PubMed Health⌕ Search

Biomedical subjects

P S Goldman-Rakic

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

At least 73 records · Page 4Linked to original sources
PubMed1997

Quantitative three-dimensional analysis of the catecholaminergic innervation of identified neurons in the macaque prefrontal cortex.

The present study provides a complete quantitative three-dimensional analysis of neurons in primate prefrontal cortex targeted by catecholaminergic axons. Individual pyramidal and nonpyramidal cells in fixed slices were filled with Lucifer yellow (LY) and recovered with anti-LY antibody combined with anti-tyrosine hydroxylase (TH) antisera to reveal catecholaminergic axons. The total number of TH contacts and TH apposition density (THAD) was obtained for pyramidal and nonpyramidal cells in different layers. Four TH contacts (two on spines and two on shafts) were selected for correlated electron microscopic examination and serially sectioned; all four were confirmed as membrane appositions. Quantitative analysis revealed 90 TH contacts per pyramidal neuron in layer III, with a density of 0.8 per 100 microm of dendritic length (i.e., averaging one contact per basal dendrite). Remarkably, pyramids of layers III, V, and VI had the same THAD values, with a highly regular distribution of TH terminals on their spiny dendritic trees. In contrast, TH contacts on nonpyramidal neurons in layer III were half as dense and, moreover, were distributed irregularly and showed large variation from cell to cell. Neurons in layers II and superficial III had the highest THAD, as compared with deeper layers (1.4 vs 0.7 per 100 micron of dendritic length for pyramids; 0.53 vs 0.4 for interneurons). The highly organized TH innervation of pyramidal neurons, with at least one contact on virtually every dendrite, indicates that catecholaminergic, presumably dopaminergic, terminals are placed strategically along the entire dendritic tree to modulate most, if not all, of the excitatory input of a neuron. At the same time, the sparsity of contacts per dendrite may explain cortical vulnerability in diseases involving dopamine.

Animals↗
PubMed1997

An interface holding chamber for anatomical and physiological studies of living brain slices.

The popularity of infrared DIC videomicroscopy for a variety of anatomical and physiological studies in living brain slices has created a need for holding chambers to allow more than one slice to be examined during a single experiment. As is well known, the yield of experiments requiring living brain slices is severely limited by the conditions under which these slices are maintained prior to being examined. Previous electrophysiological and morphological studies have demonstrated that slices maintained submerged in solution deteriorate dramatically compared to those kept at the gas/fluid interface, even after only 1.5 hours and many recording chambers incorporate the interface principle in their design. However, to our knowledge, as obvious as it may seem, this principle has not been applied to the design of holding chambers, and those which are in current use are of the non-optimal, submerged type. We have designed a simple, but extremely effective holding chamber for incubation of brain slices floating at the gas-fluid interface. The slices held in this chamber have been maintained for at least 12 hours in excellent condition as shown here by rich labeling of their local axonal arbors. In addition, the chamber is designed to hold individual slices (up to 1 cm2 in size) in separate compartments for better preservation of brain slices from valuable species (e.g. animals subjected to experimental treatments, nonhuman primates and human biopsy tissue).

Animals↗
PubMed1997

Differential activation of the caudate nucleus in primates performing spatial and nonspatial working memory tasks.

The caudate nucleus is part of an anatomical network subserving functions associated with the dorsolateral prefrontal cortex (DLPFC). The aim of the present study was to investigate whether the metabolic activity in the striatum reflects specific changes in working memory tasks, which are known to be dependent on the DLPFC, and whether these changes reflect the topographic ordering of prefrontal connections within the striatum. Local cerebral glucose utilization (LCGU) rates were assessed in the striatum by the 14C-2-deoxyglucose method in monkeys that performed a spatial (delayed spatial alternation), a nonspatial (delayed object alternation) visual working memory task, or tasks that did not involve working memory, i.e., a visual pattern discrimination or sensorimotor paradigm. The results show a topographic segregation of activation related to spatial and nonspatial working memory, respectively. The delayed spatial alternation task increases LCGU rates bilaterally by 33-43% in the head of the caudate nucleus, where efferents from the dorsolateral prefrontal cortex project most densely. The delayed object alternation task enhances LCGU rates bilaterally by 32-37% in the body of the caudate nucleus, which is innervated by the temporal cortex. The visual pattern discrimination task similarly activated the body of the caudate, but in a smaller region and only in the right hemisphere. These findings provide the first evidence for metabolic activation of the caudate nuclei in working memory, supporting the role of this nucleus as a node in a neural network mediating DLPFC-dependent working memory processes. The double dissociation of activation observed suggests an anatomical and functional segregation of cortico-striatal circuits subserving spatial and nonspatial cognitive operations.

Animals↗
PubMed1997

Topographic organization of medial pulvinar connections with the prefrontal cortex in the rhesus monkey.

The medial nucleus of the pulvinar complex (PM) has widespread connections with association cortex. We investigated the connections of the PM with the prefrontal cortex (PFC) in macaque monkeys, with tracers placed into the PM and the PFC, respectively. Injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) placed into the PM resulted in widespread anterograde terminal labeling in layers III and IV, and retrograde cellular labeling in layer VI of the PFC. Injections of tracers centered on the central/lateral PM resulted in labeling of dorsolateral and orbital regions, whereas injections centered on caudal, medial PM resulted in labeling of dorsomedial and medial PFC. Since injections of the PM included neighboring thalamic nuclei, retrograde tracers were placed into distinct cytoarchitectonic regions of the PFC and retrogradely labeled cells in the posterior thalamus were charted. The results of this series of tracer injections confirmed the results of thalamic injections. Injections placed into areas 8a, 12 (lateral and orbital), 45, 46 and 11, retrogradely labeled neurons in the central/lateral PM, while tracer injections placed into areas 9, 12 (lateral), 10 and 24, labeled medial PM. The connections of the PM with temporal, parietal, insular, and cingulate cortices were also examined. The central/lateral PM has reciprocal connections with posterior parietal areas 7a, 7ip, and 7b, insular cortex, caudal superior temporal sulcus (STS), caudal superior temporal gyrus (STG), and posterior cingulate, whereas medial PM is connected mainly with the anterior STS and STG, as well as the cingulate cortex and the amygdala. These connectional studies suggest that the central/ lateral and medial PM have divergent connections which may be the substrate for distinct functional circuits.

Animals↗
PubMed1997

Functional and anatomical aspects of prefrontal pathology in schizophrenia.

Clinical and experimental research have provided anatomical, pharmacological, and behavioral evidence for a prominent prefrontal dysfunction in schizophrenia. Negative symptoms and behavioral disorganization in the disorder can be understood as a failure in the working memory functions of the prefrontal cortex by which information is updated on a moment-to-moment basis or retrieved from long-term stores, held in mind, and used to guide behavior by ideas, concepts, and stored knowledge. This article recounts efforts to dissect the cellular and circuit basis of working memory with the goal of extending the insights gained from the study of normal brain organization in animal models to an understanding of the clinical disorder; it includes recent neuropathological findings that indicate that neural dystrophy rather than cell loss predominates in schizophrenia. Evidence from a variety of studies is accumulating to indicate that dopamine has a major role in regulating the excitability of the cortical neurons upon which the working memory function of the prefrontal cortex depends. Interactions between monoamines and a compromised cortical circuitry may hold the key to the salience of frontal lobe symptoms in schizophrenia, in spite of widespread pathological changes. We outline several direct and indirect intercellular mechanisms for modulating working memory function in the prefrontal cortex based on the localization of dopamine receptors on the distal dendrites and spines of glutamatergic pyramidal cells and on gamma-aminobutyric acid (GABA) ergic interneurons in the prefrontal cortex. Understanding the interactions between the major cellular constituents of cortical circuits-pyramidal and nonpyramidal cells-is a necessary step in unraveling the receptor mechanisms, which could lead to an effective pharmacological treatment of negative and cognitive symptoms, as well as improved insight into the pathophysiological basis of the disorder.

Attention↗
PubMed1997

Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs.

D2 dopamine receptor antagonism is postulated to be the key to antipsychotic efficacy in the treatment of schizophrenia. Yet the D1 dopamine family of receptors is far more prevalent in the cortical areas of the brain, such as the prefrontal cortex, which have frequently been implicated in schizophrenia. Moreover, the prefrontal cortical D1 sites have recently been shown to be down-regulated by chronic treatment with several commonly used antipsychotic drugs (Lidow and Goldman-Rakic, 1994). To provide further insight into the pharmacological regulation of the D1 class of dopaminergic receptors, we have now used ribonuclease protection assays to examine the regulation of D1 and D5 dopamine receptor mRNAs in the prefrontal cortex and the neostriatum of nonhuman primates after chronic treatment with eight different drugs representing a wide structural and pharmacological spectrum of antipsychotic medications. The medications were administered for 6 months twice daily at doses that fall within the therapeutic range recommended for human patients. The study also included a substituted benzamide, tiapride, which is a D2 antagonist like the eight aforementioned drugs but reportedly lacks antipsychotic activity. Remarkably, all drugs used in this study, including tiapride, down-regulated the levels of both D1 and D5 mRNAs in the prefrontal cortex by 30% to 60% compared with a vehicle control group, whereas mRNAs in the neostriatum were not affected. This observation indicates that a reduction in the levels of prefrontal cortical dopamine receptors of the D1 class may be an obligatory consequence of D2 receptor antagonism and thus may be a pharmacological property of antipsychotic drugs.

Animals↗
PubMed1997

Differential regulation of D2 and D4 dopamine receptor mRNAs in the primate cerebral cortex vs. neostriatum: effects of chronic treatment with typical and atypical antipsychotic drugs.

The RNase Protection Assay was used to examine the regulation of D2 and D4 dopamine receptor mRNAs in the cerebral cortex and neostriatum of nonhuman primates after chronic treatment with a wide spectrum of antipsychotic medications (chlorpromazine, clozapine, haloperidol, molindone, olanzapine, pimozide, remoxipride and risperidone). Tiapride, a D2 antagonist that lacks antipsychotic activity, was also included. All drugs were administered orally for 6 months at doses recommended for humans. All antipsychotic drug treatments examined in this study caused a statistically significant up-regulation of both the long and short isoforms of the D2 receptor mRNAs in the prefrontal and temporal cortex. Tiapride, in contrast, significantly up-regulated only the level of D2-long mRNA in these areas. The same drug treatments produced less uniform effects in the neostriatum than in the cortex: clozapine and olanzapine failed to significantly elevate either D2-long or D2-short receptor messages in this structure unlike all other drugs, including tiapride. In both the cerebral cortex and striatum, D4 receptor mRNA was upregulated by certain typical (chlorpromazine and haloperidol) and certain atypical (clozapine, olanzapine and risperidone) antipsychotic agents as well as by tiapride. Other drugs of the typical (molindone and pimozide) and atypical (remoxipride) classes had no effect on D4 mRNA levels in either cortical or striatal tissue. The finding that up-regulation of D2 dopamine receptor mRNAs was a consistently observed effect of a wide range of antipsychotic agents in the cerebral cortex but not in the neostriatum, coupled with the fact that the D2-short isoforms in the cortex were not regulated by a nonantipsychotic D2 antagonist, tiapride, draws attention to the importance of the D2 dopamine receptor in the cerebral cortex as a potentially critical, common site of action of antipsychotic medications.

Animals↗
PubMed1996

Regional and cellular fractionation of working memory.

This chapter recounts efforts to dissect the cellular and circuit basis of a memory system in the primate cortex with the goal of extending the insights gained from the study of normal brain organization in animal models to an understanding of human cognition and related memory disorders. Primates and humans have developed an extraordinary capacity to process information "on line," a capacity that is widely considered to underlay comprehension, thinking, and so-called executive functions. Understanding the interactions between the major cellular constituents of cortical circuits-pyramidal and nonpyramidal cells-is considered a necessary step in unraveling the cellular mechanisms subserving working memory mechanisms and, ultimately, cognitive processes. Evidence from a variety of sources is accumulating to indicate that dopamine has a major role in regulating the excitability of the cortical circuitry upon which the working memory function of prefrontal cortex depends. Here, I describe several direct and indirect intercellular mechanisms for modulating working memory function in prefrontal cortex based on the localization of dopamine receptors on the distal dendrites and spines of pyramidal cells and on interneurons in the prefrontal cortex. Interactions between monoamines and a compromised cortical circuitry may hold the key to understanding the variety of memory disorders associated with aging and disease.

Animals↗
PubMed1996

The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive.

The functional architecture of prefrontal cortex is central to our understanding of human mentation and cognitive prowess. This region of the brain is often treated as an undifferentiated structure, on the one hand, or as a mosaic of psychological faculties, on the other. This paper focuses on the working memory processor as a specialization of prefrontal cortex and argues that the different areas within prefrontal cortex represent iterations of this function for different information domains, including spatial cognition, object cognition and additionally, in humans, semantic processing. According to this parallel processing architecture, the 'central executive' could be considered an emergent property of multiple domain-specific processors operating interactively. These processors are specializations of different prefrontal cortical areas, each interconnected both with the domain-relevant long-term storage sites in posterior regions of the cortex and with appropriate output pathways.

Animals↗
PubMed1996

Localization of dopamine D4 receptors in GABAergic neurons of the primate brain.

Dopamine receptors are the principal targets of drugs used in the treatment of schizophrenia. Among the five mammalian dopamine-receptor subtypes, the D4 subtype is of particular interest because of its high affinity for the atypical neuroleptic clozapine. Interest in clozapine stems from its effectiveness in reducing positive and negative symptoms in acutely psychotic and treatment-resistant schizophrenic patients without eliciting extrapyramidal side effects. We have produced a subtype-specific antibody against the D4 receptor and localized it within specific cellular elements and synaptic circuits of the central nervous system. The D4-receptor antibody labelled GABAergic neurons in the cerebral cortex, hippocampus, thalamic reticular nucleus, globus pallidus and the substantia nigra (pars reticulata). Labelling was also observed in a subset of cortical pyramidal cells. Our findings suggest that clozapine's beneficial effects in schizophrenia may be achieved, in part, through D4-mediated GABA modulation, possibly implicating disinhibition of excitatory transmission in intrinsic cortical, thalamocortical and extrapyramidal pathways.

Animals↗
PubMed1996

Serotonergic axons in monkey prefrontal cerebral cortex synapse predominantly on interneurons as demonstrated by serial section electron microscopy.

Anatomical approaches were used to describe the distribution, appearance, and synaptic interactions of serotonin (5-HT)-immunoreactive axons in monkey prefrontal cortex. A plexus of 5-HT axons was found throughout the gray matter, with an especially high density in layer I and a slight increase in layer IV. They were strikingly heterogeneous, with a gradient of morphologies ranging from fine and nonvaricose to highly varicose or thick and nonvaricose. Electron microscopy showed that both varicose and nonvaricose axons were typically filled with clear vesicles and less abundant dense core vesicles. A serial section analysis of 5-HT varicosities in layers I, III, and V showed consistent results across layers. Only about 23% of labeled varicosities formed identifiable synapses. These synapses were consistently asymmetric and were 2-5 serial sections (or 0.08-0.38 mu) in diameter. Targets of identified 5-HT synapses were dendritic shafts with the exception of one cell soma. Followed in serial sections, postsynaptic dendrites typically had morphological features of interneurons, i.e. they lacked spines, had a high density of synaptic inputs, and often had a varicose morphology. Only 8% of postsynaptic shafts were classified as pyramidal dendrites. This is in striking contrast to our previous study in this cortex of dopamine axons, which synapsed predominantly on pyramidal dendrites. These are the first results to indicate that interneurons are the major recipient of identifiable 5-HT synapses in the monkey prefrontal cortex.

Animals↗
PubMed1996

Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys.

The selective activation of the prefrontal cortical dopamine system by mild stress can be mimicked by anxiogenic beta-carbolines such as FG7142. To investigate the functional relevance of elevated levels of dopamine turnover in the prefrontal cortex, the current study examined the effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortical dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discrimination, a task with similar motor and motivational demands (rats), or delayed response performance following zero-second delays (monkeys) was unaffected by FG7142. Further, biochemical analysis in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task. The cognitive deficits in both rats and monkeys were prevented by pretreatment with the benzodiazepine receptor antagonist, RO15-1788, which blocked the increase in dopamine turnover and by the dopamine receptor antagonists, haloperidol, clozapine, and SCH23390. These findings indicate that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the prefrontal cortex.

Analysis of Variance↗
PubMed1995

Modulation of memory fields by dopamine D1 receptors in prefrontal cortex.

Dopamine has been implicated in the cognitive process of working memory but the cellular basis of its action has yet to be revealed. By combining iontophoretic analysis of dopamine receptors with single-cell recording during behaviour, we found that D1 antagonists can selectively potentiate the 'memory fields' of prefrontal neurons which subserve working memory. The precision shown for D1 receptor modulation of mnemonic processing indicates a direct gating of selective excitatory synaptic inputs to prefrontal neurons during cognition.

Animals↗
PubMed1995

Intrinsic circuit organization of the major layers and sublayers of the dorsolateral prefrontal cortex in the rhesus monkey.

Intrinsic connections are likely to play important roles in cognitive information processing in the prefrontal association cortex. To gain insight into the organization of these circuits, intracortical connections of major laminar and sublaminar divisions were retrogradely labeled in Walker's area 9 and 46 in rhesus monkeys by using cholera toxin (B-subunit) conjugated to colloidal gold. Microinjections placed within particular cortical laminae produced unique patterns of retrograde labeling. Injections in layers II/III yielded labeling which was laterally widespread (2-7 mm) in supragranular layers, and more narrowly focused, i.e., conforming to a column, in layers IV-VI. In contrast, local circuits associated with layers IV and Vb displayed a regular, cylindrical organization, whereas intrinsic connections of layer Va were laterally extensive (3-5 mm) in layers III and Va. Finally, injections in layer VI gave rise to a narrow column of cell labeling traversing all layers, augmented by laterally extensive labeling (approximately 7 mm) in layer VI. The intrinsic connections of the prefrontal cortex were arrayed within mediolaterally elongated stripes which were often distributed asymmetrically in either the medial or lateral direction. In addition, labeled cells within these mediolaterally oriented fields were frequently grouped within discrete clusters or narrow bands. The intrinsic connections identified in this study differ from the local circuits of corresponding layers reported for primary visual cortex; the unique intrinsic wiring diagram of the prefrontal cortex may be related to its specialized cognitive and mnemonic functions.

Animals↗
PubMed1995

Cholinergic synaptic circuitry in the macaque prefrontal cortex.

Surprisingly little is known about the synaptic architecture of the cholinergic innervation in the primate cerebral cortex in spite of its acknowledged relevance to cognitive processing and Alzheimer's disease. To address this knowledge gap, we examined serially sectioned cholinergic axons in supra- and infragranular layers of the macaque prefrontal cortex by using an antibody against the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT). The tissue bound antibody was visualized with both immunoperoxidase and silver-enhanced diaminobenzidine sulfide (SEDS) techniques. Both methods revealed that cholinergic axons make synapses in all cortical layers and that these synapses are exclusively symmetric. Cholinergic axons formed synapses primarily on dendritic shafts (70.5%), dendritic spines (25%), and, to a lesser extent, cell bodies (4.5%). Both pyramidal neurons and cells exhibiting the morphological features of GABAergic cells were targets of the cholinergic innervation. Some spiny dendritic shafts received multiple, closely spaced synapses, suggesting that a subset of pyramidal neurons may be subject to a particularly strong cholinergic influence. Analysis of synaptic incidence of cholinergic profiles in the supragranular layers of the prefrontal cortex by the SEDS technique revealed that definitive synaptic junctions were formed by 44% of the cholinergic boutons. An unexpected finding was that cholinergic boutons were frequently apposed to spines and small dendrites without making any visible synaptic specializations. These same spines and dendrites often received asymmetric synapses, presumably of thalamocortical or corticocortical origin. Present ultrastructural findings suggest that acetylcholine may have a dual modulatory effect in the neocortex: one through classical synaptic junctions on dendritic shafts and spines, and the other through nonsynaptic appositions in close vicinity to asymmetric synapses. Further physiological studies are necessary to test the hypothesis of the nonsynaptic release of acetylcholine in the cortex.

Animals↗
PubMed1995

Characterization of subtype-specific antibodies to the human D5 dopamine receptor: studies in primate brain and transfected mammalian cells.

To achieve a better understanding of how D5 dopamine receptors mediate the actions of dopamine in brain, we have developed antibodies specific for the D5 receptor. D5 antibodies reacted with recombinant baculovirus-infected Sf9 cells expressing the D5 receptor but not with the D1 receptor or a variety of other catecholaminergic and muscarinic receptors. Epitope-tagged D5 receptors expressed in mammalian cells were reactive with both D5 antibodies and an epitope-specific probe. A mixture of N-linked glycosylated polypeptides and higher molecular-mass species was detected on immunoblots of membrane fractions of D5-transfected cells and also of primate brain. D5 receptor antibodies intensely labeled pyramidal neurons in the prefrontal cortex, whereas spiny medium-sized neurons and aspiny large interneurons of the caudate nucleus were relatively lightly labeled. Antibodies to the D5 dopamine receptor should prove important in experimentally determining specific roles for the D5 and D1 receptors in cortical processes and diseases.

Amino Acid Sequence↗