Experimentally induced visual projections into auditory thalamus and cortex.

Retinal cells have been induced to project into the medial geniculate nucleus, the principal auditory thalamic nucleus, in newborn ferrets by reduction of targets of retinal axons in one hemisphere and creation of alternative terminal space for these fibers in the auditory thalamus. Many cells in the medial geniculate nucleus are then visually driven, have large receptive fields, and receive input from retinal ganglion cells with small somata and slow conduction velocities. Visual cells with long conduction latencies and large contralateral receptive fields can also be recorded in primary auditory cortex. Some visual cells in auditory cortex are direction selective or have oriented receptive fields that resemble those of complex cells in primary visual cortex. Thus, functional visual projections can be routed into nonvisual structures in higher mammals, suggesting that the modality of a sensory thalamic nucleus or cortical area may be specified by its inputs during development.

Physiological evidence for serial processing in somatosensory cortex.

Removal of the representation of a specific body part in the postcentral cortex of the macaque resulted in the somatic deactivation of the corresponding body part in the second somatosensory area. In contrast, removal of the entire second somatosensory area had no grossly detectable effect on the somatic responsivity of neurons in the postcentral cortex. This direct electrophysiological evidence for serial cortical processing in somesthesia is similar to that found earlier for vision and, taken together with recent anatomical evidence, suggests that there is a common cortical plan for the processing of sensory information in the various sensory modalities.

Massive cortical reorganization after sensory deafferentation in adult macaques.

After limited sensory deafferentations in adult primates, somatosensory cortical maps reorganize over a distance of 1 to 2 millimeters mediolaterally, that is, in the dimension along which different body parts are represented. This amount of reorganization was considered to be an upper limit imposed by the size of the projection zones of individual thalamocortical axons, which typically also extend a mediolateral distance of 1 to 2 millimeters. However, after extensive long-term deafferentations in adult primates, changes in cortical maps were found to be an order of magnitude greater than those previously described. These results show the need for a reevaluation of both the upper limit of cortical reorganization in adult primates and the mechanisms responsible for it.

Dynamic features of sensory and motor maps.

Recent data support the idea that the functional organizations of sensory and motor maps in the mature brain are dynamically maintained. Experiments employing peripheral injuries or other manipulations indicate that these maps are capable of extensive reorganization. A number of candidate mechanisms for these changes have been suggested, providing avenues for further research.

Hierarchical, parallel, and serial arrangements of sensory cortical areas: connection patterns and functional aspects.

Recent studies have led to a better understanding of the organization and connections of somatosensory and visual cortex in a number of mammalian species. Lesion studies have provided information on the significance of particular connections. The variable effectiveness of cortical lesions in deactivating target areas suggests that serial processing may be emphasized in higher primates.

Asymmetric connections, duplicate layers, and a vertically inverted map in the primary visual system.

The achiasmatic mutation is a remarkable and rare visual system mutation carried in a line of black sheepdogs. In affected animals, the optic chiasm is missing, and each retina projects entirely to the ipsilateral hemisphere. As a result of this navigational error, maps of visual space in the lateral geniculate nucleus (LGN) have a unique structure with mirror reversals of field position across the A-A1 border. Animals also have a persistent and severe congenital nystagmus. In this report we analyze a novel variant of the achiasmatic mutation, one in which retinal axons from only one eye successfully cross midline and in which the great majority of fibers from both eyes terminate in a single lateral geniculate nucleus. The dominant optic tract contains four times as many axons as the other tract. The hyperinnervated LGN has a lamination pattern consisting of duplicate and partly interwoven layers. A multiunit mapping study of visual cortex (primarily area 17 along the marginal gyrus) shows that receptive field topography and orientation selectivity are normal. The size of central binocular visual space is nearly normal and is flanked by monocular domains in the periphery. However, there is an inexplicable vertical inversion in the orientation of the cortical representation: superior fields are located rostrally, and inferior fields are located caudally. Despite a host of drastic abnormalities at all level of the visual system, from retina to cortex, this animal was behaviorally indistinguishable from normal dogs and did not have any detectable oculomotor abnormalities.

The effects of phenytoin on the performance of rats in a delayed match-to-place task.

We have shown previously that phenytoin impairs learning in rats in several different behavioral paradigms (Churchill et al., 1998, 2003; Banks et al., 1999). The present study has examined this drug's effects on performance in a delayed match-to-place water maze paradigm developed by Steele and Morris (1999). We find that phenytoin retards performance, but only when the inter-trial interval (ITI) is short (i.e., 15-sec). With longer ITIs (i.e., 20-min, 2-hr), the performance of the phenytoin-treated rats was quite comparable to the controls. We suggest that this pattern of results stems from a disruption of spatial working memory, perhaps due to the effects of the drug on hippocampal function (cf., Churchill et al., 1998, 2003). This disruption is, however, not so profound that consolidation is prevented.

NMDA receptors and plasticity in adult primate somatosensory cortex.

Topographic maps in adult primate somatosensory cortex are capable of dramatic reorganizations after peripheral nerve injuries. In the present experiments, we have deprived a circumscribed portion of the hand map in somatosensory cortex of our adult squirrel monkeys by transecting the median nerve to one hand, and evaluated the hypothesis that N-methyl-d-aspartate (NMDA) glutamatergic receptors are necessary for the reorganization that follows within four weeks. In one monkey, we confirm previous results demonstrating that the deprived cortex has regained responsiveness in its expanse four weeks after median nerve transection. However, in three monkeys in which NMDA receptors were concurrently blocked, most of the deprived cortex remained unresponsive. Thus, much of the cortical "recovery" that typically follows peripheral nerve injury in adult monkeys is apparently dependent on NMDA receptors and may well be due to Hebbian-like changes in synaptic strength. Perhaps the elimination of the normally dominant inputs to "median nerve cortex" permits the gradual strengthening of correlations between the activity of the formally impotent presynaptic and deprived postsynaptic elements. These enhanced correlations may also have been made possible by reductions in intracortical inhibition as a necessary but not sufficient condition.

Morphology of single intracellularly stained axons terminating in area 3b of macaque monkeys.

We have studied the morphology of single thalamocortical axons innervating area 3b of postcentral somatosensory cortex in macaque monkeys. We recorded from axons in the white matter below the representation of the hand in postcentral cortex in two monkeys (Macaca fascicularis) by using micropipettes filled with horseradish peroxidase (HRP). When an axon was recorded, we delineated its receptive field and determined its modality, and if cutaneous, whether it was slowly or rapidly adapting (SA or RA). We then impaled the axon and injected it with HRP. We recorded and successfully injected many more RA than SA axons, possibly because of differences in their true proportions. The RA axonal arbors varied in mediolateral extent from 350 to 800 microns with a mean of 600 microns. One of the RA axons gave rise to four separate arbors spanning 2.5-3.0 mm of cortex. The single SA axon we recovered was 370 microns in width. We suggest that the individual terminal zones underlie the columnar parcellation of the somatosensory cortex. The presence of arbors spanning several such columns suggests that all regions within the arbor may not be equally effective in driving cortical cells under normal conditions, and such arbors may provide the substrate for a cortical response to alterations in the pattern of input.

Tonotopic organization, architectonic fields, and connections of auditory cortex in macaque monkeys.

Microelectrode recordings were used to investigate the tonotopic organization of auditory cortex of macaque monkeys and guide the placement of injections of wheat germ agglutinin-horse radish peroxidase (WGA-HRP) and fluorescent dyes. Anatomical and physiological results were later related to histological distinctions in the same brains after sections were processed for cytoarchitecture, myeloarchitecture, acetylcholinesterase (AchE), or cytochrome oxidase (CO). The experiments produced several major findings. (1) Neurons throughout a broad expanse of cortex were highly responsive to pure tones, and best frequencies could be determined for neurons in arrays of recording sites. (2) The microelectrode recordings revealed two systematic representations of tone frequencies, the primary area (AI) and a primary-like rostral field (R) as previously described. The representation of high to low frequency tones in A1 was largely caudorostral along the plane of the sulcus. A reversal of the order of representation of frequencies occurred in R. (3) AI and R together were coextensive with a koniocellular, densely myelinated zone that expressed high levels of AchE and CO. These architectonic features were somewhat less pronounced in R than AI, but a clear border between the two areas was not apparent. (4) Cortex bordering AI and R was less responsive to tones, but when best frequencies for neurons could be determined, they matched those for adjoining parts of AI and R. (5) Architectonically distinct regions were apparent within some of the cortex bordering AI and R. (6) The major ipsilateral cortical connections of AI were with R and cortex immediately lateral and medial to AI. (7) Callosal connections of AI were predominantly with matched locations in the opposite AI, but they also included adjoining fields. (8) Neurons in the ventral (MGV), medial (MGM), and dorsal (MGD) nuclei of the medial geniculate complex projected to AI and cortex lateral to AI. (9) Injections in cortex responsive to high frequency tones labeled more dorsal parts of MGV than injections in cortex responsive to low frequency tones.

Terminal arbors of single ON-center and OFF-center X and Y retinal ganglion cell axons within the ferret's lateral geniculate nucleus.

The lateral geniculate nucleus of the ferret contains not only eye-specific layers, but a further subdivision of layers A and A1 into inner and outer sublaminae that contain, respectively, ON-center and OFF-center cells (Stryker and Zahs, '83). To study how the arbors of single retinal ganglion cell axons correlate with these cellular divisions, we have examined the morphology of physiologically classified retinal axons in the ferret's lateral geniculate nucleus. As in cats, we could classify retinal axons as X or Y on the basis of a number of physiological criteria. X and Y axons have distinct patterns of termination in the lateral geniculate nucleus. Contralateral X axons innervate lamina A and ipsilateral axons lamina A1. X axons are further segregated in these laminae so that ON-center axons terminate in the inner sublamina, and OFF-center axons in the outer sublamina. We did not observe any branches of X axons innervating the medial interlaminar nucleus or the midbrain. Y axons have much larger terminal arbors and exhibit greater variation in their terminations. Generally, within layers A and A1, ON-center Y axons innervate the inner sublamina and OFF-center Y axons innervate the outer sublamina. However, they often innervate both sublaminae, and occasionally have a few boutons in the inappropriate lamina as well. Y axons also terminate in the dorsal C laminae, the interlaminar zones, and the media interlaminar nucleus; branches of these axons course toward the midbrain, presumably to innervate the superior colliculus. Thus, whereas the Y pathway in the ferret is one of high divergence, the X pathway appears to be the substrate for segregated ON and OFF channels through the lateral geniculate nucleus.

Role of competitive interactions in the postnatal development of X and Y retinogeniculate axons.

The cat's retinogeniculate pathway is largely composed of X and Y axons, which represent two distinct neuronal streams organized in parallel. Our earlier data, summarized in the previous paper, suggest that the postnatal development of retinogeniculate axon arbors is characterized by competitive interactions between the X and Y axons. Thus, during development, X arbors in lamina A or A1 are initially broad or exuberant before the Y arbors begin to develop adultlike arbors; the X arbors then shrink to their adult form as the Y arbors grow and establish their mature complement of connections; monocular lid suture prevents the rapid growth of Y arbors, which in turn prevents the pruning of X arbors; and monocular enucleation at birth allows X arbors from the remaining eye to retain their exuberance although completely confined to their appropriate lamina A or A1, whereas the Y arbors develop aberrant extensions into adjacent, previously denervated laminae. We now provide additional evidence for the role of competition between retinogeniculate X and Y axons during development. The addition of visual deprivation by lid suture of the remaining eye to monocular enucleation at birth causes no apparent change in the morphology of X arbors in laminae A and A1. In contrast, the Y arbors of such cats continue to form extensive translaminar sprouts in the previously denervated laminae despite severely reduced terminations in the lamina A or A1 normally innervated by the remaining eye. We interpret these new data, in conjunction with our earlier data, as follows. If retinogeniculate X and Y arbors complete for synaptic space during postnatal development, terminations of Y axons can be affected by lid suture only in geniculate laminae where terminations of X axons are also present. Thus, Y axon arbors are severely reduced in deprived lamina A or A1 following lid suture whether or not the other eye is removed. Where X arbors are not present, such as in lamina C or the laminae inappropriate for the remaining eye after removal of the other, the lid suture has no obvious effect on development of the Y arbors.

Effects of convergent strabismus on the development of physiologically identified retinogeniculate axons in cats.

We have studied the effects of surgically induced convergent strabismus (esotropia) on the morphological development of retinogeniculate X and Y axon arbors in cats. Single axons were recorded in the lateral geniculate nucleus or in the optic tract adjacent to the nucleus, classified physiologically, and injected intracellularly with horseradish peroxidase. The arbors of recovered axons were compared with X and Y axon arbors from normally reared adult cats. Our data demonstrate that while X axon arbors are relatively normal, the arbors of Y axons are profoundly affected by rearing with strabismus. Y axons, whether originating from the deviated or the nondeviated eye, have substantially smaller arbors and fewer boutons in the A-laminae of the lateral geniculate nucleus compared to Y axons in normal cats. The C-lamina terminations of contralaterally projecting Y axons in the strabismic cats are unaffected. These results suggest that the postnatal development of retinogeniculate Y axon arbors in the A-laminae is strongly influenced by abnormalities in postnatal visual experience. Furthermore, the present data suggest that, in addition to intraocular competitive interactions between X and Y axons previously proposed to account for the effects of other rearing conditions, interactions between afferents from the two eyes must also be involved in the development of at least Y axons.

Role of NMDA receptors in adult primate cortical somatosensory plasticity.

We have previously shown that most of the reorganization that typically follows median nerve transection in adult squirrel monkeys is dependent on normally functioning N-methyl-D-aspartate (NMDA) receptors. Here, we have evaluated two additional hypotheses: (1) is the immediate "unmasking" found after median nerve transection NMDA receptor-dependent? and (2) are NMDA receptors necessary for both the initiation and maintenance of the second phase of reorganizational changes, or only the former? To address these issues, we implanted osmotic minipumps subcutaneously to deliver an NMDA receptor antagonist (3-((+/-)-2- carboxypiperazin-4-yl)propyl-1-phosphonic acid, CPP) systemically either before examining the immediate effects of median nerve transection, or after reorganization had presumably occurred. For the first set of experiments, NMDA receptor blockade was initiated either 1 or 4 weeks prior to multi-unit mapping in area 3b followed by transection of the median nerve and remapping of the cortex. In the second set of experiments, median nerve transection was followed 4 weeks later by either 1 or 4 weeks of NMDA receptor blockade prior to terminal mapping. We report that the immediate unmasking of new receptive fields after acute nerve injury is not prevented by NMDA receptor blockade; nor are completely reorganized cortical maps dependent upon NMDA receptors for their maintenance. We conclude that the immediate changes in cortical topography are not due to an NMDA receptor-dependent mechanism, but more likely due to release from tonic inhibition. Furthermore, the later phase of reorganization, as for some forms of hippocampal long-term potentiation (LTP), is dependent on normally functioning NMDA receptors for its initiation, but not for its maintenance.

Morphology of retinogeniculate X and Y axon arbors in monocularly enucleated cats.

We examined the terminal arbors of single, physiologically identified retinogeniculate X and Y axons from the remaining retinas of adult cats raised from birth with monocular enucleation. These were compared with arbors of X and Y axons in normally reared cats. We used intra-axonal injections of horseradish peroxidase to label each axon after recording its response properties. While the axons in monocularly enucleated cats exhibited normal response properties, both X and Y axons in these cats had abnormally large terminal arbors. Each of the hypertrophied X arbors appeared to be completely confined to the single geniculate lamina A or A1 appropriate to its eye of origin (i.e., lamina A for the contralateral retina and lamina A1 for the ipsilateral retina). In contrast, in addition to their normal terminations, most of the Y arbors seemed to extend well into laminae normally innervated only by the retina that was removed. Thus most or all of the translaminar sprouting previously reported for monocularly enucleated cats appears to reflect extensions of Y axon arbors. These data, in addition to earlier, analogous data from young kittens and cats reared with monocular lid suture, suggest the following sequelae during postnatal development: the retinogeniculate X arbors mature first and develop exuberant arbors that are later competitively pruned as the Y axons expand their innervation of the lateral geniculate nucleus; monocular lid suture prevents the Y axons from succeeding in this competition, so they fail to establish normal arbors and cannot reduce the exuberant X arbors; monocular enucleation offers a less resistant path in the denervated laminae for the rapidly growing Y arbors from the remaining eye, and the expansion of these arbors there reduces the competitive pressure on the exuberant X arbors. Thus, in monocularly enucleated cats, sprouting is limited to Y axons, either because only they possess the capacity to sprout or because they are in the midst of a period of relatively rapid growth at the time of the neonatal enucleation. The X axon arbors are also abnormally large within their appropriate laminae. This occurs presumably because they are able to maintain their immature exuberance, although we cannot rule out the possibility that they are pruned and later regrow to the final size seen in our experiments.

Experimentally induced visual projections to the auditory thalamus in ferrets: evidence for a W cell pathway.

We have previously reported that following specific neonatal brain lesions in ferrets, a retinal projection is induced into the auditory thalamus (Sur et al., Science 242:1437, '88). In these "rewired" ferrets, a novel visual pathway is established through auditory thalamus [the medial geniculate nucleus (MGN)] and primary auditory cortex (A1); cells in both MGN and A1 are visually responsive and exhibit properties similar to those of visual cells in the normal visual pathway. In this paper, we use three approaches--physiological, anatomical, and developmental--to examine which of the retinal ganglion cells project to the MGN in these rewired ferrets. We find that: 1) physiological response properties of postsynaptic visual cells in the MGN are W-like; 2) retinal ganglion cells back-filled from the MGN are small and similar to soma sizes of subsets of the normal retinal W cell population; and 3) subpopulations of these small cells can be preferentially rerouted to the MGN in response to different surgical manipulations at birth, consistent with differential W cell projection patterns in normal animals. These data suggest that retinal W cells come to project to the MGN in rewired animals. These findings not only provide a basis on which to interpret functional properties of this novel visual pathway, but also provide important information about the developmental capabilities of specific retinal ganglion cell classes and the regulation of their projections by target structures in the brain during development.

The somatotopic organization of area 2 in macaque monkeys.

Area 2 is a traditional architectonic subdivision of anterior parietal cortex in macaque monkeys, but its overall somatotopic organization and responsiveness to different types of somatic stimuli are poorly understood, and there are uncertainties concerning its rostral and caudal extent. The goals of the present study were to define the rostral and caudal borders of area 2 better, and to describe its overall organization and responsiveness. Somatic receptive fields were defined for hundreds of closely spaced microelectrode recording sites in postcentral parietal cortex of individual macaque monkeys anesthetized with ketamine. Electrophysiological and architectonic evidence suggested that a 3-4 mm-wide strip of cortex along the caudal border of area 1 includes all or most of area 2. The most lateral explored portion of area 2 adjoined the representation of the face in area 1. Much of this sector of area 2 was activated by cutaneous stimulation of the face, especially the chin, but more caudal parts of the head also were represented there. Medially, an adjacent sector of area 2 represented the hand. Rostrally, in the cortex within 1.5 mm from the area 1 border, the glabrous surfaces of digits 5 through 1 were represented in a mediolateral cortical sequence, and from tip to base in a rostrocaudal sequence, mirroring the organization in the adjacent portion of area 1. More caudally at this mediolateral level of area 2, digit tips and other phalanges were represented for a second time. The pads of the palm and the dorsal surfaces of the hand were represented laterally and medially within the portion of area 2 devoted to the hand. More medially, the wrist, forearm, and arm were represented in a lateromedial cortical sequence in area 2, roughly matching the mediolateral organization within the bordering area 1. However, immediately caudal to the representation of the occiput, neck, and shoulder in area 1, a rostrocaudal strip of cortex extending across area 2 represented the arm and forearm for a second time in area 2. This cutaneously activated strip of cortex extended into area 5, where the proximal portion of the hand was represented. More medially, next to the trunk representation in area 1, area 2 was devoted to the trunk and limbs. Next to the representations of the ankle, leg, and thigh in area 1, area 2 was activated from similar locations on the hindlimb.(ABSTRACT TRUNCATED AT 400 WORDS)

Parallel thalamic activation of the first and second somatosensory areas in prosimian primates and tree shrews.

In Tupaia belangeri and Galago senegalensis, microelectrode recordings immediately after ablation of the representation of the forelimb in the midportion of the first somatosensory area, S-I, revealed that all parts of the second somatosensory area, S-II, remained highly responsive to cutaneous stimuli. In this way, prosimian primates, close relatives of simian primates, and tree shrews differ markedly from monkeys in which S-II is deactivated by comparable ablations, and resemble such mammals as cats and rabbits in which S-II also remains highly responsive following ablations in S-I. Thus, it appears that the generalized mammalian condition is that S-I and S-II are independently activated via parallel thalamocortical pathways. A dependence of S-II on serial connections from the thalamus to the S-I region and then to S-II apparently evolved with the advent of anthropoid primates, and may be present only in monkeys and perhaps other higher primates.

Functional reorganization in adult monkey thalamus after peripheral nerve injury.

Large changes in somatotopic organization can be induced in adult primate somatosensory cortex by cutting peripheral afferents. The role, if any, of the thalamus in these changes has not been investigated previously. In the present experiments, electrophysiological recording in the ventroposterior lateral nucleus (VPL) has revealed that not only can reorganization occur in the thalamus, but it may be as extensive as that revealed in the cortex of the same monkeys. Thus, for at least some types of deafferentation, the reorganization revealed in the cortex may depend largely on subcortical changes.

Possible use-dependent changes in adult primate somatosensory cortex.

Topographic changes in adult primate somatosensory cortical maps have been reported to follow well-regulated manipulations in the animals' experience. We report briefly here cortical mapping data from one monkey which arrived at our laboratory with a chronic paralytic condition in one hand that resulted in a unique pattern of skin surface stimulation. Isolated receptive fields across the mediolateral extent of cortical area 3b were highly unusual with respect to normal topography, but they were completely consistent with the hypothesis that the correlated activation of peripheral afferents acts to shape expressed cortical receptive fields.