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.

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).

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.

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.

Parvalbumin and calbindin are differentially distributed within primary and secondary subregions of the mouse auditory forebrain.

The calcium binding proteins parvalbumin and calbindin are thought to differentially regulate physiological functions and often show complementary distributions in the CNS. Our goal was to determine parvalbumin and calbindin distributions in the different subdivisions of mouse auditory thalamus and auditory cortex. Following fixation, FVB mouse brains (postnatal days 38-80) were sectioned along coronal and horizontal planes, then processed for parvalbumin and calbindin immunohistochemistry (antibodies: parvalbumin pa-235, calbindin-d-28k cl-300).

Suppression of hindlimb inputs to S-I forelimb-stump representation of rats with neonatal forelimb removal: GABA receptor blockade and single-cell responses.

Neonatal forelimb removal in rats results in the development of inappropriate hindlimb inputs in the forelimb-stump representation of primary somatosensory cortex (S-I) that are revealed when GABA(A) and GABA(B) receptor activity are blocked. Experiments carried out to date have not made clear what information is being suppressed at the level of individual neurons. In this study, three potential ways in which GABA-mediated inhibition could suppress hindlimb expression in the S-I stump representation were evaluated: silencing S-I neurons with dual stump and hindlimb receptive fields, silencing neurons with receptive fields restricted to the hindlimb alone, and/or selective silencing of hindlimb inputs to neurons that normally express a stump receptive field only.

Source of inappropriate receptive fields in cortical somatotopic maps from rats that sustained neonatal forelimb removal.

Previously this laboratory demonstrated that forelimb removal at birth in rats results in the invasion of the cuneate nucleus by sciatic nerve axons and the development of cuneothalamic cells with receptive fields that include both the forelimb-stump and the hindlimb. However, unit-cluster recordings from primary somatosensory cortex (SI) of these animals revealed few sites in the forelimb-stump representation where responses to hindlimb stimulation also could be recorded. Recently we reported that hindlimb inputs to the SI forelimb-stump representation are suppressed functionally in neonatally amputated rats and that GABAergic inhibition is involved in this process.

Thalamocortical and intracortical projections to the forelimb-stump SI representation of rats that sustained neonatal forelimb removal.

We previously reported the abnormal expression of hindlimb receptive fields in the stump representation of the primary somatosensory cortex (SI) in rats that sustained neonatal forelimb removal when cortical gamma-aminobutyric acid (GABA) receptors were pharmacologically blocked (Lane et al. [1997] J. Neurophysiol.

Sensitive period for lesion-induced reorganization of intracortical projections within the vibrissae representation of rat's primary somatosensory cortex.

Previous experiments from this laboratory demonstrated that intracortical connections in lamina IV of the rat primary somatosensory cortex (SI) are most dense outside the patches of cytochrome oxidase (CO) staining that correspond to the mystacial vibrissae. This pattern of intracortical connections becomes apparent on postnatal day 4 (P-4), at least 2 days after the appearance of the vibrissae-related pattern of thalamocortical afferents. Transection of the infraorbital nerve (ION) on the day of birth (P-0) disrupts both the CO and intracortical projection patterns.

Blockade of GABAergic inhibition reveals reordered cortical somatotopic maps in rats that sustained neonatal forelimb removal.

A previous study from this laboratory demonstrated that forelimb removal at birth results in invasion of the cuneate nucleus (CN) by sciatic nerve axons and the development of CN cells including thalamic projection neurons with receptive fields that include both the forelimb stump and the hindlimb. However, recordings from unit clusters in lamina IV of the primary somatosensory cortex (SI) of these animals revealed the presence of only a very few sites in the forelimb stump representation where responses to hindlimb stimulation could also be recorded. In the present study we tested the possibility that input from the hindlimb was suppressed in lamina IV of the cortical stump representation via GABAergic inhibitory mechanisms by mapping this cortical region, applying the gamma-aminobutyric acid-A (GABA(A)) and GABA(B) receptor antagonists bicuculline and phaclofen (50 microM each), and then remapping the same sites.

Phenotypic characterisation of respecified visual cortex subsequent to prenatal enucleation in the monkey: development of acetylcholinesterase and cytochrome oxidase patterns.

Prenatal bilateral enucleation induces cortex, which normally would have become striate cortex, to follow a default developmental pathway and to take on the cytoarchitectonic appearance of extrastriate cortex (default extrastriate cortex, Dehay et al. [1996] J. Comp.

Development and plasticity of local intracortical projections within the vibrissae representation of the rat primary somatosensory cortex.

Labelling with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Di-A) was used to assess the development of projections within the primary somatosensory cortex (SI) of rats aged between postnatal day 2 and 8 (P-2 and P-8). 1,1'-Dioctadecyl-3,3,3,"3'-tetramethylindocarbocyanine perchlorate (Di-I) was used in these same animals to label thalamocortical afferents. Particular attention was paid to the emergence of lamina IV intracortical projections that form a pattern complementary to vibrissae-related thalamocortical afferents.

Contribution of thalamic input to the specification of cytoarchitectonic cortical fields in the primate: effects of bilateral enucleation in the fetal monkey on the boundaries, dimensions, and gyrification of striate and extrastriate cortex.

Bilateral enucleation was performed at different fetal ages during corticogenesis, and the brains were prepared for histological examination. Early-enucleated fetuses (operated prior to embryonic day 77) showed morphological changes at the level of the thalamus and the cortex. In the thalamus, there was a loss of lamination and a decrease in size of the lateral geniculate nucleus.

Individual axon morphology and thalamocortical topography in developing rat somatosensory cortex.

The morphology of individual thalamocortical axons in developing rat primary somatosensory cortex was studied using lipophilic tracers. Anterograde labeling with lipophilic dyes demonstrated a topographical organization of thalamocortical projections exiting the thalamus as early as embryonic day (E) 16; retrograde labeling studies demonstrated topography of these projections as they reached the cortex as early as E18. At E17, axons course tangentially within the intermediate zone and turn or branch near the deepest layer of cortex (layer VIb), suggesting the presence of guidance cues in this region.

The formation of a cortical somatotopic map.

The primary somatosensory cortex of small rodents is an isomorphic representation of the body surface. Similar representations are characteristic of the subcortical pathways, leading from the periphery to the cortex, and these representations develop in a sequence that begins at the periphery, and that ends in the cortex. Furthermore, central representations at all levels of the neural axis are altered by perinatal perturbations of the peripheral surface.

Lesion-induced reorganization in the brainstem is not completely expressed in somatosensory cortex.

Electrophysiological and neuroanatomical methods were used to determine the extent to which neonatal forelimb removal altered the organization of the cuneate nucleus and representations of the fore- and hindlimbs in the primary somatosensory cortex of adult rats. Neonatal forelimb removal resulted in invasion of the cuneate nucleus by sciatic nerve primary afferents and development of cuneothalamic projection neurons with split receptive fields that included both the hindlimb and forelimb stump. Mapping in the primary somatosensory cortex of the neonatally manipulated adult rats demonstrated abnormalities, but the major change observed in the cuneate nucleus was demonstrable at only a few (5%) cortical recording sites in the remaining stump representation and there were none at all in the hindlimb representation.

Patterning of local intracortical projections within the vibrissae representation of rat primary somatosensory cortex.

Anterograde and retrograde tracing with biotinylated dextran amine and Phaseolus vulgaris leukoagglutinin was used to assess projection patterns within the vibrissae representation of the rat's primary somatosensory cortex (S-I). Large and small injections of either tracer into the center of the vibrissae representation yielded dense anterograde and retrograde labelling throughout much of the tangential extent of the vibrissae representation within S-I. In all layers, the pattern and extent of retrograde and anterograde label was in rough congruence.

Rapid alteration of thalamocortical axon morphology follows peripheral damage in the neonatal rat.

The effect of day of birth (postnatal day 0; P0) infraorbital nerve section on the morphology of individual thalamocortical axons in rat somatosensory cortex was examined on P3. Thalamic fibers were labeled in fixed brains with the carbocyanine dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, and individual photo-converted thalamocortical fibers were reconstructed. In normal animals on P3, axon arbor terminal formation within layer IV has commenced and terminal arbor width is comparable to that of a cortical "barrel.

Peripheral influences on the size and organization of somatotopic representations in the fetal rat cortex.

Nerve lesions at different fetal ages and on the day of birth were used to determine the role of the periphery in establishing territories devoted to representations of different portions of the body surface in rat somatosensory cortex. Transection of the infraorbital nerve (ION), the trigeminal branch that supplies the whisker pad, resulted in a significant reduction in the area within the primary somatosensory cortex devoted to the representation of the mystacial vibrissae in fetal, but not newborn, rats. Such lesions in fetal, but not neonatal, rats also resulted in significant increases in the cortical area devoted to the representation of the lower lip and jaw.

Lesion-induced changes in the central terminal distribution of galanin-immunoreactive axons in the dorsal column nuclei.

Rats that sustained forelimb removal on either embryonic day (E) 16, on the day of birth (P-0), or transection of the brachial plexus in adulthood had brainstem sections stained for galanin, calcitonin gene-related peptide (CGRP), or substance P (SP) at various intervals after these lesions were made. In normal adult rats, only a few galanin-immunoreactive fibers are present in the cuneate nucleus and most are located in its caudal portion. CGRP-positive axons are also sparse in the cuneate and are distributed mainly in the periphery of the nucleus.

Anatomical and functional changes in the organization of the cuneate nucleus of adult rats after fetal forelimb amputation.

A previous study has shown that fetal forelimb removal in the rat results in an increase in the size of the hindlimb representation in primary somatosensory cortex and suggested that this anomalous cortical organization may have resulted from alterations in the primary afferent innervation of the dorsal column nuclei (Killackey and Dawson, 1989). The present study used both anatomical and electrophysiological techniques to examine the effects of fetal forelimb amputation on the dorsal column nuclei. Rats sustained forelimb removals on embryonic day 16 and were used in terminal experiments when they reached adulthood (> 60 d of age).

Thalamic processing of vibrissal information in the rat: II. Morphological and functional properties of medial ventral posterior nucleus and posterior nucleus neurons.

Extracellular recording, intracellular recording, intracellular horseradish peroxidase injection, and receptive field mapping techniques were employed to evaluate the physiological and morphological properties of medial ventral posterior nucleus (VPM) and posterior nucleus (POm) neurons in normal adult rats. Overall, we physiologically characterized 148 VPM and 121 POm neurons. Over 82% of the VPM cells were excited only by deflection of one or more mystacial vibrissae, 10% were activated by displacement of guard hairs, and the remainder were either excited by indentation of the skin or were unresponsive.

Thalamic processing of vibrissal information in the rat. I. Afferent input to the medial ventral posterior and posterior nuclei.

Retrograde tracing with true blue (TB) and diamidino yellow (DY) and anterograde tracing with either wheatgerm agglutinin-conjugated horseradish peroxidase (WGA-HRP) or Phaseolus vulgaris leucoagglutinin (PHA-L) were employed to investigate the projections from trigeminal nucleus principalis (PrV) and trigeminal subnucleus interpolaris (SpI) to their targets in the medial ventral posterior (VPM) and posterior (POm) nuclei of the thalamus. Many more cells in both PrV and SpI were labeled by tracer injections into VPM than into POm. Only a very small number of double-labeled neurons were observed in either PrV or SpI.

The effects of bilateral enucleation in the primate fetus on the parcellation of visual cortex.

Bilateral enucleation in the macaque fetus causes an areal reduction of an otherwise normal striate cortex. Here we show that in early operated animals this reduction is accompanied by a separation of striate and prostriate cortices which are normally contiguous. However this induced separation does not correspond to the areal reduction of striate cortex, indicating that extrinsic signals regulate either the proliferation and/or survival of striate cortical neurons.

Early ingrowth of thalamocortical afferents to the neocortex of the prenatal rat.

The initial ingrowth of thalamocortical afferents into the presumptive somatosensory cortex was examined in the fetal rat. Thalamic fibers were labeled in fixed brains with the carbocyanine dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). On embryonic day 16, thalamocortical afferents arrive in the neocortex and course tangentially within the intermediate zone immediately underneath the cortical plate.