Patricia S. Goldman-Rakic

D1 dopamine receptors in prefrontal cortex: involvement in working memory

The prefrontal cortex is involved in the cognitive process of working memory. Local injections of SCH23390 and SCH39166, selective antagonists of the D1 dopamine receptor, into the prefrontal cortex of rhesus monkeys induced errors and increased latency in performance on an oculomotor task that required memory-guided saccades. The deficit was dose-dependent and sensitive to the duration of the delay period. These D1 antagonists had no effect on performance in a control task requiring visually guided saccades, indicating that sensory and motor functions were unaltered. Thus, D1 dopamine receptors play a selective role in the mnemonic, predictive functions of the primate prefrontal cortex.

The reduced neuropil hypothesis: a circuit based model of schizophrenia

In recent years, quantitative studies of the neuropathology of schizophrenia have reignited interest in the cerebral cortex and focused attention on the cellular and subcellular constituents that may be altered in this disease. Findings have ranged from compromised circuitry in prefrontal areas to outright neuronal loss in temporal and cingulate cortices. Herein, we propose that a reduction in interneuronal neuropil in the prefrontal cortex is a prominent feature of cortical pathology in schizophrenia and review the growing evidence for this view from reports of altered neuronal density and immunohistochemical markers in various cortical regions. The emerging picture of neuropathology in schizophrenia is one of subtle changes in cellular architecture and brain circuity that nonetheless have a devastating impact on cortical function.

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.

Comparison of human infants and rhesus monkeys on Piaget's AB task: evidence for dependence on dorsolateral prefrontal cortex

SummaryThis paper reports evidence linking dorsolateral prefrontal cortex with one of the cognitive abilities that emerge between 7.5–12 months in the human infant. The task used was Piagets Stage IV Object Permanence Test, known as AB (pronounced “A not B”). The AB task was administered (a) to human infants who were followed longitudinally and (b) to intact and operated adult rhesus monkeys with bilateral prefrontal and parietal lesions. Human infants displayed a clear developmental progression in AB performance, i.e., the length of delay required to elicit the AB error pattern increased from 2–5 s at 7.5–9 months to over 10 s at 12 months of age. Monkeys with bilateral ablations of dorsolateral prefrontal cortex performed on the AB task as did human infants of 7.5–9 months; i.e., they showed the AB error pattern at delays of 2–5 s and chance performance at 10 s. Unoperated and parietally operated monkeys succeeded at delays of 2, 5, and 10 s; as did 12 month old human infants. AB bears a striking resemblance to Delayed Response, the classic test for dorsolateral prefrontal function in the rhesus monkey, and indeed performance on AB and Delayed Response in the same animals in the present study was fully comparable. These findings provide direct evidence that AB performance depends upon dorsolateral prefrontal cortex in rhesus monkeys and indicates that maturation of dorsolateral prefrontal cortex may underlie the developmental improvement in AB performance of human infants from 7.5–12 months of age. This improvement marks the development of the ability to hold a goal in mind in the absence of external cues, and to use that remembered goal to guide behavior despite the pull of previous reinforcement to act otherwise. This confers flexibility and freedom to choose and control what one does.

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.

Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction.

Background and rationaleReinstatement of the function of working memory, the cardinal cognitive process essential for human reasoning and judgment, is potentially the most intractable problem for the treatment of schizophrenia. Since deficits in working memory are associated with dopamine dysregulation and altered D1 receptor signaling within prefrontal cortex, we present the case for targeting novel drug therapies towards enhancing prefrontal D1 stimulation for the amelioration of the debilitating cognitive deficits in schizophrenia.ObjectivesThis review examines the role of dopamine in regulating cellular and circuit function within prefrontal cortex in order to understand the significance of the dopamine dysregulation found in schizophrenia and related non-human primate models. By revealing the associations among prefrontal neuronal function, dopamine and D1 signaling, and cognition, we seek to pinpoint the mechanisms by which dopamine modulates working memory processes and how these mechanisms may be exploited to improve cognitive function.Results and conclusionsDopamine deficiency within dorsolateral prefrontal cortex leads to abnormal recruitment of this region by cognitive tasks. Both preclinical and clinical studies have demonstrated a direct relationship between prefrontal dopamine function and the integrity of working memory, suggesting that insufficient D1 receptor signaling in this region results in cognitive deficits. Moreover, working memory deficits can be ameliorated by treatments that augment D1 receptor stimulation, indicating that this target presents a unique opportunity for the restoration of cognitive function in schizophrenia.

Synaptic development of the cerebral cortex: implications for learning, memory, and mental illness

Publisher Summary This chapter explores various questions: Are synapses added as we learn? Are there more synapses in some cortical areas than in others? Are there gender differences in synaptic density and do we lose synapses as we age? If we lose synapses with age, what is the timing and rate of this dissolution? To address these issue this chapter present the finding reported in the rhesus monkey. The study of major structural and functional subdivisions of the cortex over the primate lifespan offers a particularly comprehensive view of synapse formation. From study, it is eminently clear that knowledge of the normal course and mechanisms of synapse formation, the influence of various exogenous and endogenous events upon synapse stability and turnover, are essential prerequisites to determining the locus and timing of etiological factors in diseases that affect the cortex and alter cognitive function.

Auditory belt and parabelt projections to the prefrontal cortex in the rhesus monkey.

Recent anatomical and electrophysiological studies have expanded our knowledge of the auditory cortical system in primates and have described its organization as a series of concentric circles with a central or primary auditory core, surrounded by a lateral and medial belt of secondary auditory cortex with a tertiary parabelt cortex just lateral to this belt. Because recent studies have shown that rostral and caudal belt and parabelt cortices have distinct patterns of connections and acoustic responsivity, we hypothesized that these divergent auditory regions might have distinct targets in the frontal lobe. We, therefore, placed discrete injections of wheat germ agglutinin‐horseradish peroxidase or fluorescent retrograde tracers into the prefrontal cortex of macaque monkeys and analyzed the anterograde and retrograde labeling in the aforementioned auditory areas. Injections that included rostral and orbital prefrontal areas (10, 46 rostral, 12) labeled the rostral belt and parabelt most heavily, whereas injections including the caudal principal sulcus (area 46), periarcuate cortex (area 8a), and ventrolateral prefrontal cortex (area12vl) labeled the caudal belt and parabelt. Projections originating in the parabelt cortex were denser than those arising from the lateral or medial belt cortices in most cases. In addition, the anterior third of the superior temporal gyrus and the dorsal bank of the superior temporal sulcus were also labeled after prefrontal injections, confirming previous studies. The present topographical results suggest that acoustic information diverges into separate streams that target distinct rostral and caudal domains of the prefrontal cortex, which may serve different acoustic functions. J. Comp. Neurol. 403:141–157, 1999.

Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional, stereologic counting method.

Neuropsychologic testing in schizophrenic patients has underscored the prominence of dysfunction in cognitive processes associated with the dorsolateral prefrontal cortex. Quantitative cytometric analysis of area 46 was undertaken in brains from schizophrenic patients to determine whether there are morphologic changes underlying these cognitive deficits. Postmortem brain specimens from 9 schizophrenic patients, 10 normal subjects, and 8 Huntingtons diseased patients were fixed in formalin and celloidin embedded. A direct, three‐dimensional counting method was used to determine cell density and cortical thickness in Nissl‐stained sections of area 46. Overall neuronal density was 21% greater in brains from schizophrenic patients in comparison to normal controls. Significant elevations in neuronal density were observed in layers II, III, IV, and VI. The cortical ribbon was slightly (8%) but not significantly thinner. However, layer II exhibited disproportionate thinning compared with all other layers. In brains from Huntingtons diseased patients, increases in neuronal (35%) and glial (61%) density with substantial cortical thinning (30%) were observed. The neuropathology of area 46 in schizophrenia is similar in direction and magnitude to that previously described in area 9 (Selemon et al. [1995] Arch. Gen. Psychiatry 52:805–818), except for the abnormalities in layer II, which are specific to area 46. In contrast to Huntingtons disease, in which cortical atrophy and gliosis are present, no evidence for cortical cell loss was uncovered in the schizophrenic cohort. The observed elevation in neuronal density suggests that a reduction in interneuronal neuropil may constitute the anatomical substrate for prefrontal cortical dysfunction in schizophrenia. J. Comp. Neurol. 392:402–412, 1998. Published 1998 Wiley‐Liss, Inc.

Chapter 16 Cellular and circuit basis of working memory in prefrontal cortex of nonhuman primates

Publisher Summary Working memory is applied by cognitive psychologists and theorists to the type of memory that is active and relevant only for a short period of time. This chapter reviews the role of prefrontal cortex (PFC) in working memory. In the cerebral cortex, a variety of neuronal responses is recorded from prefrontal neurons and they all play some role in integrated delayed-response performance and in the fundamental process of working memory. Neuronal activities are related to the cue, to the delay, to the response, or to some combination of these in manual delayed-response tasks. All major classes of neuron are found in the caudal portion of the dorsolateral prefrontal cortex and all major classes of neuron are identified in oculomotor, as well as in manual delayed-response tasks. Thus, the functions of the prefrontal cortex pertain to several motor systems and are amenable to cellular and circuit analyses. The principal sulcus in the prefrontal cortex is the anatomical focus for spatial delayed-response function and the knowledge of its connections with other structures helps to understand the circuit and cellular basis of working memory.