior medial nuclei of the somatosensory thalamus in rats, we injected small aliquots of tracer into each nucleus and analyzed the pattern of retrograde labeling in the posteromedial barrel subfield of primary somatosensory cortex, which can be divided into barrel and nonbarrel zones. The ventral posterior nucleus is innervated by neurons in layer VIa of both zones, whereas the posterior medial nucleus is innervated by neurons in layers Vb and VIb of both zones with additional innervation from layer VIa of nonbarrel cortex. Thus, only the posterior medial nucleus receives a layer Vb input. Because the layer Vb input is interpreted as the initiation of a feedforward cortico-thalamocortical pathway, this implies that the target of the posterior medial nucleus, which includes the nonbarrel cortex, is a higher-order cortical area. We thus suggest that this cortical zone, which is classically considered part of the primary somatosensory cortex, should be reclassified as higher-order cortex.

Expansion of the Central Hindpaw Representation Following Fetal Forelimb Removal in the Rat.

We provide evidence that prenatal removal of a rat forelimb results in both a disruption of the anatomical representation which would normally correspond to the forepaw and in an enlargement of the adjacent hindpaw representation in the brainstem and cortex. This enlargement, which in some cases is as much as 100%, only occurs following complete forelimb amputation on embryonic day 17 (E17) or earlier. This coincides with the age at which forepaw afferents first arrive in the brainstem, suggesting to us that the expansion is permitted in part because ingrowing hindpaw afferents are in the presence of cuneate cells which have never been previously innervated; in animals older than E17, the expansion is prohibited by either an intrinsic age-dependent change in the cuneate cells, or a change imposed upon them by forelimb afferents. The number of cells in dorsal root ganglia subserving the expanded hindpaw areas does not differ from normal suggesting that the expansion of hindpaw territory within the brainstem reflects an increased terminal arborization by a normal complement of primary hindpaw afferents. We interpret the cortical enlargement to be an upstream reflection of the brainstem events. In cortex, the enlargement seems to result from an invasion of the dysgranular cortex by thalamic afferents arising from the ventral posterior nucleus.

The Topographic Organization and Axis of Projection within the Visual Sector of the Rabbit's Thalamic Reticular Nucleus.

The organization of the visual field representation within the thalamic reticular nucleus (TRN) of the rabbit was studied. Focal injections of horseradish peroxidase (HRP) and/or [3H]proline were made into visuocortical areas V1 and V2 and the dorsal lateral geniculate nucleus (dLGN). The resultant labelling in the thalamus was analysed. A single injection in V1 or V2 results in a single zone of terminal label within the TRN that is restricted to the dorsocaudal part of the sheet-like nucleus. In comparisons of the zones of label following injections at two different cortical sites in V1, a medial to lateral shift in label across the thickness of the TRN sheet is accompanied by a medial to lateral shift in label in the dLGN; a dorsal to ventral shift in label within the plane of the TRN sheet is accompanied by a dorsal to ventral shift in label in the dLGN. Thus, like the dLGN the TRN receives a precise topographic projection from V1. In reconstructions from horizontal sections the zones of label within the TRN resemble 'slabs', which lie within the plane of the nucleus parallel to its borders. Thus, the slabs of visuocortical terminals and reticular dendrites are similarly oriented. As revealed by the orientation of the slabs, the lines of projection representing points in visual space are represented by the oblique rostrocaudal dimension of the TRN. Injections restricted to V1 produce terminal labelling that is confined to the outer two-thirds of the TRN across its thickness, whilst those involving V2 result in terminal labelling within the inner one-third of the nucleus. Thus, the adjacent cortical areas V1 and V2 project in a continuous fashion across the mediolateral dimension of the TRN. The organization of the map within the TRN, which was revealed by visuocortical injections, was confirmed by the pattern of retrograde labelling within the nucleus following geniculate injections of HRP. On the basis of these findings and those in other mammalian species, two major conclusions can be reached that alter our view of the TRN. First, rather than mapping onto the whole nucleus in a continuous fashion, the cortical projection to the TRN has significant discontinuities. Second, rather than integrating efferents from widespread cortical areas, the reticular dendrites are related to focal areas of cortex.