Catecholamines and cognitive decline in aged nonhuman primates.
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Acetylcholine↗
Biomedical subjects
P S Goldman-Rakic
Publications and source records attributed to P S Goldman-Rakic.
Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey.
Anterograde tracing methods were used to examine the topographic organization and interrelationship of projections to the neostriatum arising from various areas of association cortex. In contrast to the currently accepted topographic schema, all cortical areas examined project to longitudinal territories that occupy restricted medial-lateral domains of the neostriatum. The posterior parietal and superior arcuate cortices project to dorsolateral portions of the neostriatum; the dorsolateral and dorsomedial frontal cortices project centrally; and the orbitofrontal, anterior cingulate, and superior temporal projections are distributed to ventromedial regions of the caudate nucleus and putamen. In coronal section, cortical terminal fields form a diagonal strip, extending from the dorsal, ventricular border of the caudate nucleus, through the fiber bundles of the internal capsule, to the ventral margin of the putamen. Double labeling studies, in which two cortical areas were injected in the same animal, indicated that convergence of input within neostriatal domains is not governed by reciprocity of corticocortical connectivity. Thus, the interrelationship of projections arising from connectionally linked cortical areas ranged from nearly complete segregation of terminal fields (e.g., from dorsolateral prefrontal and orbital cortices) to extensive overlap of terminal domains (e.g., from frontal and temporal cortices). In the latter case, detailed analysis revealed that frontal and temporal terminals actually were interdigitated rather than intermixed within the zone of overlap. The present findings suggest a new conceptualization of corticostriatal topography in the primate which emphasizes the longitudinal arrangement of cortical terminal domains. Additionally, these findings provide a map for functional parcellation of the neostriatum on the basis of its cortical innervation which may prove useful to understanding normal striatal function, as well as the symptomatology associated with neostriatal injury and disease.
Animals↗
Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey.
Descending cortical projections to the region of the noradrenergic locus coeruleus (LC) and the serotonergic dorsal and central superior raphe nuclei were analyzed in the rhesus monkey using anterograde labeling techniques. HRP pellets or tritiated leucine were injected into one of 7 cortical areas: the dorsolateral prefrontal cortex, the dorsomedial prefrontal cortex, the orbital prefrontal cortex, the parietal association cortex, somatosensory cortex, the anterior portion of the inferior temporal gyrus, and the posterior portion of the inferior temporal gyrus. Anterogradely labeled fibers were found in and adjacent to the LC and raphe nuclei only following the dorsolateral and dorsomedial prefrontal cortical injections. Terminal labeling was densest at rostral levels of the LC, particularly in the area directly medial to the nucleus. Labeled fibers could not be followed beyond caudal levels of the LC. The projections to the contralateral LC and raphe nuclei were similar to, but less dense than that to the ipsilateral region. Injections into cortical areas other than the dorsal prefrontal cortex resulted in anterograde labeling of the pontine nuclei or pyramids, but not the LC/raphe region. These data, in conjunction with studies in the rat, suggest that the dorsal prefrontal cortex may be the only cortical area to have direct influence on the LC and raphe nuclei and secondary influence on the monoaminergic innervation of large areas of cerebral cortex.
Animals↗
Callosal and intrahemispheric connectivity of the prefrontal association cortex in rhesus monkey: relation between intraparietal and principal sulcal cortex.
Horseradish peroxidase (HRP) histochemistry and double labeling with the fluorescent dyes nuclear yellow (NY) and fast blue (FB) were used to examine and compare the laminar and tangential arrangement of ipsilateral (associational) and contralateral (callosal) neurons and their relative density in three regions of prefrontal granular cortex: Walker's area 46 (principal sulcus), area 8A (superior limb of the arcuate sulcus), and area 11 (lateral orbital sulcus). In all three prefrontal regions, neurons with ipsilateral projections were labeled following injections of tracers into the intraparietal sulcus (IPS) and neurons with callosal projections were sequentially or simultaneously labeled with injections into the contralateral principal sulcus (PS). Quantitative analysis indicates that associational and callosal neurons in prefrontal cortex are distinct cell populations with strikingly similar organization including (1) common topography; (2) common laminar positions in layers III, IV, and V; (3) two- to three-fold higher densities in supragranular than infragranular layers; (4) common morphologies including a high proportion of nonpyramidal soma in the deeper cortical layers; (5) common uneven tangential distribution reminiscent of the interdigitation of their terminal fields; and (6) common subpopulations differing on the basis of terminal arbors. These findings indicate that the posterior parietal cortex and the prefrontal cortex form part of an integrated neural system important for spatiotemporal behaviors.
Animals↗
Columnar organization of callosal and associational projections from rat frontal cortex.
Autoradiography and HRP histochemistry were used to study the laminar and columnar distribution of callosal and associational connections of areas 6 and 10 of Krieg in the rat frontal cortex. In coronal sections through homotopic contralateral areas and ipsilateral somatosensory cortex, terminations of projections arising in frontal cortex formed discrete vertical columns; these were 250-750 micron wide and alternated with unlabeled or poorly labeled areas of approximately equal width. In reconstructions from serial coronal sections through these areas, the terminal fields formed a series of bands. The location of retrogradely labeled neurons tended to reciprocate the distribution of terminal label, although the boundaries of terminal and cell label were not always in precise register. These findings indicate that in the rat, both association and callosal projections exhibit a terminal organization remarkably similar in width and spacing to that observed in primates. Thus, a columnar mode of termination of cortico-cortical fibers may be an organizational feature common to mammalian neocortex.
Animals↗
Functional analysis of spatially discriminative neurons in prefrontal cortex of rhesus monkey.
The present study addresses the question of whether prefrontal neurons that exhibit spatially selective patterns of discharge during the delay period in spatial delayed-response tasks code a mnemonic event. To examine this question, rhesus monkeys were trained to perform two variants of the classical spatial delayed-response task in both of which a delay intervened between cue presentation and response and the discriminative stimulus had to be recalled at the moment of response. They were also trained to perform two control tasks in which memory was not required since cues present throughout the delay informed the monkey of the correct response. Extracellular recordings were obtained from 192 neurons located in and around the principal sulcus of the frontal lobe during performance of both control and delay tasks. Comparison of the same neuron's activity across the 4 task conditions revealed a class of neuron that displayed spatially discriminative activity in the delay period only during delayed-response tasks and not during the same period of the control tasks. These neurons are candidates for units engaged in a central mnemonic process. Other neurons either exhibited similar activity in the delay period of control and delayed-response tasks or stronger discriminative behavior during this period in control tasks than in delayed response tasks. We conclude that delay-related spatially discriminative neurons found in the prefrontal association cortex are diversified and that certain of them play a specific role in mnemonic coding.
Animals↗
Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey.
Anterograde and retrograde tracing methods including autoradiography, horseradish peroxidase histochemistry and fluorescent dye transport were used to demonstrate that the dorsolateral prefrontal cortex is connected with the hippocampal formation and associated cortical regions by two distinct pathways. Fibers forming a lateral pathway travel in the fronto-occipital fasciculus and connect the dorsolateral prefrontal cortex with the fundus of the rhinal sulcus, posterior subdivisions of the parahippocampal gyrus, and the presubiculum. A larger medial pathway forms in the cingulum bundle and terminates in the most caudal part of the presubiculum, as well as in adjacent transitional cortices. These cortices form a caudomedial promontory that is located between the posterior cingulate and prestriate areas. In all allo- and mesocortical targets of prefrontal cortex, labeled terminals form banding patterns reminiscent of the columnar organization of afferent fiber columns in neocortex. The same cytoarchitectonic areas that receive prefrontal afferents issue reciprocal projections. The largest source is the caudomedial lobule including its presubicular portion. Neurons in the parahippocampal gyrus and adjacent presubiculum also are retrogradely labeled following implants of horseradish peroxidase or injection of fluorescent dyes into prefrontal cortex. In addition, subicular neurons project to the prefrontal cortex although the subiculum does not appear to receive prefrontal afferent input. These findings emphasize that multiple channels of communication link the dorsolateral prefrontal cortex and the hippocampus via the parahippocampal gyrus, subiculum, presubiculum and adjacent transitional cortices. We speculate that each of these prefrontal projections may carry highly specific information into the hippocampus, whereas the reciprocal projections may allow retrieval by prefrontal cortex of memories stored in the hippocampus.
Animals↗
Columnar organization of corticocortical projections in squirrel and rhesus monkeys: similarity of column width in species differing in cortical volume.
To compare the size and pattern of the terminal distribution of corticocortical projections in two primate species with brains of different size, tritiated amino acids were injected into the prefrontal cortex of New World squirrel monkeys (Saimiri sciureus) and Old World rhesus monkeys (Macaca mulatta), and their brains were processed for light microscopic autoradiography. In both species, prefrontal efferents are directed to a number of cortical targets in the same and opposite hemispheres, where in coronal sections, they generally terminate as radially oriented columns. In the rhesus monkey, the median width of the columns in transverse sections is 685 micrometers. In squirrel monkey, corresponding columns have a median with of 555 micrometers. Considering that the volume of the neocortex in rhesus monkey is approximately 4.5 x larger than that of squirrel monkey, the dimensions of cortical columns in the two species are surprisingly similar. This finding suggests that phylogenetic expansion in cortical surface area is accompanied by an increase in the number, rather than the width of afferent fiber columns. The increase in number of modular units may be relevant to the increasing computational and information processing capacity of the cerebral cortex in the course of evolution.
Animals↗
Transient cholinesterase staining in the mediodorsal nucleus of the thalamus and its connections in the developing human and monkey brain.
The histochemical and morphological maturation of the mediodorsal nucleus (MD) and its connections were compared in human and rhesus monkey using acetylthiocholine iodide and Nissl methods. Histochemical analysis in fetuses, neonates, and adults of both primate species revealed that MD passes through three major stages of cholinesterase (ChE) reactivity. In Stage I (up to about 16 fetal weeks in man; 9 fetal weeks in monkey), ChE staining gradually increases in the MD nucleus and is intense in axons directed toward the frontal lobe through the internal and external capsules. In Stage II (about 16-28 fetal weeks in man; about 9-14 weeks in monkey), ChE staining in MD reaches peak intensity so that reaction product in the neurons and neuropil blackens the entire nucleus in both species. In favorable planes of section, ChE-positive fibers appear to connect MD and the basal forebrain both of which stain intensely. ChE-positive fibers can also be traced from the lateral margins of MD to the subplate zone beneath the developing frontal cortical plate where they continue to accumulate before later invading the cortex with heaviest concentration in presumptive layers 3 and 5. In Stage III (after 28 weeks of gestation to 6 postnatal months in man; from about 14 fetal weeks until 2 postnatal months in monkey), except for scattered positive cells, ChE staining gradually disappears in MD and the formerly dense laminar pattern in the cortex begins to lighten. The dramatic but transient increase in ChE staining in MD during fetal development as well as the sequentially related changes in its projections indicate that this early appearing enzyme may play a role in the development of the frontal lobe by influencing the differentiation of thalamoprefrontal connections.
Animals↗
Intermittent thiamine deficiency in the rhesus monkey. I. Progression of neurological signs and neuroanatomical lesions.
Rhesus monkeys were subjected to one, two, or four periods of thiamine deficiency to determine how the number of deprivation episodes affects the development and progression of neurological and neuropathological changes. Recurrent thiamine deprivation produced all major neurological signs and most of the anatomical lesions found in Wernicke-Korsakoff syndrome. Neither the number and gravity of neurological symptoms nor the extent or location of lesions was related to the number of deprivation periods in a simple way. Thus, some structures, such as the inferior colliculus and medial vestibular nuclei, were affected after only one period of deficiency. Other structures, such as the parafascicular nucleus of the thalamus, were more resistant and exhibited degeneration only after four periods of thiamine deprivation. Severe damage in the basal ganglia was infrequent and was associated with prolonged rather than multiple periods of deprivation. No parenchymal damage was found in the mammillary bodies or mediodorsal nucleus of the thalamus, suggesting that lesions in these prominent sites of damage in Wernicke-Korsakoff disease develop only in the most advanced stages of thiamine deprivation. As a consequence of individual differences in susceptibility to thiamine deficiency, neurological symptoms and signs were more related to the profile of neural damage than to the number or duration of deprivation episodes.
Animals↗
Intermittent thiamine deficiency in the rhesus monkey. II. Evidence for memory loss.
Thiamine-deprived rhesus monkeys exhibited a pattern of impairments in spatial-reversal learning and in recognition of highly familiar items reminiscent of certain memory deficits shown by Wernicke-Korsakoff patients. Postmortem examination in these experimental animals showed neuronal degeneration in the basal ganglia, the parafascicular nucleus of the thalamus, and discrete nuclei of the brainstem and cerebellum. No abnormalities were found in the mammillary bodies and mediodorsal nucleus of the thalamus, structures that have been incriminated in the genesis of the memory impairment of the Wernicke-Korsakoff syndrome of man.
Animals↗
The corticostriatal fiber system in the rhesus monkey: organization and development.
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Aging↗
Delay-related activity of prefrontal neurons in rhesus monkeys performing delayed response.
Activity of dorsolateral prefrontal cortical neurons was examined in rhesus monkeys while they performed a spatial delayed-response task with delays of 2, 4, 8 or 12 s interposed between cue and response. Of the 600 neurons recorded for at least 10 trials under each delay condition, 95 displayed a pattern of discharge during the delay period which was significantly different from neuronal firing before or after this period. Changes in the duration of the delay elicit two distinct patterns of activity in these neurons: some (59/95, 62%) exhibit a fixed pattern of discharge regardless of the duration of the ensuing delay; others (31/95, 33%) alter their pattern of activity in relation to the temporal changes. Although both types of delay-related neurons display a variety of discharge profiles, more than half of each class exhibit their highest activity in the early part of the delay period. A related finding concerns a small subclass of spatially selective neurons which fire significantly more when the cue is presented on the left than on the right or vice versa. A striking 80% of these spatially discriminative neurons exhibit peak activity in the first few seconds of the delay period. These findings provide cellular evidence that (1) prefrontal neurons are responsive to temporal as well as spatial features of the delayed-response task; and (2) the involvement of a subset of these is particularly critical in the first few seconds of the delay. The latter finding emphasizes that prefrontal neurons may play an important role in the registration process of spatial memory.
Animals↗
Operant behavioral analysis of memory loss in monkeys with prefrontal lesions.
The effects of dorsolateral prefrontal cortical ablation were examined in rhesus monkeys preoperatively trained to perform two versions of an indirect spatial delayed-response task. In one task (DR I), the stimulus keys that signaled the position of the reward were accessible throughout a trial. Thus, the monkeys could orient to the positive side ('rehearse') by continuing to press the correct key during the delay. The other task, DR II, was designed to disrupt bodily orientation and to prevent 'rehearsal'. In this task the monkeys were required to press an extraneous upper key during the delay. After bilateral ablation of the prefrontal cortex, 3 out of the 4 monkeys easily regained preoperative levels of performance on the DR I task, but all subjects were markedly impaired in the DR II task on which they exhibited strong positive preferences. These deficits were ameliorated by eliminating the position biases through training with short delay intervals followed by gradual increments in delay length. Analysis of the location of key presses during each phase of delayed-response trials showed that the monkeys press the correct key in the cue period even when they subsequently made incorrect responses. A consistent finding was that operated monkeys shifted their response to the incorrect key early in the delay period regardless of its duration, whenever the correct side was the nonpreferred side. These results support the idea that delayed-response deficits in monkeys with prefrontal lesions may be due in part to a defect in registering or encoding the correct spatial position in memory rather than to a loss in storage or retrieval processes.
Animals↗
Single cortical neurones have axon collaterals to ipsilateral and contralateral cortex in fetal and adult primates.
In the adult brain, cortical neurones that project to other cortical areas have traditionally been classified as either "associational' (having connections with the ipsilateral hemisphere) or "callosal' (projecting to areas in the contralateral hemisphere). Using double-labelling with fluorescent dyes, we have now identified a novel category of mature cortical neurone that has both an "associational' and a "callosal' axon. Such neurones can direct their callosal axons either to a cytoarchitectonic area homotopic to the one in which their cell bodies reside or to an entirely different heterotopic region in the contralateral hemisphere. These cortical neurones with divergent axon collaterals in the adult neocortex differ from recently described neurones that have two axons only transiently during development.
Animals↗
Interdigitation of contralateral and ipsilateral columnar projections to frontal association cortex in primates.
The combined use of two anterograde axonal transport methods reveals that in the prefrontal association cortex of macaque monkeys, associational projections from the parietal lobe of one hemisphere interdigitate with callosal projections from the opposite frontal lobe, forming adjacent columns 300 to 750 micrometers wide. The finding of separate and alternating ipsilateral and contralateral inputs in the frontal association cortex opens up new possibilities for the functional analysis of this large but unexplored area of the primate brain.
Amino Acids↗
Cytoarchitectonic heterogeneity of the primate neostriatum: subdivision into Island and Matrix cellular compartments.
The cytoarchitecture of the caudate nucleus was examined in Nissl-stained sections from rhesus monkeys, in some of which the corticostriatal terminals had also been labeled by anterograde transport of tritiated amino acids injected into prefrontal cortex. The cytoarchitectonic analysis revealed the existence of two cellular compartments that could be distinguished on the basis of cell size, density, orientation, and tinctorial properties: (1) cell islands consisting of approximately 1,500 to 15,000 densely packed neurons that form aggregates of variable shapes and sizes embedded in (2) a matrix compartment of slightly larger and more loosely packed neurons that comprise the remaining and greater part of the caudate nucleus. In coronal sections, cellular islands appear mostly as round or elliptically shaped areas, 300-600 micrometer in diameter, but can assume more elongated and complex forms particularly in the sagittal and horizontal planes. They are encircled by fibers arranged in a thin, cell-sparse capsule that sets them apart from the matrix compartment. Analysis of cellular organization and corticostriatal connections in counterstained autoradiograms indicates that the prefrontal cortex projects only to the matrix zone and not to the territory occupied by island cells. Therefore, according to present observations the neostriatum in primates should be viewed as a cytoarchitectonically heterogeneous structure composed of at least two distinct cellular compartments with specific connectivity. These compartments may be related to the histochemical and functional diversity of the neostriatum.
Afferent Pathways↗
Brainstem innervation of prefrontal and anterior cingulate cortex in the rhesus monkey revealed by retrograde transport of HRP.
The cells of origin of projections from the brainstem to the dorsolateral and orbital prefrontal granular cortex and to the anterior cingulate cortex of the rhesus monkey were analyzed by means of retrograde axonal transport of the enzyme horseradish peroxidase (HRP). Following injections in various portions of the dorsolateral prefrontal and in the cingulate cortex, HRP-positive neurons were found in three main locations: (1) the ventral midbrain including the anterior ventral tegmental area, the medial one-third of the substantia nigra pars compacta, and the retrorubral nucleus; (2) the central superior nucleus and the dorsal raphe nucleus, primarily in its caudal subdivision; and (3) the locus coeruleus and adjacent medial parabrachial nucleus. Labeled neurons in the raphe nuclei and locus coeruleus were distributed bilaterally. A basically similar pattern of labeled somata was found in the brainstem with HRP injections in the orbital prefrontal cortex. Scattered HRP-positive cells were found throughout the ipsilateral ventral tegmental area and in ventromedial portions of the retrorubral nucleus, and a large number of HRP-positive cells were distributed bilaterally in the dorsal raphe and central superior nuclei as well as the dorsolateral pontine tegmentum. However, in contrast to the results obtained with injections on the dorsolateral and medial aspects of the hemisphere, labeled neurons were not found in any portion of the substantia nigra. The neurons labeled retrogradely after injection of HRP in these various regions of the frontal lobe in rhesus monkey correspond both in location and morphology to the monoamine-containing neurons of the brainstem and are thus very likely the source of dopamine, norepinephrine, and serotonin found in the frontal cortex of the same species.
Animals↗