Comparison of Intrinsic Connectivity in Different Areas of Macaque Monkey Cerebral Cortex

We have used small injections of biocytin to label and comparepatterns of intreareal, laterally spreading projections of pyramidalneurons in a number of areas of macaque monkey cerebral cortex.In visual areas (V1, V2, and V4), somatosensory areas (3b, 1,and 2), and motor area 4, a punctate discontinuous pattern ofconnections is made from 200-µm-diameter biocytin injectionsin the superficial layers. In prefrontal cortex (areas 9 and46), stripe-like connectivity patterns are observed. In allareas of cortex examined, the width of the terminal-free gapsis closely scaled to the average diameter of terminal patches,or width of terminal stripes. In addition, both patch and gapdimensions match the average lateral spread of the dendriticfield of single pyramidal neurons in the superficial layersof the same cortical region. These architectural features ofthe connectional mosaics are constant despite a twofold differencein scale across cortical areas and different species. They thereforeappear to be fundamental features of cortical organization.A model is offered in which local circuit inhibitory "basket"interneurons, activated at the same time as excitatory pyramidalneurons, could veto pyramidal neuron connections within eithercircular or stripe-like domains; this could lead to the formationof the pattern of lateral connections observed in this study,and provides a framework for further theoretical studies ofcerebral cortex function.     

Processing of Contrast Polarity of Visual Images in Inferotemporal Cortex of the Macaque Monkey

Cells in the anterior part of the inferotemporal cortex (anteriorIT) respond to moderately complex stimulus features of objectimages. To study dependency of their responses on contrast polarityof stimulus images, we selected cells with optimal stimuli thatwere defined only by shape and not related to texture or color,and examined effects of reversing the contrast of the imageor removing it except for edges between dark and bright partsof the image ("outlining").The contrast reversal produced areduction of the response to the optimal stimulus by >50%in 60% of tested cells; the outlining, in 70%. When the twotransformations were considered together, 94% of the cells showeda reduction by >50%. Effects of the transformations on shapeselectivity were also studied by comparing responses to severaldifferent shapes each of whose contours were expressed in differentways. Statistically significant changes in relative effectivenessof the different shapes as a function of contour expressionwere observed in more than half of the cells. These resultssuggest that responses of individual cells in anterior IT carryinformation about contrast polarity as well as about shape.     

Direct Temporal-Occipital Feedback Connections to Striate Cortex (V1) in the Macaque Monkey

Although there have been reports of sparse projections fromtemporal areas TE, TF, and even TH to area V1, it is generallybelieved that cortical afferents to V1 originate exclusivelyfrom prestriate areas. Injections of anterograde tracers inanterior occipital and temporal areas, however, consistentlyproduce labeled terminals in area V1. In order to confirm theseresults and display the full range of foci projecting to V1,we injected V1 in two monkeys with the retrograde tracer fastblue. Feedback connections were found, as expected, from severalprestriate areas (V2, V3, V4, and MT). These originate fromneurons in layers 3A and 6. Connections were also found fromseveral more distal regions, namely, areas TEO, TE, TF, TH,and from cortex in the occipitotemporal and superior temporal(STS) sulci. Filled neurons occurred in two small foci in thecaudal intraparietal sulcus. These more distal feedback connectionstend to originate only from layer 6. An additional injectionof the retrograde tracer diamidino yellow in area V2 of oneanimal revealed a similarly widespread network of feedback connections.In some areas (In the STS and in TEO), 10–15% of fluorescentneurons were double-labeled. These results indicate that feedback connections to early visualcortex derive from a widespread network of areas, includinglimbic-associated cortices. These connectional patterns testifyto the massive recursiveness of anatomical pathways. As thereare no reports of projections from V1 to anterior temporal cortices,our results also indicate that some cortical feedback connectionsmay not be strictly reciprocal.     

Relation between Patterns of Intrinsic Lateral Connectivity, Ocular Dominance, and Cytochrome Oxidase-Reactive Regions in Macaque Monkey Striate Cortex

To help understand the role of long-range, clustered lateralconnections in the superficial layers of macaque striate cortex(area V1), we have examined the relationship of the patternsof intrinsic connections to cytochrome oxidase (CO) blobs, interblobs,and ocular dominance (OD) bands, using biocytin based neuroanatomicaltracing, CO histochemistry, and optical imaging. Microinjectionsof biocytin in layer 3 resulted in an asymmetric field (averageanisotropy of 1.8; maximum spread—3.7 mm) of labeled axonterminal clusters in layers 1–3, with the longer axisof the label spread oriented orthogonal to the rows of blobsand imaged OD stripes, parallel to the V1/V2 border. These labeledterminal patches (n = 186) from either blob or interblob injections(n = 20) revealed a 71% (132 out of 186) commitment of patchesto the same compartment as the injection site; 11% (20 out of186) to the opposite compartment, and 18% (34 out of 186) toborders of blob-interblob compartments, indicating that theconnectivity pattern is not strictly blob to blob, or interblobto interblob (p < 0.005; $$$²) In injections placed withinsingle OD domains (n = 11), 54% of the resulting labeled terminalpatches (43 out of 79) fell into the same OD territories asthe injection sites, 28% (22 out of 79) into the opposite ODregions, and 18% (14 out of 79) on borders, showing some connectionalbias toward same-eye compartments (p < 0.02; ANOVA). Individualinjection cases, however, varied in the degree (50–100%for CO patterns, 22–100% for 0D patterns) to which theyshowed same-compartment connectivity. These results reveal thatwhile connectivity between similar compartments predominates(e.g., blob to blob, right eye column to right eye column),interactions do occur between functionally different regions.     

Postnatal Maturation of the Direct Corticospinal Projections in the Macaque Monkey

Postnatal changes in the topography of the multiple corticospinalprojections in the macaque monkey were followed using retrogradelytransported fluorescent tracers, and related to the monkey'sacquisition of manual dexterity; both behavioral and anatomicalmaturation were completed by about 8 postnatal months. Cortical origins of the corticospinal projections were examinedby constructing planar projection maps of the distributionsof labeled corticospinal neuron somas; these somas were foundonly in lamina V. At birth elaborate somatotopically organizedcorticospinal projections from primary motor cortex (area 4),the mesial supplementary motor area and cingulate areas 23 and24, area 12, dorsolateral area 6aß, the dorsolateraland ventral area 6e     

Development of Inferior Temporal Cortex in the Monkey

Inferior temporal (IT) cortex is critical for visual patternrecognition in adult primates. However, the functional developmentof IT cortex appears to be incomplete until late in the firstyear of life in monkeys and probably beyond. Responses of neuronsin IT are substantially weaker, of longer latency, and moresusceptible to anesthesia within at least the first half yearof life. In addition, refinement of connections of IT, particularlythose with regions in the opposite hemisphere and with regionsrelated to memory and attention, continues for at least severalmonths after birth. Moreover, many of the pattern recognitionfunctions that IT supports in adulthood themselves show a veryprotracted period of development, and damage to IT cortex ininfancy appears to have relatively little effect on patternrecognition abilities, despite the pronounced effects of comparabledamage in adulthood. These findings all suggest that IT undergoesan extended period of postnatal development, during which bothvisual experience and the maturation of other brain structuresmay contribute to the emergence of mechanisms of pattern recognitionwithin IT. In other respects, fundamental characteristics of IT emergequite early. For example, despite their weaker responses, ITneurons have adult-like patterns of responsiveness—includingpronounced form selectivity and large bilateral receptive fields—asearly as we were able to test (     

Mechanisms of Stereopsis in Monkey Visual Cortex

A substantial proportion of neurons in the striate and prestriatecortex of monkeys have stereoscopic properties; that is, theyrespond differentially to binocular stimuli that are known inhumans to provide cues for stereoscopic depth perception. Stereoscopicneurons, as these cells may be called, are selective for horizontalpositional disparity (i.e., display disparity selectivity) andfor the textural correlation between images over their receptivefields (i.e., they show correlation selectivity). Many neuronshave tuned disparity response profiles that collectively coverthe entire range of physiological disparities. Neurons withpeak responses at or about the zero disparity ("tuned zero neurons,"excitatory or inhibitory) have narrow and symmetrical profiles.Neurons that are tuned to larger disparities, either crossed("tuned near neurons") or uncrossed ("tuned far neurons"), havebroader excitatory profiles that are asymmetrically wider towardthe smaller disparities, and commonly include an inhibitorycomponent about the zero disparity. Other stereoscopic neuronshave reciprocal profiles ("near" or "far" neurons, respectively)in the sense that they respond with excitation to crossed oruncrossed disparities, and with suppression to disparities ofopposite sign. Stereoscopic neurons can also signal the texturalcorrelation between paired retinal images by giving differentresponses to random-dot patterns that have, and to those thatdo not have, the same dot distribution over the neuron's leftand right receptive fields. Tuned-zero excitatory neurons characteristicallyrespond to uncorrelation with suppression; tuned-zero inhibitoryneurons, with excitation; and both types give the opposite responsesto correlated stereopatterns. Neurons selective for nonzerodisparities, both tuned and reciprocal, also give excitatoryresponses to uncorrelated stimuli, but these responses are smallerand more variable than those evoked by correlated patterns atthe effective disparities. These findings suggest that stereoscopicneurons in the visual cortex of the macaque comprise three operationalsystems: (1) a zero-disparity system that is involved in finedepth discrimination with the obligatory singleness of vision,and the maintenance of vergence; and (2) a near-, and (3) afar-disparity system that together signal qualitative estimatesof depth with double vision, and vergence responses to largedisparities.     

Halothane and Diazepam Inhibit Ketamine-induced c-fos Expression in the Rat Cingulate Cortex

Background: Ketamine, a noncompetitive N-methyl-D-aspartate antagonist, has psychotomimetic side effects. Recent studies have shown that noncompetitive N-methyl-D-aspartate antagonists cause morphologic damage to the cingulate and retrosplenial cortices and induce c-fos protein (c-Fos) in the same regions. Although benzodiazepines are effective in preventing these side effects, the neural basis of the drug interactions has not been established.

Methods: The effects of diazepam and halothane on c-Fos expression induced by ketamine were studied. Diazepam (1 and 5 mg/kg) or vehicle were administered subcutaneously, followed 7 min later by 100 mg/kg ketamine given intraperitoneally. Halothane (1.0 and 1.8%), was administered continuously from 10 min before ketamine administration until brain fixation. Two hours after ketamine injection, rats were perfused and their brains fixed and extracted. Brain sections were prepared in a cryostat and c-Fos expression was detected using immunohistochemical methods.

Results: Ketamine induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices, thalamus, and neocortex. Diazepam suppressed the ketamine-induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices in a dose-dependent manner, leaving the thalamus and neocortex less affected. Halothane suppressed the ketamine-induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices and the neocortex in a dose-dependent manner, leaving the thalamus relatively unaffected.     

Evidence for Visual Cortical Area Homologs in Cat and Macaque Monkey

The maps of visuotopically discrete visual cerebral corticalareas in the cat and the macaque monkey are compared and gapsin knowledge are identified that limit such comparisons. Catareas 17, 18, and 19 can be equated with macaque areas VI, V2,and V3, respectively, based on criteria of relative positionin the cortical mantle, internal organization of visual fieldrepresentations, and trans- and subcortical connections. Usingthese same criteria, a visual area on the medial bank of thelateral suprasylvian sulcus (area PMLS) in the cat can be equatedwith macaque area V5. The equivalences are supported by dataon neuronal receptive field properties and the contributionsthe areas make to visual behavior. Although the data are scantyfor most other visual areas, there are enough data tentativelyto equate collectively cat areas 20a and 20b with macaque areasTF and TH and to liken cat areas 21a and 21b with macaque areaV4. What is not clear is if there is a region in cat that isequivalent to area TE in the macaque monkey. If there is, itlikely lies on the banks of the posterior suprasylvian sulcusbetween areas 20 and 21 and the polysensory cortex of the posteriorectosylvian gyrus. Knowledge gained from prior research on macaqueareas V4 and TE can be used to formulate specific additionalinvestigations of cat area 21 and the uncharted posterior suprasylviansulcus. In addition, prior investigations carried out on catarea 20 can be used to devise specific explorations of macaqueareas TF and TH.     

Color Architecture in Alert Macaque Cortex Revealed by fMRI

doi:10.1093/cercor/bhj099 Cerebral Cortex      

Minicolumnar Activation Patterns in Cat and Monkey SI Cortex

The distribution of stimulus-evoked ¹⁴C-2-deoxyglucose (2DG)labeling in primary somatosensory cortex (SI) of monkey (Macacafasciculans) and cat was investigated. Reconstructions of theglobal pattern of labeling reveal that discrete skin stimulievoke activity within an extensive region of SI, and that theactivation pattern typically consists of multiple, elongatedregions of above-background labeling ("modules," typically 0.5–1.0mm wide, and 1–4 mm long). Evidence obtained using recentlydeveloped methods (Tommerdahl, 1989) for quantitative analysisof 2DG activity patterns is shown to be consistent with theidea (Whitsel et al., 1991) that SI modules typically are boundedby zones dominated by stimulus-evoked inhibition. The labelingpat tern within individual 2DG modules In SI of both cats andmonkeys is analyzed quantitatively (in the frequency domain).Within-module spatial activation patterns are demonstrated tohe periodic, consisting of radially on ent.d profiles of above-backgroundlabeling separated from each other by less strongly labeledradial profiles. The spectral characteristics of within-module2DG la beling change systematically with location along themodule's long axis: spatial frequencies htween 18 and 35 cycles/mmare prominent in the labeling that oc cupies both the middleand upper layers at central locations in the module, but area less obvious component of the labeling in both the middleand upper layers at locations remote to the module center. Sincethe radially oriented periodic variation both (1) in 2DG labelingin regions of SI outside modules and (2) in optical densityin images of Nissl-stained sections of SI consists pre dominantlyof spatial frequencies in the range of 18–35 cycles/mm,it is concluded that the radial profiles of labeling withinindividual 2DG modules correspond to groupings of minicolumnadistinguishable from their neighbors on the basis of labelingintensity. The findings raise the possibility that highly structured,within-mod ule spatial patterns of SI minicolumnar activationen code information about the physical properties of tactilestimuli.     

The Dopaminergic Innervation of Monkey Entorhinal Cortex

Dopamine has been implicated in the pathophysiology of schizophrenia,and the entorhinal cortex (ERC) is thought to be a site of structuralpathology in this disorder. However, relatively little is knownabout the dopaminergic (DA) innervation of ERC in the primatebrain. In this study, immunohistochemical methods and antibodiesdirected against tyrosine hydroxylase (TH) and dopamine wereused to determine the organization of DA axons in the ERC ofmacaque monkeys. The anti-TH antibody used in this study appearedpredominantly to identify DA axons, as demonstrated by its failureto label fibers that were immunoreactive with an antibody againstdopamine-ß-hydroxylase in double-labeling experiments.In addition, the regional and laminar distributions of TH-immunoreactivefibers were strikingly similar to those labeled with the anti-dopamineantibody. With both antibodies, cytoarchitectonically identified subdivisionsof monkey ERC (Amaral et al., 1987) differed in both the densityand laminar distribution of labeled fibers. Immunoreactive processesexhibited a substantial rostral-to-caudal gradient of decreasingdensity across subdivisions of ERC, and the density of labeledfibers also decreased from medial to lateral in the rostralbut not in the caudal subdivisions of ERC. The laminar distributionof labeled fibers differed both between and within subdivisions.For example, in the olfactory and rostral subdivisions of ERC,the superficial layers contained a very high density of immunoreactiveprocesses, whereas in the intermediate region, three bands oflabeled fibers were seen in layers I, III-IV, and VI. In addition,radial columns of fibers interdigi-tated with areas of decreaseddensity were present between layers I and III. Although theoverall density of labeled fibers was greater in lateral thanin the caudal subdivisions of ERC, these regions had similarlaminar distribution patterns. In these areas of monkey ERC,labeled processes were highest in density in deep layer I, andhomogeneously distributed in the other cortical layers. These findings demonstrate that the DA innervation of monkeyERC is complex, and follows laminar- and subdivision-specificpatterns. These patterns of distribution suggest the possibleinteractions that DA axons may have with other elements of ERCcircuitry, and may provide insight into the possible functionalroles of dopamine in ERC in both normal and disease states.     

Specific and Columnar Projection from Area TEO to TE in the Macaque Inferotemporal Cortex

The organization of connections from area TEO to TE was studiedby the use of the anterogrado tracer Phasaclus vulgans leucoagglutinin(PHA-L). Single or, in one case, two small injections of thetracer were made in the lateral pert of TEO. Labeled terminalswore found in restricted regions of TE within two to five densefoci. In these foci, terminals wore distributed beyond the middlolayers to form a columnar duster elongated ver tical to thecortical surface. This specificity of connections may derivefrom an organization that is feature specific rather than retinotopic. Single axons reconstructed from the columnar foci showed heterogeneousfeatures in the laminar distribution. Arbors of some axons werelocalized in the superficial layers, and those of other werein the middle layers.     

A Numerical Analysis of the Geniculocortical Input to Striate Cortex in the Monkey

Using data that are available in various publications, a quantitativeanalysis has been made of the geniculocortical input to layerIVC of the macaque striate cortex. The data suggest that only1.3–1.9% of the excitatory, or asymmetric synapses inlayer IVC     

Regulation of Calcium-Binding Protein Immunoreactivity in GABA Neurons of Macaque Primary Visual Cortex

Monocular deprivation produces an imbalance in visual drivefrom the two eyes, which in adult macaque V1 leads to markedchanges in the neurochemistry of GABA interneurons. Such changeswere further examined by studying immunoreactivity for calbindin,calretinin, and parvalbumin, three calcium-binding proteinsthat mark distinct subpopulations of GABA neurons, in macaquesthat had been monocularly deprived by intravitreal injectionof tetrodotoxin. Deprivation for 5 d or longer produced a reversalin the normal pattern of calbindin immunostaining in layer III,from one in which intense neuronal immunostaining surroundedthe cytochrome oxidase-rich puffs to one in which it occupiedthe puffs. Over the same period, calbindin immunostaining inother layers was reduced across the entire width of deprived-eyecolumns or extended into flanking regions of normal-eye columns.In contrast, reduction in parvalbumin immunostaining occurredonly in deprived-eye columns and included only terminals withshort periods of deprivation (up to 17 d) but both terminalsand somata with longer periods. No change in calretinin immunoreactivitywas observed. These findings demonstrate that GABA neurons ofmacaque V1 vary in their response to monocular deprivation accordingto their neurochemistry and position, suggesting that the weightof inputs from the two eyes and the intrinsic characteristicsof each GABA population determine how a neuron responds to achange in visual input.     

Neural Correlates of Learning in the Prefrontal Cortex of the Monkey: A Predictive Model

The principles underlying the organization and operation ofthe prefrontal cortex have been addressed by neural networkmodeling. The involvement of the prefrontal cortex in the temporalorganization of behavior can be defined by processing unitsthat switch between two stable states of activity (bistablebehavior) in response to synaptic inputs. Long-term representationof programs requiring short-term memory can result from activity-dependentmodifications of the synaptic transmission controlling the bistablebehavior. After learning, the sustained activity of a givenneuron represents the selective memorization of a past eventthe selective anticipation of a future event, and the predictabilityof reinforcement A simulated neural network illustrates theabilities of the model (1) to learn, via a natural step-by-steptraining protocol, the paradigmatic task (delayed response)used for testing prefrontal neurons in primates, (2) to displaythe same categories of neuronal activities, and (3) to predicthow they change during learning. In agreement with experimentaldata, two main types of activity contribute to the adaptiveproperties of the network. The first is transient activity time-lockedto events of the task and its profile remains constant duringsuccessive training stages. The second is sustained activitythat undergoes nonmonotonic changes with changes in reward contingencythat occur during the transition between stages.     

Connections of Inferior Temporal Areas TEO and TE with Parietal and Frontal Cortex in Macaque Monkeys

Inferior temporal cortex is perhaps the highest visual processingarea and much anatomical work has focused on its connectionswith other visual areas in temporal and occipital cortex. Herewe report connections of inferior temporal cortex with regionsin the frontal and parietal lobes. Inferior temporal areas TEOand TE were injected with WGA-HRP and ³H-AA, respectively, orvice versa, in 1-week-old infant and 3–4–year-oldadult monkeys (Macaca mulatta). The results indicated that whereasTEO has more extensive connections with parietal areas, TE hasmore extensive connections with prefrontal areas. Thus, in theintraparietal sulcus, area TEO is connected with areas LIPd,LIPv, and V3A, and with the as yet undefined region betweenLIPv and V3A, whereas the connections of TE are predominantlywith LIPd, and to a lesser extent with LIPv. In the prefrontalcortex, area TE is connected with areas 8 and 45 in the inferiorlimb of the anterior bank of the arcuate sulcus, with area 12on the inferior prefrontal convexity, and with areas 11 and13 on the orbital surface. By contrast, the connections of areaTEO are limited to areas 8, 45, and 12. Furthermore, withinprefrontal cortex, the projections from areas TEO and TE terminatein different layers in areas 8 and 45, such that those fromTEO terminate in all layers, whereas those from TE terminatein layers I and V/VI only. In contrast to the connections ofareas TEO and TE with various medical temporal-lobe and subcorticalstructures, which are immature in infant monkeys (Webster etal., 1991, 1993b), the connections with parietal and prefrontalareas appear adult-like as early as 1 week of age.     

Recognition of Objects and Their Component Parts: Responses of Single Units in the Temporal Cortex of the Macaque

We investigated the role that different component parts playin the neural encoding of the visual appearance of one complexobject in the temporal cortex. Cells responsive to the sightof the entire human body (but no to control stimuli) were testedwith two subregions (head alone with the body occluded fromsight and the body alone with the head occluded). Forty-twopercent (22 of 53) of cells responded to the whole body andto one of the two body regions tested separately: 72% (17 of22) responding to the head and 28% (5 of 22) to the rest ofthe body. Forty-two percent (22 of 53) of cells responded independentlyto both regions of the body when tested in isolation. The remainingcells (17%, 9 of 53) were selective for the entire body andunresponsive to component parts. The majority of cells tested(90%, 35 of 39) were selective for perspective view (e.g., somecells respond optimally to the side view of the body, othersto the back view). Comparable levels of view sensitivity werefound for responses to the whole body and its parts. Resultsindicate (1) separate neuronal analysis of body parts and (2)extensive integration of information from different parts. Contraryto influential models of object recognition (Marr and Nishihara,1978; Biederman, 1987), the results indicate view-specific processingboth for the appearance of separate object components and forintegration of information across components.     

Form, Function, and Intracortical Projections of Neurons in the Striate Cortex of the Monkey Macacus nemestrinus

Single neurons were recorded in the striate visual cortex (area17) of the old-world monkey Macacus namestrinus. Eight pyramidalneurons, seven spiny stellate neu rons, two basket cells, aclutch cell, and a chandelier cell were filled intracellularywith HRP. Their receptive fields were consistent with previoussingle-unit studies. Their axonal arbors were less elaboratethan in equivalent neurons in the cat, but the laminar specificityof the houtons was very much more precise in the monkey thanin the cat. Nevertheless, the basic cortical circuits in catand monkey appear to hevery similar.     

Functional Development of the Corticocortical Pathway for Motion Analysis in the Macaque Monkey: A 14C-2-Deoxyglucose Study

The corticocortical pathway for motion analysis transmits visualinformation from striate cortex (V1) via V2. V3d, superior temporalsulcal areas MT, MST, and FST to motion-sensitive areas in thefloor and upper bank of the anterior part of the superior temporalsulcus (AST). We studied the functional development of thispathway by applying the ¹⁴C-2-deoxyglucose method to rhesusmonkeys (Macaca mulatta) ranging in age from 2 d to 3–4years. A comparison of local cerebral glucose utilization (LCGU)in an intact and a visually deafferented hemisphere in eachanimal across the age range revealed that this pathway, immatureat birth, reaches adult-like levels at 3 months of age. Thisdevelopmental time course is reflected both in absolute LCGUand in the interhemispheric LCGU differences in all the areasof the pathway. At all ages, the interhemispheric differencein LCGU is largest in V1 and gradually declines along the pathwayuntil a minimum is reached in AST. This decline likely reflectsan increasing proportion of nonvisual inputs to the higher-orderareas of the pathway. Measurements like those above taken inareas of inferior parietal cortex indicate that they matureat the same rate as those in the motion analysis pathway. However,comparison with findings on the functional development of thetemporal areas of the occipitotemporal pathway for object vision(Bachevalier et al., 1991) suggests that areas along the motionanalysis pathway and those in parietal cortex mature about 1month earlier.