Sensory processing by novel, experimentally induced cross-modal circuits.
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Biomedical subjects
D O Frost
Publications and source records attributed to D O Frost.
Effects of dark rearing on the development of visual callosal connections.
It is now well established that during normal postnatal development there is a partial elimination of the callosal projections of cortical areas 17 and 18 in the cat and that visual experience early in life can modulate this process. In the present experiments, we quantitatively studied the influence of light, per se, by rearing cats in total darkness. Dark rearing exaggerates the normally occurring partial elimination of immature callosal projections: it causes a significant reduction in the total number of neurons in both the supra- and infragranular layers that send an axon through the corpus callosum and slightly narrows the distribution of these neurons across areas 17 and 18. These data demonstrate that visual stimulation is not necessary either to initiate the partial elimination of immature callosal projections or to stabilize a large fraction of the callosal projections present at birth. However, normal visual stimulation is necessary for the stabilization of the normal complement of callosal projections.
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Visual responses of neurons in somatosensory cortex of hamsters with experimentally induced retinal projections to somatosensory thalamus.
These experiments investigate the capacity of thalamic and cortical structures in a sensory system to process information of a modality normally associated with another system. Retinal ganglion cells in newborn Syrian hamsters were made to project permanently to the main thalamic somatosensory (ventrobasal) nucleus. When the animals were adults, single unit recordings were made in the somatosensory cortices, the principal targets of the ventrobasal nucleus. The somatosensory neurons responded to visual stimulation of distinct receptive fields, and their response properties resembled, in several characteristic features, those of normal visual cortical neurons. In the visual cortex of normal animals and the somatosensory cortex of operated animals, the same functional categories of neurons occurred in similar proportions, and the neurons' selectivity for the orientation or direction of movement of visual stimuli was comparable. These results suggest that thalamic nuclei or cortical areas at corresponding levels in the visual and somatosensory pathways perform similar transformations on their inputs.
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Synaptic organization of anomalous retinal projections to the somatosensory and auditory thalamus: target-controlled morphogenesis of axon terminals and synaptic glomeruli.
These experiments examine which morphological features of axon terminals and their synaptic glomeruli are determined by afferent axons, and which by their targets. In normal, adult hamsters, electron microscopy reveals that, with respect to multiple ultrastructural features, the terminals and synaptic glomeruli of retinal afferent axons in the dorsal lateral geniculate nucleus differ from those of ascending auditory and somatosensory afferents in the medial geniculate and ventrobasal nuclei, respectively. These features include: (1) the location of specific sensory axon terminals on the somata and dendrites of their targets neurons, (2) the constitutents of the glomeruli and their synaptic relationships, (3) the number of specific sensory terminal boutons per glomerulus, (4) bouton size, (5) the number of dendritic and somatic appendages contacted by each bouton, and (6) the mitochondrial morphology of the specific sensory afferent boutons. In order to ascertain which of these features are determined by afferent axons and which by their targets, we subjected newborn Syrian hamsters to surgical procedures known to produce permanent, abnormal retinal projections to the main thalamic auditory (medial geniculate) and somatosensory (ventrobasal) nuclei. When the animals were adults, we examined the terminals and synaptic glomeruli of abnormal retino-auditory and retino-somatosensory axons that were anterogradely labeled by intraocular injection of horseradish peroxidase. With respect to all of the preceding features except mitochondrial morphology, the terminals and synaptic glomeruli of retino-medial geniculate and retino-ventrobasal axons more nearly resembled those of normal, auditory and somatosensory afferent axons, respectively, than they did those of normal, retino-lateral geniculate axons. These results demonstrate that the differentiation of all the features that we have examined, except mitochondrial morphology, is determined by factors in target neurons or their environment. This finding suggests that the differentiation of morphological features involved in contacts among neurons (including the type, number and size of interconnected neuronal elements and the loci at which they contact each other) is responsive to interactions among the connected elements, or between neural elements and their environment (e.g., glia, extracellular matrix), whereas the differentiation of structures reflecting intrinsic functions of individual neuronal elements is not responsive to such interactions.
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Expression of a surface-associated antigen on Y-cells in the cat lateral geniculate nucleus is regulated by visual experience.
The monoclonal antibody Cat-301, generated against cat spinal cord (McKay and Hockfield, 1982), recognizes a surface-associated antigen that, in the cat lateral geniculate nucleus (LGN), is selectively expressed on Y-cells (Hockfield et al., 1983; Hendry et al., 1984; Sur et al., 1984). We now report that the antigen recognized by Cat-301 appears late in development, along a time course similar to that described for the maturation of the physiological properties of Y-cells in the LGN, and that its expression is sharply reduced by monocular lid suture or dark-rearing from birth, 2 visual deprivation procedures that lead to a reduction in the proportion of Y-cells recorded physiologically in the LGN (Sherman et al., 1972; Kratz et al., 1979; reviewed in Sherman and Spear, 1982). Monocular lid suture in the adult has no effect on Cat-301 antigen levels or, as previously reported (Sherman et al., 1972), on the proportion of physiologically recorded Y-cells. In addition, reversing the monocular deprivation in adulthood by opening the neonatally sutured eye and suturing closed the previously normal eye for 6 months restores neither normal levels of Cat-301 labeling nor, as previously reported (Geisert et al., 1982), the proportion of recordable Y-cells. The development of Cat-301 immunoreactivity thus parallels the development of LGN Y-cell physiology. The relative reduction in levels of immunoreactivity consequent to neonatal, but not adult, visual deprivation shows that Cat-301 antigen expression does not simply reflect the level of visually evoked electrical activity in the LGN, but rather reflects a process that depends on the nature of visual experience early in life.(ABSTRACT TRUNCATED AT 250 WORDS)
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The morphology of retinogeniculate X- and Y-cell axonal arbors in dark-reared cats.
The cat's retinogeniculate pathway, immature at birth, develops physiologically and anatomically over the first three postnatal months. Visual deprivation from birth interferes with this maturation. Thus, monocular eye lid suture from birth leads to pronounced abnormalities in the morphology of retinogeniculate terminations and geniculate neurons, and to a reduction in the proportions of Y-cells recorded physiologically in the lateral geniculate nucleus (e.g. see Sherman and Spear 1982). This "loss" of geniculate Y-cells could possibly be due to reduced retinogeniculate Y-cell terminations and expanded X-cell terminations in the A-laminae (Sur et al. 1982), so that many geniculate cells that normally receive retinal Y-cell input accept and retain retinal X-cell input (Friedlander et al. 1982). Dark-rearing from birth also leads to a reduction in the proportions of Y-cells recorded in the lateral geniculate nucleus (Kratz et al. 1979). Such a loss might also be due to abnormalities in retinogeniculate X- and Y-cell terminations. To test this possibility, we injected horseradish peroxidase into physiologically identified retinogeniculate axons of dark-reared cats. Surprisingly, we found that our sample of retinogeniculate X- and Y-cell axons in dark-reared cats had normal morphology. If our sample is representative of the entire population of retinogeniculate X- and Y-cell axons, retinogeniculate axon morphology in dark-reared cats differs from that in monocularly sutured cats. Yet, using extracellular recording, we replicated the observation that physiologically identified geniculate Y-cells are encountered less often in dark-reared cats than in normal cats. Given the apparent normality of the retinogeniculate axons in these cats, the "loss" of geniculate Y-cells in dark-reared cats could then conceivably be due to conduction block in retinogeniculate afferents, tonic inhibition on Y-cells, or deficits in non-retinal influences that may importantly affect Y-cell development.
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Target-controlled differentiation of axon terminals and synaptic organization.
These experiments investigate the processes regulating the morphological differentiation of synaptic connections. Electron microscopy showed that the terminal boutons and synaptic complexes of retinal afferent axons in the main thalamic visual nucleus, the dorsal lateral geniculate nucleus, differ in their morphology from those of ascending afferent axons in the main thalamic somatosensory (ventrobasal) nucleus. Developing retinal ganglion cell axons in hamsters were made to project permanently to the ventrobasal nucleus, rather than to the lateral geniculate nucleus. With respect to most of the ultrastructural features examined, the terminals and synaptic complexes of mature, anterogradely labeled retino-ventrobasal axons more closely resembled those of normal somatosensory afferents to the ventrobasal nucleus than they did those of normal retinofugal axons within the lateral geniculate nucleus. These results suggest that the ultrastructural differentiation of axon terminals and synaptic complexes is regulated largely by the target environment, although some features appear to be intrinsic to the afferent axons themselves.
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Development of anomalous retinal projections to nonvisual thalamic nuclei in Syrian hamsters: a quantitative study.
When two of the principal targets of retinofugal axons, the superior colliculus and dorsal nucleus of the lateral geniculate body, are ablated in newborn hamsters and the somatosensory (ventrobasal) or auditory (medial geniculate) thalamic nuclei are partially deafferented, the optic axons form permanent, abnormal connections in the latter nuclei. The lateral posterior nucleus of the operated hamsters also receives an anomalously large retinal projection. Here, we report on the results of a quantitative study that was undertaken in order to elucidate how these abnormal connections are formed. In normal, newborn hamsters, there is a transient retinal projection to the ventrobasal nucleus that disappears 3-4 days postnatally. Our quantitative data show that postoperatively, the volume of the retino-ventrobasal projection increases proportionately more than the volume of the ventrobasal nucleus so that the retino-ventrobasal projection in operated adult hamsters is due both to the stabilization of the normally transient projection and to a reactive sprouting that increases the size of the projection. The retino-medial geniculate projection arises de novo by reactive sprouting of optic tract fibers that normally pass over and through the nucleus; in unoperated hamsters, terminating projections are never seen at any age. The quantitative data also show that the anomalously large retino-lateral posterior projection is due almost entirely to the reactive sprouting of the normal projection and/or normal fibers of passage that are already present on the day of birth, although it is possible that a minor component can be attributed to the stabilization of a small population of normally transient retino-lateral posterior axons. The present results demonstrate that the transient retino-ventrobasal axons in normal, newborn hamsters are capable of making permanent connections with ventrobasal neurons. This finding raises the important question of the cellular mechanisms that determine whether immature neuronal connections are stabilized or eliminated. The results also suggest that during both normal and abnormal development, the choice of a target by growing axons may depend upon the axons being in proximity to a potential terminal site just at the time when that site is capable of receiving afferents.
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Retinotectal projection in reeler mutant mice: relationships among axon trajectories, arborization patterns and cytoarchitecture.
The distribution of axons in the midbrain and thalamus of homozygous reeler mutant mice is anomalous. The cytoarchitecture of these regions is normal. In the normal mouse SC there is a distinct SO in which fascicles of retinotectal axons pass caudally before terminating in the overlying SGS. In reeler, by contrast, fascicles of retinotectal axons are distributed through the entire thickness of SGS as well as through SO. There are also abnormalities of fiber pattern in the thalamus, most notably in the region of the dorsal nucleus of the LGd. Retinotectal axon trajectory and patterns of terminal arborization in reeler and normal animals were compared by single-fiber HRP axonography. In normal mice, two distinct morphological classes of retinotectal axons form focal terminal arborizations at different radial levels in the superficial layers of the SC. Class U axons are of relatively small diameter and terminate in upper portions of SGS. Class L1 axons are of larger diameter and form terminal arbors which are confined to SO and deeper regions of SGS. Axons of both classes ascend to their terminal zones from parent axons which course through SO. Similarly, in reeler mice axons of both large and small diameter can be distinguished. However, many axons of both classes pass caudally in anomalous fascicles distributed through the full thickness of SGS and descend to terminate. Other axons pass in normal fashion in SO and ascend to terminate in SGS. Regardless of their trajectories, the small axons terminate superficially in SGS while the thick axons terminate deeper in SGS and/or SO, as in normal mice. These findings suggest that the ingrowth of afferents and the formation of terminal arbors are regulated by different mechanisms and that fiber architecture and cytoarchitecture are regulated by different mechanisms. It is not known if the anomalous fiber pattern in reeler adults arises in development through a defect in initial patterns of axon fasciculation or from a failure of axon elimination.
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Maturation of visual callosal connections in visually deprived kittens: a challenging critical period.
The number of callosally projecting neurons (callosal neurons) which can be labeled in cortical areas 17 and 18 by horseradish peroxidase (HRP), injected in the contralateral visual cortex, is reduced to about 50% of normal in cats reared with their eyelids bilaterally sutured. In the same animals the density of HRP anterogradely transported to areas 17 and 18 is also decreased. The apparent loss of callosal neurons is limited to layers III and IV (subzone a), whereas layer VI (subzone c) is unaffected. The effect is obtained after 3 months or more but not after 1 month of deprivation. Two months of visual experience following deprivation do not restitute a normal number of callosal neurons. However, 10 days of normal visual experience preceding the deprivation are sufficient to prevent the effects of the latter. Animals deprived of vision after a short period of normal visual experience and animals allowed normal vision after 1 month of visual deprivation have a more widespread distribution of callosal neurons than do normal animals; in this way they are similar to previously described cats reared with convergent or divergent strabismus, monocular enucleation, or monocular eyelid suture. The results suggest that: vision is actively responsible for both the maintenance and the elimination of fractions of the juvenile callosal connections; the elimination which normally takes place during the second postnatal month requires normal binocular vision; and activity-dependent competition between callosal and other axons can explain the role of vision.
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Axonal growth and target selection during development: retinal projections to the ventrobasal complex and other "nonvisual" structures in neonatal Syrian hamsters.
In newborn hamsters, there is a direct retinal projection to the ventrobasal complex, the principal thalamic somatosensory nucleus. The projection decreases precipitously between the second and third postnatal days. A few retinofugal axons remain dorsally along the lateral border of the nucleus on day 4, and none are present thereafter. In neonatal hamsters, retinofugal axons project to additional "nonvisual" nuclei including the periventricular and anterior nuclei of the hypothalamus, zona incerta, substantia nigra, inferior colliculus, pons, and mesencephalic tegmentum. Some of these connections remain in adult hamsters, although in apparently reduced density or relative volume, while others disappear. The contribution of transient connections to the normal morphological or functional development of the brain remains to be clarified. The combined results of this and other studies show that the normally transient retino-ventrobasal projection is a substrate for abnormal connections in that it can be permanently stabilized by appropriate neurosurgery on the day of birth.
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Thalamocortical projections in the reeler mutant mouse.
The normal radial distribution of the different neocortical cell classes is inverted in the reeler mutant mouse. The organization of the thalamocortical projection in adult reelers has been investigated by using anterograde degeneration techniques. Thalamocortical axons follow anomalous trajectories to their target cytoarchitectonic fields in the mutant. After leaving the internal capsule, the axons ascend in sigmoid-shaped fascicles to enter a fiber stratum near the cortical surface. The axons course through this superficial stratum until they reach their target fields and then descend to terminate in deeper cortical planes. In the normal animal, by contrast, the axons course tangentially at the interface of the cortex with the subcortical white matter; upon reaching their target fields, they ascend to terminate more superficially in the cortex. Thus, in both genotypes the tangential portions of the axon trajectories pass through the polymorphic cell population. Both with respect to degree of divergence and the radial distribution of terminals within the different cytoarchitectonic fields, the thalamocortical projection in reeler, like that in the normal animal, appears to be composed of two distinct axon classes. The "class I" axons, the less-divergent system which terminates densely in two or three tiers within the cortex, are the subject of the present analysis. The "class I" projections form an orderly cortical representation of the thalamus: Despite distortions in the topography of the reeler thalamus and cortex, both the nucleus to field relationships and the detailed topologic organization of the projection appear to be normal. The terminals of class I projections are distributed in radially segregated tiers that resemble the tiered pattern of termination as in normal mice, and there are field-specific variations in the tiers that, like those of normal mice, are systematically related to variations of cortical cytoarchitecture. Thus, similar mechanisms, which may depend in part on the interaction of ingrowing axons with specific postsynaptic cell surfaces, must determine the restricted radial distribution of thalamocortical projections in both genotypes. However, there is an abnormal mix of somata and dendrites at all radial levels of the mutant cortex, suggesting that the spatial domain of termination of thalamocortical axons may be governed to some extent by factors other than the distribution of specific prospective postsynaptic cell surfaces. The reeler mutation alters the radial but not the tangential structure of the neocortex, suggesting that these two aspects of cortical organization develop under the control of independent mechanisms. The present results suggest that despite the anomalies of radial position, normal relationships between thalamocortical afferents and distinct classes of postsynaptic elements with characteristic radial distributions are largely conserved in reeler. Certain types of aberrant connections are highly probable, however.
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Anomalous visual connections to somatosensory and auditory systems following brain lesions in early life.
When the principal sites of termination of retinofugal axons are removed in newborn hamsters and alternative terminal space is created by partial deafferentation of somatosensory or auditory thalamic nuclei, the optic axons form permanent ectopic connections in those nuclei. In operated hamsters, intraocularly injected radioactive label is transported transneuronally to the somatosensory or auditory cortices, suggesting that these higher order brain structures may process visual information.
Afferent Pathways↗
Orderly anomalous retinal projections to the medial geniculate, ventrobasal, and lateral posterior nuclei of the hamster.
Experiments were performed to determine (1) under what conditions early brain surgery can cause sensory afferents to the thalamus to form connections at abnormal thalamic sites and (2) the extent to which such ectopic projections are receptotopically organized. In newborn Syrian hamsters, two of the retina's principal synaptic targets, the superior colliculus and dorsal lateral genicultae nucleus, were destroyed, respectively, by a direct lesion and by retrograde degeneration following a lesion of the occipital cortex. In th same brains, alternative terminal space for the retinofugal axons was made available in auditory (medical geniculate) or somatosensory (ventrobasal)thalamic nuclei by lesions of ascending auditory or somatosensory pathways, respectively; additional terminal space was made in the lateral posterior nucleus by degeneration of afferents from the superior colliculus. The projections of the contralateral retina were traced in neonatally operated adults by making one or two small peripheral retinal lesions and intraocular injections of 3H-proline 5 days and 1 day, respectively, prior to sacrifice. The neonatal surgery reliably produced anomalous crossed retinal projections to the partially deafferented structures. These projections terminate preferentially at the nuclear surfaces. Computer reconstructions from serial sections demonstrated several signs of spatial order suggestive of receptotopic organization in the anomalous retinothalamic projections. In order of increasing stringency, these signs (which are not mutually exclusive) are: (1) In each nucleus, a restricted retinal sector gives rise to a limited part of the abnormal projection. (2) In each nucleus, different parts of the retina give rise to different parts of the anomalous projection. (3) In each nucleus, there is more or less consistent polarity of the anomalous connection. Each small retinal sector appears to be represented along a "line of projection" in each of its abnormal thalamic targets, as it normally is in the dorsal and ventral lateral geniculate nuclei and in the superior colliculus. In some brains, some of the abnormal projections produce only a partial representation of the retina. However, in a single animal, a retinal sector not represented in the anomalous projections to one nucleus can contribute to the abnormal connections with another nucleus. In additional experiments, and attempt was made to direct developing auditory and somatosensory fibers normally terminating in the medial geniculate and ventrobasal nuclei, respectively, to anomalous thalamic targets. The axons were deprived of some of their normal thalamic sites of termination and alternative terminal space was made available in another thalamic sensory nucleus. These experiments failed to produce reliable evidence of ectopic auditory or somatosensory thalamic projections.
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Tangential organization of thalamic projections to the neocortex in the mouse.
Using the anterograde degeneration technique, we examine the tangential organization of a thalamofugal axon population (class I of Frost and Caviness, '80) whose terminations are preferentially distributed to the middle tier (located in layers III and/or IV) of three radially separated tiers of thalamic projections to the neocortex. Less extensive data are also presented on the tangential organization of thalamofugal axon populations (class II of Frost and Caviness, '80) that do not terminate preferentially in the middle tier, but that are otherwise heterogeneous with respect to their radial pattern of intracortical termination. The projections of class I axons are distributed to all neocortical fields with the possible exception of fields 13,25, and 35. The class I projections to a given cortical field (with the possible exception of the cortex of the second somatosensory representation) originate in only one thalamic nucleus. The class I projections of an individual thalamic nucleus form a cortical representation of the nucleus that constitutes a "first order line-to-line" (topologic) transformation of the nuclear volume. The ensemble of class I projections forms a cortical representation of the corresponding thalamic regions that constitutes a "second order line-to-line" (non-topologic) transformation of the thalamic volume. Class II axons project to all neocortical fields. Classs II and class I projections contrast in that the class II projections of multiple thalamic nuclei overlap in the tangential plane of any given sector of the cortex. While the class II projections of the intralaminar nuclei and the widely projecting ventromedial nucleus are known to be topologically organized, the tangential organization of class II projections arising in other nuclei is incompletely understood.
Afferent Pathways↗
Radial organization of thalamic projections to the neocortex in the mouse.
The intracortical distributions of the thalamic projections to a large number of neocortical fields are studied by the anterograde degeneration methods in the mouse. The basic radial distribution of terminating thalamofugal axons is uniform throughout the mouse cortex and is essentially the same as that encountered in other mammalian species. Terminating axons are concentrated in three tiers: an outer tier in layer I, a middle tier in layers IV and/or III, and an inner tier in layer VI. In most fields, terminating axons also extend, to some extent, into layer V. Variations are encountered from field to field, particularly in the density and degree of divergence of projections and in the radial extent of individual tiers with respect to cytoarchitectonic layers. In accord with other studies, the thalamic projections to each field appear to be composed of two general axon classes. Class I axons terminate densely in the middle tier, seem to be of large caliber, and often have collaterals to the other tiers. Class II axons do not terminate densely in the middle tier and seem to be of small caliber. Terminating class II axons may be distributed to one or more tiers and may be concentrated in the inner and/or outer tiers. The thalamic projection to each field has its origin in multiple nuclei. All thalamic nuclei projecting to the neocortex appear to have class II projections and many also have class I projections. Patterns of degeneration in the cortex associated with lesions in different positions in many nuclei suggest that thalamic relay neurons are organized along "lines of projection"--neurons in the same line projecting to the same tangentially restricted cortical region. The neurons of origin of class I and class II axons are intermixed along the lines of projection.
Afferent Pathways↗
The postnatal development of visual callosal connections in the absence of visual experience or of the eyes.
Counts of callosal neurons retrogradely labeled by horseradish peroxidase (visualized using multiple substrates) were obtained in areas 17 and 18 of five kittens reared with their eyelids bilaterally sutured and of three kittens which had undergone bilateral enucleation on postnatal days 1--4. These counts were compared with those obtained in normal adult cats. The normal adult distribution of the callosal neurons results from the gradual postnatal reduction of a more widespread juvenile population. Binocular visual deprivation by lid suturing dramatically decreases the final number of callosal neurons and narrows their region of distribution (callosal zone) in areas 17 and 18. A less severe reduction in the final number of callosal neurons is caused by bilateral enucleation, which also increases the width of the callosal zone compared to that of normal cats. Thus, visual experience is necessary for the normal stabilization of juvenile callosal connections. However, since some callosal neurons form connections in the absence of vision, other influences capable of stabilizing juvenile callosal neurons also exist. These influences are probably antagonized by destabilizing influences or inhibited, when the eyes are intact.
Aging↗
Effects of visual experience on the maturation of the efferent system to the corpus callosum.
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