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P S Goldman-Rakic

Publications and source records attributed to P S Goldman-Rakic.

At least 91 records · Page 5Linked to original sources
PubMed1995

Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17.

BACKGROUND: In the past two decades, gross morphologic changes have been uncovered in the schizophrenic brain, eg, increased ventricular width and decreased cortical volume; however, relatively little is known about the area-specific and laminar density of cells in the schizophrenic cortex, particularly in prefrontal areas. METHODS: A direct, three-dimensional counting method was used to determine cell density in 16 brains from patients with schizophrenia, 19 from normal subjects, six from patients with schizoaffective disorder, and nine from patients with advanced-stage Huntington's disease. RESULTS: Increased neuronal density was found in prefrontal area 9 (17%) and occipital area 17 (10%) in the schizophrenic brains. In area 9, neuronal density was increased in layers III to VI; cell packing of pyramidal and nonpyramidal neurons was elevated. Cortical thickness in the schizophrenic brains was slightly but not significantly reduced in both areas, with a disproportionate reduction in layer V in area 9. In contrast, brains with Huntington's disease exhibited markedly higher glial density (50%) and drastically reduced cortical thickness (28%). CONCLUSION: Abnormally high density in the cerebral cortices of schizophrenics suggests that neuronal atrophy is the anatomic substrate for deficient information processing in schizophrenia.

Adult↗
PubMed1995

Spatial working memory deficits in the relatives of schizophrenic patients.

BACKGROUND: Studies in nonhuman primates provide evidence that intact spatial working memory depends on the integrity of specific areas in the prefrontal cortex. Patients with schizophrenia have been shown to be impaired on spatial working memory tasks. Relatives of schizophrenic patients show a range of cognitive deficits in the absence of clinical symptoms (eg, thought disorder, eye tracking dysfunctions). We predicted that a significant proportion of relatives of schizophrenic patients would show deficits in working memory as measured by a delayed response task. METHODS: In experiment 1, we tested 18 schizophrenic patients, 15 first-degree relatives of schizophrenic patients, and 18 normal control subjects on an oculomotor delayed response task. In experiment 2, we assessed the performance of another group of 12 first-degree relatives of schizophrenic patients and 16 different normal control subjects on a visual-manual delayed response task. RESULTS: Relatives of schizophrenic patients showed significant deficits in working memory on both the oculomotor and visual-manual delayed response tasks. CONCLUSIONS: Some relatives of schizophrenic patients are impaired on tasks that tap spatial working memory and that implicate the prefrontal system. The delayed response paradigm may be useful in elucidating the multidimensionality of the schizophrenic phenotype.

Adult↗
PubMed1995

Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys.

The D2 dopamine (DA) receptor agonist, quinpirole, was characterized in young adult monkeys, young reserpine-treated monkeys and aged monkeys to assess the contribution of DA to age-related loss of prefrontal cortical (PFC) cognitive function. Monkeys were tested on a delayed response memory task that depends on the PFC, and a fine motor task that taps the functions of the motor cortex. In young adult monkeys, low quinpirole doses impaired performance of the PFC and fine motor tasks, while higher doses improved memory performance and induced dyskinesias and "hallucinatory-like" behaviors. The pattern of the quinpirole response in reserpine-treated monkeys suggested that the impairments in delayed response and fine motor performance resulted from drug actions at D2 autoreceptors, while the improvement in delayed response performance, dyskinesias and "hallucinatory-like" behaviors resulted from actions at postsynaptic receptors. In aged monkeys, low doses of quinpirole continued to impair fine motor performance, but lost their ability to impair delayed response performance. The magnitude of cognitive improvement and the incidence of "hallucinatory-like" behaviors were also reduced in the aged animals, suggesting some loss of postsynaptic D2 receptor function. The pattern of results is consistent with the greater loss of DA from the PFC than from motor areas in aged monkey brain (Goldman-Rakic and Brown, 1981; Wenk et al., 1989), and indicates that DA depletion contributes significantly to age-related cognitive decline.

Aging↗
PubMed1995

Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain.

The pathways governing signal transduction in the mesocortical and nigrostriatal dopamine systems of the brain are of central importance in a variety of drug actions and neurological diseases. We have analyzed the regional, cellular, and subcellular distribution of the closely related D1 and D5 subtypes of dopamine receptors in the cerebral cortex and selected subcortical structures of rhesus monkey using subtype specific antibodies. The distribution of D1 and D5 receptors was highly differentiated in subcortical structures. In the neostriatum, both D1 and to a lesser extent D5 antibodies labeled medium spiny neurons, while only D5 antibodies labeled the large aspiny neurons typical of cholinergic interneurons. In the caudate nucleus, D1 labeling was concentrated in the spines and shafts of projection neurons, whereas D5 antibodies predominantly labeled the shafts, and less commonly, the spines of these cells. The D1 receptor was abundantly expressed in the neuropil of the substantia nigra pars reticulata while the D5 antibodies labeled only a few scattered cell bodies in this structure. Conversely, D5 antibodies labeled cholinergic neurons in the basal forebrain more intensely than D1 antibodies. Within the cerebral cortex and hippocampus, D1 and D5 antibody labeling was prominent in pyramidal cells. Double-label experiments revealed that the two receptors were frequently coexpressed in neurons of both structures. Ultrastructurally, D1 receptors were especially prominent in dendritic spines whereas dendritic shafts were more prominently labeled by the D5 receptor. The anatomical segregation of the D1 and D5 receptors at the subcellular level in cerebral cortex and at the cellular level in subcortical areas suggest that these closely related receptors may be preferentially associated with different circuit elements and may play distinct regulatory roles in synaptic transmission.

Animals↗
PubMed1994

D1 dopamine receptor immunoreactivity in human and monkey cerebral cortex: predominant and extrasynaptic localization in dendritic spines.

Antibodies to the D1 dopamine receptor were used to localize this protein in several areas of human and monkey cerebral cortex with light and electron microscopy. In addition to cell body labeling in monkeys, all areas of humans and monkeys had a neuropil label with a laminar distribution predicted by previous D1 receptor autoradiography studies. Using electron microscopy, this neuropil label was seen in numerous dendritic spines, in dendritic shafts, and in occasional axon terminals. While labeled spines were common, they represented only a subset of all cortical spines. Serial sectioning through labeled spines showed that the diaminobenzidine reaction product was usually not at postsynaptic densities but instead was displaced to the side of the large asymmetric (presumed glutamatergic) synapse. Furthermore, most labeled spines did not receive synapses with dopaminergic features, suggesting that many D1 receptors are at extrasynaptic sites, possibly receiving dopamine via diffusion in the neuropil. Similarly, double labeling failed to reveal D1 labeling at synapses of tyrosine hydroxylase immunoreactive axons. Localization to numerous dendritic spines suggests that a primary role of D1 receptors is modulation of glutamatergic input to cortical pyramidal cells.

Animals↗
PubMed1994

A common action of clozapine, haloperidol, and remoxipride on D1- and D2-dopaminergic receptors in the primate cerebral cortex.

The potencies of the major neuroleptics used in the treatment of schizophrenia, including haloperidol and remoxipride, correlate with their ability to bind D2-dopaminergic receptors in subcortical structures. On the other hand, the neuroleptic clozapine has a low affinity for these sites, and the pharmacological basis of its beneficial action is less clear. We have found that chronic treatment with clozapine, haloperidol, and remoxipride up-regulates D2 receptors in specific cortical areas of the rhesus monkey frontal, parietal, temporal, and occipital lobes. Of particular interest, all three neuroleptics down-regulated D1 receptors in prefrontal and temporal association regions--the two areas most often associated with schizophrenia. This latter finding raises the possibility that down-regulation of D1 receptors in prefrontal and temporal cortex may be an important component of the therapeutic response to neuroleptic drugs. Further, the common effects of three neuroleptics with different pharmacological profiles in the cerebral cortex is consistent with the idea that this structure is a major therapeutic target in the treatment of schizophrenia.

Analysis of Variance↗
PubMed1994

Functional synergism between putative gamma-aminobutyrate-containing neurons and pyramidal neurons in prefrontal cortex.

The responses of putative gamma-aminobutyratergic interneurons (fast-spiking) and pyramidal (regular-spiking) cell pairs were compared in monkeys performing visual and memory-guided oculomotor tasks. Both fast- and regular-spiking neurons had similar receptive fields, indicating that gamma-aminobutyratergic interneurons carry a specific informational signal, as opposed to providing nonspecific modulation. However, the responses of the pairs were inverted and the timing of excitatory and inhibitory responses appeared to be phased, a property consistent with gamma-aminobutyrate-mediated shaping of receptive fields. These observations (i) provide evidence that interneurons and pyramidal cells can be differentiated in vivo and (ii) begin to elucidate the role of gamma-aminobutyratergic mechanisms in cognition.

Action Potentials↗
PubMed1994

Viewing preferences of rhesus monkeys related to memory for complex pictures, colours and faces.

In order to determine the preferences of rhesus monkeys for visual stimuli, their eye movements were measured in response to presentations of complex pictures, fields of uniform colour, and of faces using the scleral search coil technique. The monkeys (n = 4) controlled both the onset and offset of the stimuli by the direction of their gaze. Each stimulus was presented 4 times, with 0 or 2, and 36 or 38 trials between successive presentations. Several trends were apparent in their scanning behaviour: (1) all 4 monkeys spent more time looking at pictures and faces compared to colour fields. As individuals, they differed in their overall propensity in looking at visual stimuli: monkeys that spent the most (or least) time looking at pictures spent the most (or least) time looking at colour fields. (2) Although the monkeys appeared to prefer pictures and faces to colour fields as measured by gaze duration, preferences for individual pictures, faces and colour fields were not evident. (3) Memory for recently presented stimuli substantially affected gaze duration which was significantly longer for the first compared to the second presentation of the pictures and faces, and memory was estimated to influence gaze duration over as many as 38 intervening trials. These effects were not significant in the case of colour fields. (4) There were no significant differences either in the average latencies to initiate eye movements or the number of saccades on the first and second presentations of pictures, colors or faces for the 4 monkeys. However, the average latencies to the first eye movement within a trial were longer for colour fields than for pictures for all 4 monkeys. Individual monkeys differed substantially in their mean latencies for the initiation of the first eye movement within a trial, which ranged from 235 ms to 414 ms in the two extreme cases. (5) At the presentation of faces, the monkeys tended to make saccades to major facial features, and only occasionally to the perimeter of faces. We conclude, firstly, that patterns of eye movements in monkeys reflect their natural predilection for sampling novel stimuli and that monkeys are motivated to view visual arrays. Secondly, that the protracted viewing of novel stimuli and long latencies to initiate saccades contrasts with short latency neuronal responses recorded in inferior temporal cortex. These behavioural and neurophysiological data suggest that neuronal activity specific to novel stimuli and to faces is not a consequence of oculomotor responses to these stimuli.

Animals↗
PubMed1994

Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys.

Dopamine (DA) D1 receptor compounds were examined in monkeys for effects on the working memory functions of the prefrontal cortex and on the fine motor abilities of the primary motor cortex. The D1 antagonist, SCH23390, the partial D1 agonist, SKF38393, and the full D1 agonist, dihydrexidine, were characterized in young control monkeys, and in aged monkeys with naturally occurring catecholamine depletion. In addition, SKF38393 was tested in young monkeys experimentally depleted of catecholamines with chronic reserpine treatment. Injections of SCH23390 significantly impaired the memory performance of young control monkeys, but did not impair aged monkeys with presumed catecholamine depletion. Conversely, the partial agonist, SKF38393, improved the depleted monkeys (aged or reserpine-treated) but did not improve young control animals. The full agonist, dihydrexidine, did improve memory performance in young control monkeys as well as in a subset of aged monkeys. Consistent with D1 receptor mechanisms, agonist-induced improvements were blocked by SCH23390. Drug effects on memory performance occurred independently of effects on fine motor performance. These results underscore the importance of DA D1 mechanisms in cognitive function, and provide functional evidence of DA system degeneration in aged monkeys. Finally, high doses of D1 agonists impaired memory performance in aged monkeys, suggesting that excessive D1 stimulation may be deleterious to cognitive function.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Islands and striosomes in the neostriatum of the rhesus monkey: non-equivalent compartments.

Cytoarchitectonically defined cell-dense islands and regions of low acetylcholinesterase reactivity referred to as striosomes have been regarded as equivalent markers of the non-matrix compartment in the neostriatum. We examined islands and striosomes in adjacent sections to determine the degree of correspondence between the two neostriatal compartmental markers. Islands are aggregated centrally within the caudate, whereas striosomes are located throughout the entire nucleus, including the dorsolateral and ventromedial sectors. Moreover, even within the central sector, striosomes are more prevalent than islands. The present quantitative analysis suggests that islands may be further characterized as acetylcholinesterase-poor since the vast majority of islands co-localize with striosomes. However, due to the fact that striosomes are more numerous and more widely distributed throughout the neostriatum, less than a third of all striosomes are coincident with islands in adjacent sections. Comparison of each of these compartmental markers with the patterned terminal field of the prefrontal cortical projection revealed a near one-to-one correspondence between islands and terminal-free zones in the prefrontal projection. The percentage of striosomes which are aligned with fenestrations in the prefrontal projection is also quite high; however, because more striosomes than islands are found within the prefrontal terminal domain, some striosomes that fit within terminal-free zones do not have corresponding islands. These results indicate that islands and striosomes are not entirely equivalent compartmental markers and further suggest that contemporary, two-compartment models may not adequately represent the heterogeneity of the neostriatum.

Acetylcholinesterase↗
PubMed1994

The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task.

1. To examine the role of dopamine receptors in the prefrontal cortex (PFC) on working memory, we injected dopamine antagonists (SCH23390, SCH39166, haloperidol, sulpiride, and raclopride) locally into the dorsolateral PFC in two monkeys trained to perform an oculomotor delayed-response (ODR) task. In the ODR task, monkeys fixate a central spot on a cathode ray tube (CRT) monitor while a visual cue is briefly (300 ms) presented in one of several peripheral locations in the visual field. After a delay of 1.5-6 s, the fixation spot is turned off, instructing the monkey to move its eyes to the target location that had been indicated by the visuospatial cue before the delay. Each monkey also performed a control task in which the cue remained on during the delay period. In this task the monkey's response was sensory rather than memory guided. 2. Local intracerebral injection of the selective dopamine antagonists SCH23390 (10-80 micrograms) and SCH39166 (1-5 micrograms) and/or the nonselective dopamine antagonist haloperidol (10-100 micrograms) induced deficits in ODR task performance at a total of 22 sites in the dorsolateral PFC. The deficit was characterized by a decrease in the accuracy of the memory-guided saccade as well as an increase in the latency of the response. The deficit usually appeared within 1-3 min after the injection, reached a peak at 20-40 min, and recovered at 60-90 min. 3. Performance change was restricted to a few specific target locations, which varied with the injection site and were most often contralateral to the injection site. 4. The degree of impairment in the ODR task occasioned by the injection of the dopamine antagonists was sensitive to the duration of delay; longer delays were associated with larger decreases in the accuracy and delayed onset of the memory-guided saccade. 5. The deficit was dose dependent; higher doses induced larger errors and increases in the onset of the memory-guided saccade. 6. Dopamine antagonists did not affect performance on the control task, which required the same eye movements but was sensory guided. Thus, in the same experimental session in which ODR performance was impaired, the accuracy and the latency of the sensory-guided saccades were normal for every target location.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Working memory dysfunction in schizophrenia.

Recent advances in anatomical, behavioral, and physiological techniques have produced new information about the nature of prefrontal function, its cellular basis, and its anatomical underpinnings in nonhuman primates. These findings are changing our views of prefrontal function and providing insight into possible bases for human mental disorder. A major advance is the recognition that various prefrontal areas are engaged in holding information "on line" and updating past and current information on a moment-to-moment basis. Studies of animals and of cognitive function in normal, brain-injured, and schizophrenic subjects support the theory that a defect in working memory--the ability to guide behavior by representations--may be the fundamental impairment leading to schizophrenic thought disorder.

Animals↗
PubMed1994

Coactivation of prefrontal cortex and inferior parietal cortex in working memory tasks revealed by 2DG functional mapping in the rhesus monkey.

Functional studies of the dorsolateral prefrontal cortex and the inferior parietal lobe of the rhesus monkey have implicated the former in spatial mnemonic function and the latter in visuospatial processing. We used the 14C-2-deoxyglucose (2DG) method to assess the contribution of these cortical regions to the cognitive performance of monkeys on working memory tasks. In these experiments, one group of monkeys (WORK) was trained to perform tasks (delayed spatial alternation, spatial delayed response, or delayed object alternation) that specifically engaged working memory processing. Local cerebral glucose utilization (LCGU) rates in the WORK group was compared with LCGU rates for a second group of monkeys (CONT) tested on one of two tasks (visual pattern discrimination or sensory-motor) that relied upon associative memory. The results showed that in comparison to the CONT group, working memory performance significantly enhanced LCGU by 19% in the principal sulcus region of prefrontal cortex and by 11-20% in regions of the inferior parietal cortex corresponding to areas 7A, 7B, 7IP, and 7M. By contrast, LCGU in the auditory cortex was similar for both groups. In all areas examined, metabolic activation peaked in lower layer III where the majority of associational and callosal neurons lie. Correlation analyses of LCGU and behavioral task parameters indicated that LCGU in the parietal subdivisions was significantly related either to the accuracy of performance or to the number of trials completed on the 2DG test. In contrast, LCGU in the principal sulcus was positively correlated with task difficulty. These findings suggest that the enhancement of LCGU in the principal sulcus was primarily influenced by the mnemonic components of the tasks whereas LCGU in the inferior parietal cortex was influenced by their sensory-motor demands. These are the first results showing concurrent metabolic activation of the prefrontal and parietal cortex in monkeys performing working memory tasks and they support the suggestion that these cortical regions represent two important nodes in a neural network mediating spatial working memory in the monkey (Goldman-Rakic, 1988). Further, the present report reinforces the power of the 2DG method for functional mapping as these areal and laminar results could not be readily appreciated at this resolution in any other methodological context.

Animals↗
PubMed1993

Prefrontal neuronal activity in rhesus monkeys performing a delayed anti-saccade task.

Patients with damage to the dorsolateral prefrontal cortex are impaired on cognitive tasks such as the Wisconsin Card Sort Test, the Stroop Test and an anti-saccade paradigm, in which sensory-guided habitual responses must be suppressed in favour of conceptually or memory-guided responses. We report here recordings from prefrontal neurons in rhesus monkeys trained to perform a delayed anti-saccade task based on tests that have been used with humans. Activity in the same prefrontal neurons was recorded across conditions when saccades were made toward a remembered target, and also when this prepotent response was suppressed and a saccade in the opposite direction required. Our findings show that most prefrontal neurons code the location of the visual stimulus in working memory, and that this memory can be engaged to suppress as well as prescribe a response. These results establish, in a subset of prefrontal neurons, the iconic nature of the memory code, and suggest a role for visual memory in response suppression.

Animals↗