Model-based analysis of excitatory lateral connections in the visual cortex

Excitatory lateral connections within the primary visual cortex are thought to link neurons with similar receptive field properties. Here we studied whether this rule can predict the distribution of excitatory connections in relation to cortical location and orientation preference in the cat visual cortex. To this end, we obtained orientation maps of areas 17 or 18 using optical imaging and injected anatomical tracers into these regions. The distribution of labeled axonal boutons originating from large populations of excitatory neurons was then analyzed and compared with that of individual pyramidal or spiny stellate cells. We demonstrate that the connection patterns of populations of nearby neurons can be reasonably predicted by Gaussian and von Mises distributions as a function of cortical location and orientation, respectively. The connections were best described by superposition of two components: a spatially extended, orientation-specific and a local, orientation-invariant component. We then fitted the same model to the connections of single cells. The composite pattern of nine excitatory neurons (obtained from seven different animals) was consistent with the assumptions of the model. However, model fits to single cell axonal connections were often poorer and their estimated spatial and orientation tuning functions were highly variable. We conclude that the intrinsic excitatory network is biased to similar cortical locations and orientations but it is composed of neurons showing significant deviations from the population connectivity rule.     

Reciprocal point-to-point connections between parastriate and striate cortex in the squirrel monkey (Saimiri)

Experimental-anatomical evidence is presented that in Saimiri two fiber systems project from area 18 upon area 17. Both systems terminate exclusively in layer I of area 17; in some other respects they exhibit characteristic differences. The fibers of the Horizontal System ascend from their origin in area 18 directly into layer I where they travel horizontally and parallel to each other to their termination site in area 17. This system is locally restricted since it connects only posterior area 18 with anterior area 17, i.e., it connects portions of both areas located near the representation line of the zero vertical meridian of the visual field. The fibers of the U-fiber System arise from the supragranular layers of area 18. They reach their termination site in area 17 via the white matter from which they ascend perpendicularly into layer I. The U-fiber system establishes a mirrorimage point-to-point connection between area 18 and area 17. This finding combined with the results of previous reports describing the similarly ordered association of area 17 with area 18 demonstrates a precisely organized reciprocal point-to-point connection between areas 17 and 18.     

Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis

Recently, the excitatory amino acid neurotransmitter glutamate was implicated in the pathogenesis of a variety of chronic degenerative neurological diseases in humans and animals. This report describes abnormalities in excitatory amino acids in the central nervous system of 18 patients with amyotrophic lateral sclerosis (ALS). The concentration of the excitatory amino acids glutamate and aspartate in the cerebrospinal fluid were increased significantly (p less than 0.01) by 100 to 200% in patients with ALS. Similarly, the concentrations of the excitatory neuropeptide N-acetyl-aspartyl glutamate and its metabolite, N-acetyl-aspartate, were elevated twofold to threefold in the cerebrospinal fluid from the patients. There was no relationship between amino acid concentrations and duration of disease, clinical impairment, or patient age. In the ventral horns of the cervical region of the spinal cord, the level of N-acetyl-aspartyl glutamate and N-acetyl-aspartate was decreased by 60% (p less than 0.05) and 40% (p less than 0.05), respectively, in 8 patients with ALS. Choline acetyltransferase activity was also diminished by 35% in the ventral horn consistent with motor neuron loss. We conclude that excitatory amino acid metabolism is altered in patients with ALS. Based on neurodegenerative disease models, these changes may play a role in motor neuron loss in ALS.     

Visuotopic organization of projections from striate cortex to inferior and lateral pulvinar in rhesus monkey

Anatomical material from two series of monkeys (Macaca mulatta)was used to determine the full extent and visuotopic organization of striate projections to the pulvinar. One series was processed for degeneration by the Fink-Heimer procedure following unilateral lesions of lateral, posterior, or medial striate cortex (representing the central, peripheral, and far peripheral visual field, respectively); collectively, the lesions included all of area 17. The second series was processed for autoradiography following tritiated amino-acid injections into striate sites representing the center of gaze and eccentricities ranging from 0.5° to greater than 30° from fixation in both the upper and lower fields. The results indicate the existence of two separate striate projection zones within the pulvinar. One, the PI/PL zone, is located primarily within the inferiorpulvinar (PI) but extends into the adjacentlateral pulvinar (PL). The other, the PL zone, is located entirely within the lateral pulvinar and partially surrounds the first zone along its dorsal, lateral, and ventral aspects. Within the PI/PL zone, striate projections are topographically organized and represent the entire contralateral visual field. Central vision is represented laterally and posteriorly, with the fovea represented at the caudal pole of the nucleus; conversely, far peripheral vision is found medially and anteriorly, adjacent to the medial geniculate nucleus. The representation of the horizontal meridian runs obliquely across PI/PL, such that the upper visual field is located ventrolaterally and the lower visual field dorsomedially. The representation of the vertical meridian is located along the lateral margin of PI in anterior sections of the pulvinar, but within PL in posterior sections. Thus, the vertical meridian appears to form the border between the lateral margin of the PI/PL zone and the medial margin of the PL zone. At the lateral margin of the PL zone is the representation of its horizontal meridian. Striate projections to the PL zone, unlike those to the PI/PL zone, are limited to the representation of central vision. These results suggest that striate inputs contribute to the visual properties of neurons (Bender, 1981 a) throughout the PI/PL zone, but are insufficient to explain the visual properties of neurons outside of the central visual field representation in the PL zone.     

Corticothalamic connections of suprasylvian cortex in monkey

Cortical lesions were made along the superior border of the sylvian fissure in 11 squirrel and four macaque monkeys. The course of degenerating fibers in the thalamus was determined by utilizing the Nauta and Fink-Heimer I techniques. The principal projection sites of suprasylvian cortex were found to be the nuclei ventralis posterior medialis, ventralis posterior lateralis, ventralis posterior inferior, pulvinaris oralis, and pulvinaris medialis. Lesser amounts of terminal degeneration occurred in the nuclei reticularis, ventralis lateralis, lateralis posterior, the intralaminar nuclei, and the posterior and pretectal areas of the thalamus. The connections of the suprasylvian cortex that corresponds to somatosensory area II with a phylogenetically new thalamic nucleus, the pulvinaris oralis, suggests a specialization of SII functions in the monkey.     

The morphology and distribution of striate cortex terminals in the inferior and lateral subdivisions of the Macaca monkey pulvinar.

The origin of the various types of axon terminals in Macaca pulvinar remains uncertain because of the contradictory results obtained in EM degeneration studies. We have used EM-autoradiography to determine the morphology of terminals in the inferior and lateral pulvinar which originate from neurons in visual cortex. After injections of H3 proline into area 17, both the small diameter (RS) and the large diameter (RL) terminals containing round vesicles and making asymmetric contacts are labeled in the two pulvinar subdivisions. Labeled and unlabeled terminals are intermixed within the pulvinar focus which suggests that the dendrites of the same pulvinar neuron receive overlapping inputs from several cortical areas. Because only 5% of the pulvinar terminals are RLs (Ogren and Hendrickson, '79), and this small number of RLs originates from at least two visual cortical areas plus the superior colliculus (Partlow et al., '77), superior colliculus input to inferior pulvinar is small compared to the combined RS and RL cortical input. Together the findings from this study and the preceding paper (Ogren and Henderickson, '79), show that while pulvinar is typical of other thalamic nuclei in the structure of its neurons and synapses, it differs in that the input from subcortical structures is minimal. It is suggested that inferior and lateral pulvinar function principally as integrators of visula cortical information.     

Interlaminar connections of rat visual cortex: An ultrastructural study

Thermal lesions were made in layers I, II, and upper part of layer III of rat visual cortex. The distribution of degenerating axons and axon terminals in layers IV, V, and VI was studied using electron microscopic techniques. Following supragranular thermal lesions, the majority of degenerating axon terminals were found in layer V, with extension into the adjacent part of layer VI. Neural profiles postsynaptic to degenerating axon terminals were found in these layers in the following distribution: 81.7% on spines of small to medium size dendrites; 18.2% on dendrite shafts; and <1% on neuronal perikarya. Few degenerating terminals were found on or near apical dendrites. Degenerating terminals were identified on shafts of stellate-type dendrites found in the upper part of layer V. Degenerating axons oriented parallel to the cortical surface were found most often in deep layer IV and upper layer V. Degenerating axons were also seen in axon bundles coursing vertically through layer IV. Approximately 10% of the terminals within a grid square have undergone degeneration; no clustering of degenerating terminals was found in vertical or transverse sections through layers V and VI. We suggest that most axon terminals arising from pyramidal neurons in layers II and upper III synapse with spines and shafts of dendrite branches originating from pyramidal neurons in layer V and perhaps VI.     

Local circuits and ocular dominance columns in monkey striate cortex

The relationships between ocular dominance columns and intrinsic cortical circuitry were examined in brain slices prepared from the striate cortex of macaques. Ocular dominance columns in layer 4C beta were visualized in vitro following anterograde transport of rhodamine injected into the lateral geniculate nucleus in vivo. The axonal and dendritic arborizations of individual layer 4C beta cells were revealed by intracellular fluorescent dye injections. Both qualitative observations and quantitative analysis showed that the dendrites of cells close to borders remained preferentially, although not absolutely, in the "home" column (the column containing the cell body). Thus, the segregated pattern of afferent input appears to have considerable influence on the pattern of dendritic arbors. Similarly, while axon collaterals within layer 4C beta could cross into the adjacent column, their limited lateral spread produced arbors that remained primarily within the home column. The terminal arbors of collaterals that travelled from layer 4C beta to layer 3 had a larger lateral spread, and the termination pattern appeared to be independent of column borders. Thus, our observations indicate that, while the course of many layer 4C beta dendrites appears to be guided by columnar boundaries as defined by geniculate afferents, there exist morphological substrates for intercolumnar interactions even between 4C beta cells. Intercolumnar interactions are seen more commonly in layer 3, however, where larger, denser axon arbors originating from 4C beta cells can freely cross ocular dominance column boundaries.     

Ordinal position and afferent input of neurons in monkey striate cortex

From the extracellular recording of single units in the monkey striate cortex and electrical stimulation at two selected sites in the optic radiations it was possible to estimate 1) the ordinal position of striate neurons (i.e., whether they received a monosynaptic, disynaptic or polysynaptic input from the thalamus) and 2) the nature of the afferent input to these neurons (i.e., whether it came from the magnocellular or parvocellular subdivision of the lateral geniculate nucleus (LGN)). Based on receptive field properties six major classes of striate neuron were identified--three which lacked orientation specificity (the ON-center, the OFF-center, and the ON/OFF or nonoriented (N-0) receptive fields) and three with orientation specific responses (the S, the C, and the B categories of receptive field). Units lacking orientation specificity were concentrated in laminae 4A, 4C beta and 6 while, for the cells with orientation specificity, C cells were found in laminae 4B and 6, B cells in 2/3 and 5, and S cells predominantly in laminae 2/3, 4C alpha, and 5. The results of electrical stimulation indicated that cell-to-cell transmission time in the monkey striate cortex is 1.5 msec, and latency measures showed that cells with a monosynaptic drive from the thalamus were confined to laminae 4 and 6 while disynaptically driven cells were found principally in upper lamina 4 (4A and 4B). No cell class was identified exclusively with a given ordinal position and there were many types of potential first-order neurons. The conduction time from one stimulating electrode to the next in the optic radiation was used to identify the afferent input to each striate neuron. The input to color-coded neurones was found to come exclusively from parvocellular layers while the C cells and two subclasses of the S cell (S2 and S3) were driven predominantly by the magnocellular subdivision. For other cell types (those with ON-center, N-0, and S1 receptive fields) the input came from either type of LGN neuron. The laminar distribution of neurons receiving a direct input from the magnocellular and parvocellular streams is in accord with the results of anatomical studies into the site of termination of the LGN input. The cell types receiving these direct inputs vary in the two streams so that the parvocellular input terminates on cells with ON-center and N-0 receptive fields in lamina 4C beta while the magnocellular input goes to cells with S, ON-center, N-0, and C receptive fields in lamina 4C alpha and the lower part of 4B. Consideration is given to the influence of these results on models for neural processing in monkey striate cortex and a comparison is drawn with the results of similar studies in the cat.     

Intrinsic excitatory connections in the prefrontal cortex and the pathophysiology of schizophrenia

Working memory, a fundamental cognitive process that is disturbed in schizophrenia, appears to depend upon the sustained activity of specific populations of neurons in the prefrontal cortex. Understanding the neural mechanism(s) that may contribute to the sustained activity of these neurons represents a critical step in predicting the types of alterations in prefrontal circuitry that may be present in schizophrenia, and in determining how such alterations may contribute to the cognitive symptoms of this disorder. This article reviews recent findings which suggest that intrinsic horizontal connections among pyramidal neurons in layer 3 of the dorsolateral prefrontal cortex may provide a critical anatomical substrate for working memory processes, and that alterations in these connections may account for the observations of disturbed working memory, adolescence-related onset of clinical features, and certain pathological changes in the prefrontal cortex of subjects with schizophrenia.     

Developmental profiles of SMI-32 immunoreactivity in monkey striate cortex

A monoclonal antibody that recognizes a nonphosphorylated epitope on the medium and high molecular weight subunits of neurofilament (NF) proteins was used to investigate laminar and cell morphology changes in monkey striate cortex during post-natal development. Six cortices were obtained from monkeys of a variety of ages: five from developing animals with ages spanning the critical period and one adult. At post-natal day (PD) 0, immunohistochemistry with the SMI-32 antibody revealed immunoreactive (IR) cells in layer IVB and in infragranular layer VI. Early in the critical period (PD 7), these layers become more defined with an increase in the density of immunopositive cells. At the height of the critical period (PD 30 and 42), a drastic increase in the density of SMI-32 labelled pyramidal neurons in layers V and VI was observed. Similarly, layer IVC showed an abundance of dendritic fragments and dendrites that appeared to originate from the infragranular layers. At the end of the critical period (PD 103), a trend toward morphological maturation for individual neurons found within each layer was observed. During any developmental time point, neurons at first appearance tended to show an immature morphology with staining largely restricted to the cell bodies. As such, the characteristic arborizations common to mature pyramidal and multipolar cells was not evident. We propose that the staining pattern seen in this study is consistent with the idea that layers anatomically associated with the magnocellular (M) pathway develop earlier than their parvocellular (P) counterparts.     

Parvalbumin in the monkey striate cortex: a quantitative immunoelectron-microscopy study

Parvalbumin (PV) is present in a subpopulation of interneurons in the visual cortex, and also in thalamic afferents to the neocortex of primates. The object of this study is to confirm by immunoelectron-microscopy the presence of intrinsic and extrinsic connections containing parvalbumin in the monkey visual cortex, by the demonstration of parvalbumin-immunoreactivity in symmetric and asymmetric synapses. We analyzed the distribution of parvalbumin-immunoreactive profiles at the ultrastructural level in the primary visual cortex of old world monkeys (Macaca fascicularis). It has been shown by others that parvalbumin-immunoreactive cells resemble non-spiny stellate cells, double-bouquet cells, chandelier and basket cells. These neurons are known to be inhibitory and to form symmetric synapses. In fact, we observed that the vast majority of parvalbumin-immunoreactive synaptic contacts in the primary visual cortex of Macaca fascicularis are of the symmetric type (81.7%). Since parvalbumin-positive asymmetric contacts are also present (18.3%) and occur mostly in the thalamic recipient layers, 4C and 4A (9.9%), these afferents probably derive from parvalbumin-immunoreactive neurons located in the dorsal lateral geniculate nucleus of the thalamus.     

Intrinsic connections of macaque striate cortex: afferent and efferent connections of lamina 4C

We have studied the intrinsic organization of macaque striate cortex by tracing the pattern of horseradish peroxidase (HRP)-labeled axons and cell bodies produced by microinjections of HRP into single cortical laminae. Both anterograde and retrograde transport results were used to examine: (1) the pattern of projections from lamina 4C to the superficial layers; (2) the projection from lamina 4C to deeper cortical layers; and (3) the projections to lamina 4C from other cortical laminae. Laminae 4C alpha and 4C beta differ in their pattern of projections to the superficial layers of striate cortex. Axons from neurons in lamina 4C beta ascend through lamina 4B without giving off collaterals and terminate in lamina 4A and in the base of lamina 3. By contrast, axons from neurons in lamina 4C alpha terminate in lamina 4B and less densely in the 4A/3B region. The projection from lamina 4C beta to lamina 4A is particularly dense and is distributed in a patchy fashion immediately above each injection site. The projection from lamina 4C beta to lamina 3B appears less dense and more widespread; we estimate that individual 4C beta axons may spread laterally for more than 400 micron. Furthermore, the pattern of HRP-labeled cell bodies in lamina 4C beta following injections into laminae 4A and 3B provides evidence for a subdivision within 4C beta. These injections always produce a large number of labeled neurons in the upper part of lamina 4C beta, whereas the lower portion contains few labeled neurons that are located immediately under the center of the injection site. Both lamina 4C alpha and lamina 4C beta also contribute less dense projections to the deeper layers of cortex. Lamina 4C beta projects mainly to lamina 6, whereas lamina 4C alpha contributes axon terminals to both lamina 5A and lamina 6. Neurons in lamina 6 provide the bulk of the intracortical projections to lamina 4C. The axons of these neurons are fine in caliber and have a delicate side-spine morphology that is quite distinct from lateral geniculate axon arbors. Neurons in lamina 5A also project onto lamina 4C, but the projections of these neurons appear concentrated in lamina 4C alpha. These results confirm or refine many conclusions about intrinsic connections of striate cortex drawn from Golgi material and suggest new patterns of connections not suspected from previous work.     

Development of the calcium-binding protein parvalbumin and calbindin in monkey striate cortex.

The development of immunoreactivity for the calcium-binding proteins parvalbumin (PV) and calbindin-D28K (Cal) was studied in Macaca nemestrina striate cortex from fetal (F) 60 days to postnatal (P) 5 + years. We correlated changes in PV and Cal staining patterns with the well-documented developmental sequence for primate striate cortex neuron generation and maturation, synaptogenesis, and thalamocortical axon interactions in an attempt to deduce a functional role for these proteins. Our major findings is that Cal and PV have diametrically opposed developmental patterns except in layer 1. At F60 days both are present only in neurons of layer 1 and the number of labeled cell bodies and processes increases up to F125 days. Almost all Cal+ and PV+ cells in layer 1 disappear by P12 weeks. Cal is present by F113 days in pyramidal and stellate neurons, particularly layers 4-6. The numbers and staining density of cells in layers 2-6 increases up to birth and then both decline by P9-12 weeks. Supragranular layers show a second increase in Cal labeling from P20-36 weeks, and then there is a slow decline to the adult pattern which is reached by P1-2 years. Cell bodies in layers 4A, 4C alpha, and deep 4C beta are heavily Cal+ during pre- and early post-natal periods, but upper 4C beta remains unlabeled. PV is not seen until F155-162 days in layers 2-6. Large stellate and a few pyramidal cells appear first in layers 5/6 and 4C alpha, but PV+ stellate neurons are found in all layers except 4C beta by P6 weeks. Layer 4C beta contains a few PV+ cell bodies at P3 weeks, and light neuropile staining at P6 weeks, but then PV labeling rapidly increases so that by P12 weeks the density of 4C beta exceeds that of 4C alpha. Striate cortex has an adult pattern of cell number and neuropile density by P20 weeks. These developmental patterns suggest that the highest density of Cal cell body staining does not correlate with synaptogenesis, or the postnatal critical period of visually driven, binocular interactions. Rather Cal appears when lateral geniculate axons arrive in cortex, persists over the entire span of thalamocortical interactions, and disappears during the decline of cortical plasticity. The appearance of PV is highly correlated with the onset of complex visually driven activity at birth, while both the number of PV+ cell bodies and the density of PV+ neuropile reach adult levels coincident with the completion of thalamocortical connections.     

Dendritic sampling across processing streams in monkey striate cortex.

Cytochrome oxidase (CO) dense blobs in primate striate cortex provide a striking example of parallel processing of visual information. The level of isolation of the blobs from the surrounding interblob tissue was investigated in the present study by combining CO staining with Golgi impregnation of dendritic arbors in the same tissue sections. The data are based on material from two marmoset and three squirrel monkeys. The analysis was conducted on two types of Golgi preparations. In the first preparation, dense networks of overlapping dendrites were impregnated over blob margins. The results of analyzing these networks with transmission and confocal microscopy revealed that dendritic arbors penetrate freely through blob margins. Statistical analysis revealed that the density of dendritic crossings at blob margins was similar to that found at blob and interblob centers. In the second type of Golgi preparation, single, isolated neurons were impregnated. Studies of such neurons revealed occasional examples of dendritic arbors that appeared to reflect back from blob margins, but counter examples were equally abundant. Bias index analysis indicated that dendritic arbors were generally unaffected by the presence of a nearby blob margin. Scanning a large number of impregnated arbors indicated that at least half of the population of blob-related neurons had dendrites in both blob and interblob territory. Under the conditions of free dendritic penetration of blob margins, the sole factor that determines the level of blob/interblob mixing appears to be the relationship between blob size and the dendritic spread of blob neurons. Interestingly, in both the marmoset and squirrel monkeys this size ratio is similar despite a large difference in their cortical surface area. Thus, it is hypothesized that blob size is optimally matched to the dendritic span so as to create a smooth transition of dendritic sampling from blob to interblob-related processing streams.     

Residual spatial vision in the monkey after removal of striate and preoccipital cortex

Rheusus monkeys were trained to discriminate the angular velocity of moving stimuli and to reach accurately toward lighted targets. They were able to recover good performance of these tasks after large bilateral lesions that removed, in successive stages, all of striate cortex and almost all of areas OA, OB, and TEO of preoccipital cortex.