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PubMed2004

Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex.

The prefrontal cortex plays a key role in the control of higher brain functions and is involved in the pathophysiology and treatment of schizophrenia. Here we report that approximately 60% of the neurons in rat and mouse prefrontal cortex express 5-HT(1A) and/or 5-HT2A receptor mRNAs, which are highly co-localized (approximately 80%). The electrical stimulation of the dorsal and median raphe nuclei elicited 5-HT1A-mediated inhibitions and 5-HT2A-mediated excitations in identified pyramidal neurons recorded extracellularly in rat medial prefrontal cortex (mPFC). Opposite responses in the same pyramidal neuron could be evoked by stimulating the raphe nuclei at different coordinates, suggesting a precise connectivity between 5-HT neuronal subgroups and 5-HT1A and 5-HT2A receptors in pyramidal neurons. Microdialysis experiments showed that the increase in local 5-HT release evoked by the activation of 5-HT2A receptors in mPFC by DOI (5-HT2A/2C receptor agonist) was reversed by co-perfusion of 5-HT1A agonists. This inhibitory effect was antagonized by WAY-100635 and the prior inactivation of 5-HT1A receptors in rats and was absent in mice lacking 5-HT1A receptors. These observations help to clarify the interactions between the mPFC and the raphe nuclei, two key areas in psychiatric illnesses and improve our understanding of the action of atypical antipsychotics, acting through these 5-HT receptors.

Amphetamines↗
PubMed2006

Heterogeneity in the pyramidal network of the medial prefrontal cortex.

The prefrontal cortex is specially adapted to generate persistent activity that outlasts stimuli and is resistant to distractors, presumed to be the basis of working memory. The pyramidal network that supports this activity is unknown. Multineuron patch-clamp recordings in the ferret medial prefrontal cortex showed a heterogeneity of synapses interconnecting distinct subnetworks of different pyramidal cells. One subnetwork was similar to the pyramidal network commonly found in primary sensory areas, consisting of accommodating pyramidal cells interconnected with depressing synapses. The other subnetwork contained complex pyramidal cells with dual apical dendrites displaying nonaccommodating discharge patterns; these cells were hyper-reciprocally connected with facilitating synapses displaying pronounced synaptic augmentation and post-tetanic potentiation. These cellular, synaptic and network properties could amplify recurrent interactions between pyramidal neurons and support persistent activity in the prefrontal cortex.

Animals↗
PubMed2004

Maintenance in working memory or response selection? Functions of NMDA receptors in the pigeon "prefrontal cortex".

The prefrontal cortex is involved in various aspects of working memory like stimulus maintenance and response selection functions. Neurobehavioral studies and neurocomputational models assume a role for NMDA receptors in prefrontal cortex for maintenance processes, while our previous studies on NMDA receptors in the avian prefrontal cortex-analogue, the nidopallium caudolaterale (NCL), showed them to be involved in response selection functions. Various tasks used in PFC-related research address in fact both functions, so they cannot disambiguate their separate contributions to performance. In order to investigate the role of NMDA receptors in avian NCL for stimulus maintenance and response selection, we trained pigeons in a delayed matching-to sample (DMTS) task, requiring both functions, and a simultaneous matching to sample (SMTS) task, requiring only response selection. After reaching criterion, pigeons had to perform the tasks alternately under local NMDA receptor blockade in NCL (DL-AP5) and after infusion of vehicle (saline solution). Blockade of NCL-based NMDA receptors led to significant increases in error rates in both DMTS and SMTS--compared with the same subjects' performance during training and in the control condition. However, there was no additional increase in errors due to the additional maintenance component, so the impairment appears to be due to deficits in adequate selection of responses, the function necessary for both tasks. We conclude that NMDA receptors in the pigeon NCL participate in response selection rather than stimulus maintenance in tasks requiring the processing of context information.

Animals↗
PubMed1982

Development of brain stimulation reward in the medial prefrontal cortex: facilitation by prior electrical stimulation of the sulcal prefrontal cortex.

Electrical stimulation of the medial prefrontal cortex (MC) in rats delivered daily for seven days causes a marked improvement in the rate of acquisition of a self-stimulation response. In the present experiment, we looked at whether we could get the same facilitatory effect on self-stimulation of the MC by delivering pre-training stimulation to other points in the brain anatomically related to the MC. Electrical stimulation of the lateral hypothalamus was without effect. However, electrical stimulation of the sulcal prefrontal cortex (SC) either contralateral or ipsilateral to the MC electrode did facilitate acquisition of self-stimulation of the MC. Thus the Sc and MC would appear to be part of the same substrate controlling the development of positive reinforcement in the MC.

Animals↗
PubMed2004

Carbachol in the pontine reticular formation of C57BL/6J mouse decreases acetylcholine release in prefrontal cortex.

The prefrontal cortex and brainstem modulate autonomic and arousal state control but the neurotransmitter mechanisms underlying communication between prefrontal cortex and brainstem remain poorly understood. This study examined the hypothesis that microdialysis delivery of carbachol to the pontine reticular formation (PRF) of anesthetized C57BL/6J (B6) mouse modulates acetylcholine (ACh) release in the frontal association cortex. Microdialysis delivery of carbachol (8.8 mM) to the PRF caused a significant (P<0.01) decrease (-28%) in ACh release in the frontal association cortex, a significant (P<0.01) decrease (-23%) in respiratory rate, and a significant (P<0.01) increase (223%) in time to righting after anesthesia. Additional in vitro studies used the [(35)S]guanylyl-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) assay to test the hypothesis that muscarinic cholinergic receptors activate guanine nucleotide binding proteins (G proteins) in the frontal association cortex and basal forebrain. In vitro treatment with carbachol (1 mM) caused a significant (P<0.01) increase in [(35)S]GTPgammaS binding in the frontal association cortex (62%) and basal forebrain nuclei including medial septum (227%), vertical (210%) and horizontal (165%) limbs of the diagonal band of Broca, and substantia innominata (127%). G protein activation by carbachol was concentration-dependent and blocked by atropine, indicating that the carbachol-stimulated [(35)S]GTPgammaS binding was mediated by muscarinic cholinergic receptors. Together, the in vitro and in vivo data show for the first time in B6 mouse that cholinergic neurotransmission in the PRF can significantly alter ACh release in frontal association cortex, arousal from anesthesia, and respiratory rate.

Acetylcholine↗
PubMed1999

The hierarchical organization of decision making in the primate prefrontal cortex.

The prefrontal cortex plays an important role in making the association between sensory information and specific behavior. For example, in a complex stimulus response situation, such as the Wisconsin card sorting test, prefrontal patients show difficulty in making appropriate decisions. To understand the neural mechanisms, we recorded prefrontal cell activity while monkeys performed a go/no-go selective attention task where the subjects made a go or no-go response depending on the color or the motion direction of compound visual stimuli (moving colored dots). Groups of cells showed differential activity for go and no-go stimuli (go/no-go activity): some showed the activity either in the color or motion attending condition, and others showed the activity both in the color and motion conditions. Cells of shorter latencies, found mainly in the prefrontal subareas receiving visual input, showed go/no-go activity only when task demands necessitated that the monkeys attended to that cell's preferred visual dimension. We also found cells with longer latencies in the motor-related periarcuate area that showed go/no-go activity regardless of the dimension attended. These results suggest that subareas in the prefrontal cortex play different roles in associating the sensory information with its behavioral meaning and are hierarchically organized to make appropriate decisions in complex tasks.

Animals↗
PubMed2002

Story processing in patients with damage to the prefrontal cortex.

The prefrontal cortex is known to be involved in performing complex cognitive tasks requiring reasoning, planning and decision-making. Neuropsychological evidence also supports the idea that the prefrontal cortex is generally involved in encoding and retrieving complex events, such as action and narrative knowledge. Patients with frontal lobe damage are reported to have difficulty in processing different aspects of narrative representations, such as the figurative moral meaning, syntactic features, and inference generation. In the present study, we examined story processing in 17 patients with frontal lobe lesions and compared their performance to 7 amnesic patients and 17 normal controls. Two stories were presented by using two slightly different processing demands in order to assess the subject's ability to draw inferences on-line during the course of comprehension or later retrieval. Although all patients had impaired story memory, patients with frontal lobe lesions showed a pattern of deficit at an early stage of story comprehension that specifically involved the ability to reconstruct the sequential links among events and to extract inferential knowledge from the text during encoding. Amnesic patients were severely impaired in recalling story semantic units, including single events and larger narrative constituents, as well as in the event recognition task. Consequently, they were unable to establish inferential relations among the events and, thus, the global sequential structure of the stories during retrieval. In contrast, they had no difficulty in extracting inferential knowledge during story comprehension on the basis of readily available information. This study shows that damage to different cortical regions may induce impairments at various levels of story processing.

Adult↗
PubMed2006

Evidence for multiple manipulation processes in prefrontal cortex.

The prefrontal cortex (PFC) is known to subserve working memory (WM) processes. Brain imaging studies of WM using delayed response tasks (DRTs) have shown memory-load-dependent activation increases in dorsal prefrontal cortex (PFC) regions. These activation increases are believed to reflect manipulation of to-be-remembered information in the service of memory-consolidation. This speculation has been based on observations of similar activation increases in tasks that overtly require manipulation by instructing participants to reorder to-be-remembered list items. In this study, we tested the assumption of functional equivalence between these two types of WM tasks. Participants performed a DRT under two conditions with memory loads ranging from 3 to 6 letters. In an "item-order" condition, participants were required to remember letters in the order in which they were presented. In a "reordering" condition, participants were required to remember the letters in alphabetical order. Load-related activation increases were observed during the encoding and maintenance periods of the order maintenance condition, whereas load-related activation decreases were observed in the same periods of the reordering condition. These results suggest that (1) the neural substrates associated with long-list retention and those associated with reordering are not equivalent, (2) cognitive processes associated with long-list retention may be more closely approximated by item-order maintenance than by reordering, and (3) multiple forms of WM manipulation are dissociable on the basis of fMRI data.

Adolescent↗
PubMed2007

Tuning the engine of cognition: a focus on NMDA/D1 receptor interactions in prefrontal cortex.

The prefrontal cortex of the primate frontal lobes provides the capacity for judgment which can constantly adapt behavior in order to optimize its outcome. Adjudicating between long-term memory programs and prepotent responses, this capacity reviews all incoming information and provides an interpretation dependent on the events that have just occurred, the events that are predicted to happen, and the alternative response strategies that are available in the given situation. It has been theorized that this function requires two essential integrated components, a central executive which guides selective attention based on mechanisms of associative memory, as well as the second component, working memory buffers, in which information is held online, abstracted, and translated on a mental sketchpad of work in progress. In this review, we critically outline the evidence that the integration of these processes and, in particular, the induction and maintenance of persistent activity in prefrontal cortex and related networks, is dependent upon the interaction of dopamine D1 and glutamate NMDA receptor signaling at critical nodes within local circuits and distributed networks. We argue that this interaction is not only essential for representational memory, but also core to mechanisms of neuroadaptation and learning. Understanding its functional significance promises to reveal major new insights into prefrontal dysfunction in schizophrenia and, hence, to target a new generation of drugs designed to ameliorate the debilitating working memory deficits in this disorder.

Animals↗
PubMed2005

EEG activities in the orbitofrontal cortex and dorsolateral prefrontal cortex during the development of morphine dependence, tolerance and withdrawal in rhesus monkeys.

Investigating the activities of the prefrontal cortex (PFC) in the process of addiction is valuable for understanding the neural mechanism underlying the impairments of the PFC after drug abuse. However, limited data are obtained from primate animals and few studies analyze Electroencephalogram (EEG) in the gamma band, which plays an important role in cognitive functions. In addition, it is yet unclear whether drug abuse affects the orbitofrontal cortex (OFC) and dorsolateral PFC (DLPFC)--the two most important subregions of the PFC--in similar ways or not. The aim of this study is to address these issues. We recorded EEG in the OFC and DLPFC in three rhesus monkeys. All animals received a course of saline (NaCl 0.9%, 2 ml) injection (5 days) followed by 10 days of morphine injection (every 12 h), and then a further series of saline injection (7 days). A main finding in the present study was that morphine decreased EEG power in all frequency bands in a short period after injection in both the OFC and DLPFC in monkeys. And gamma power decreased not just in a short period after morphine injection but lasted to 12 h after injection. Moreover, we found that although the changes in EEG activities in the OFC and DLPFC at 30-35 min after injection were similar, the DLPFC was more sensitive to the effect of morphine than the OFC.

Analysis of Variance↗
PubMed1994

The prefrontal cortex and variants of sequential behaviour indications of functional differentiation between subdivisions of the rat's prefrontal cortex.

In two separate experiments we addressed the involvement of the rat's prefrontal cortex in mediation of the sequential ordering of the "components of behaviour". In both experiments the animals were required to operate two different and spatially distant manipulanda sequentially. While in the first experiment a light cue signalled which response would at any moment be appropriate no sensory cues offered procedural guidance during the second experiment. Both experiments focused on postoperative retention performance. In the first experiment we studied the consequences of ablation of the dorsal anteromedial cortex, the total anteromedial cortex and the suprarhinal cortex as compared to a sham operated control group. In the second experiment we compared a sham operated group to a group subjected to ablation of the total anteromedial cortex. While the proficiency of task performance was evaluated on the basis of the number of reinforcements obtained and the percentage of bar presses to be reinforced, additional analysis of behaviour included registration of the individual behavioural components and the sequential orders in which these were observed. The major findings were: (1) lesions within the anteromedial, prefrontal cortex (especially if including the ventral part of this region) are associated with significantly impaired performance of both the presently investigated tasks. (2) The demonstrated association between the anteromedial cortex and the mediation of the sequential arrangement of behavioural components does not seem to be secondary to changes in neither quality nor frequency of any individual behavioural component. (3) In the first experiment--where a cue light signalled which response would at any point in time be adequate--lesions within all parts of the prefrontal cortex (the suprarhinal as well as the anteromedial cortex) were associated with overproduction of errors, which in the behavioural sequence analysis had been characterized as "type B". We tentatively interpret such errors as reflecting a failure to utilize the visual cue offered by the signal lamp. Since lesions within all parts of the prefrontal cortex seem to be associated with "cue utilization" failures while only lesions involving the anteromedial cortex are reflected in impaired sequential arrangement of behavioural components the present studies seem to reflect a certain degree of functional specialization within the prefrontal cortex of the rat.

Animals↗
PubMed1987

Motor control function of the prefrontal cortex.

The prefrontal granular cortex, with the premotor and motor areas, forms the frontal lobe. The three areas are allied by their proximity to one another and by their role in motor control. Of these three major subdivisions, the role of prefrontal cortex has been the most obscure. However, recent anatomical studies have elucidated the circuit basis for motor regulatory functions of the principal sulcus (Brodmann's area 9; Walker's area 46). In addition to well known and well worked out prominent connections with subcortical structures, e.g. the basal ganglia and deep layers of the superior colliculus, this area of prefrontal cortex is reciprocally connected to portions of the supplementary motor and premotor fields that are but one synapse removed from primary motor cortex. The principal sulcal cortex is additionally interconnected with the primary somatosensory area and the somatosensory association areas, in the frontoparietal operculum, with area PF of von Bonin and Bailey in the posterior parietal cortex, and with parts of the 'motor' thalamus. Recent behavioural and electrophysiological studies in monkeys (Macaca mulatta) demonstrate that the principal sulcus can influence delayed-responding, whether the response is a hand or an eye movement. The anatomical and functional evidence supports the thesis that prefrontal cortex has access to and can direct the output of several motor centres.

Animals↗
PubMed2004

Interaction between perirhinal and medial prefrontal cortex is required for temporal order but not recognition memory for objects in rats.

The present study investigated the roles of the perirhinal cortex, medial prefrontal cortex, and intrahemispheric interactions between them in recognition and temporal order memory for objects. Experiment 1 assessed the effects of bilateral microinfusions of the sodium channel blocker lidocaine into either the anterior perirhinal or medial prefrontal cortex immediately before memory testing in a familiarity discrimination task and a recency discrimination task, both of which involved spontaneous exploration of objects. Inactivation of the perirhinal cortex disrupted performance in both tasks, whereas inactivation of the medial prefrontal cortex disrupted performance in the recency, but not the familiarity, discrimination task. In a second experiment, the importance of intrahemispheric interactions between these structures in temporal order memory were assessed by comparing the effects of unilateral inactivation of either structure alone with those of crossed unilateral inactivation of both structures on the recency discrimination task. Crossed unilateral inactivation of both structures produced a significant impairment, whereas inactivation of either structure alone produced little or no impairment. Collectively, these findings suggest that the perirhinal cortex, but not the medial prefrontal cortex, contributes to retrieval of information necessary for long-term object recognition, whereas both structures, via intrahemispheric interactions between them, contribute to retrieval of information necessary for long-term object temporal order memory. These data are consistent with models in which attributed information is stored in posterior cortical sites and supports lower-order mnemonic functions (e.g., recognition memory) but can also be retrieved and further processed via interactions with the prefrontal cortex to support higher-order mnemonic functions (e.g., temporal order memory).

Animals↗
PubMed1999

Visual attention task performance in Wistar and Lister hooded rats: response inhibition deficits after medial prefrontal cortex lesions.

The prefrontal cortex has traditionally been implicated in a variety of cognitive processes, including memory, attention and decision making. The detection of effects of prefrontal cortex lesions on attention has been shown to depend on the procedure used to assess the attentional process. We therefore investigated the effects of lesions of the prefrontal cortex in two different visual attention tasks, i.e. a three-choice serial reaction time task involving sustained and divided attention processes and a visual timing task involving sustained attention and response inhibition processes. In two rat strains that are frequently used in behavioural analysis, i.e. albino Wistar rats and pigmented Lister Hooded rats, lesions of the medial prefrontal cortex caused a deterioration of performance in both tasks, although the effect lasted much longer in the visual timing task. This latter task proved to be especially sensitive to detect the consequences of medial prefrontal cortex lesions, consisting of a loss of both attention control and response inhibition. In both attention tasks, Wistar rats performed less accurate and made more anticipatory responses than Listers. Strain differences could not entirely be attributed to possible visual deficits in albinos, which was also evident when locomotor activity in an open field and food-motivated behaviour in a hoarding paradigm were assessed. Due to slower habituation rates, Lister rats were more active and displayed little food hoarding behaviour. In Wistar rats, hoarding was disrupted by medial prefrontal cortex lesions, showing the effectiveness of the lesion. The results indicate that, although different rat strains provide different baseline levels of behaviour for testing lesion- or drug-induced behavioural changes, lesions of the medial prefrontal cortex do not only disrupt sustained attention processes, but also induce a strong impairment in response inhibition in both Wistar and Lister rats.

Animals↗
PubMed2006

A large-scale neurocomputational model of task-oriented behavior selection and working memory in prefrontal cortex.

The prefrontal cortex (PFC) is crucially involved in the executive component of working memory, representation of task state, and behavior selection. This article presents a large-scale computational model of the PFC and associated brain regions designed to investigate the mechanisms by which working memory and task state interact to select adaptive behaviors from a behavioral repertoire. The model consists of multiple brain regions containing neuronal populations with realistic physiological and anatomical properties, including extrastriate visual cortical regions, the inferotemporal cortex, the PFC, the striatum, and midbrain dopamine (DA) neurons. The onset of a delayed match-to-sample or delayed nonmatch-to-sample task triggers tonic DA release in the PFC causing a switch into a persistent, stimulus-insensitive dynamic state that promotes the maintenance of stimulus representations within prefrontal networks. Other modeled prefrontal and striatal units select cognitive acceptance or rejection behaviors according to which task is active and whether prefrontal working memory representations match the current stimulus. Working memory task performance and memory fields of prefrontal delay units are degraded by extreme elevation or depletion of tonic DA levels. Analyses of cellular and synaptic activity suggest that hyponormal DA levels result in increased prefrontal activation, whereas hypernormal DA levels lead to decreased activation. Our simulation results suggest a range of predictions for behavioral, single-cell, and neuroimaging response data under the proposed task set and under manipulations of DA concentration.

Action Potentials↗
PubMed2002

A role for inhibition in shaping the temporal flow of information in prefrontal cortex.

The prefrontal cortex is important in guiding or inhibiting future responses, which requires the temporal integration of events and which provides continuity to the thought process. No cellular mechanism has been proposed to explain how the mental representation of a response or idea is linked to the next. Using simultaneous recordings in monkeys, we revealed inhibitory interactions between neurons active at different time points relative to the cue presentation, delay interval and response period of a working memory task. These findings suggest an important role of inhibition in the cerebral cortex-controlling the timing of neuronal activities during cognitive operations and thereby shaping the temporal flow of information.

Animals↗
PubMed2003

The architecture of cognitive control in the human prefrontal cortex.

The prefrontal cortex (PFC) subserves cognitive control: the ability to coordinate thoughts or actions in relation with internal goals. Its functional architecture, however, remains poorly understood. Using brain imaging in humans, we showed that the lateral PFC is organized as a cascade of executive processes from premotor to anterior PFC regions that control behavior according to stimuli, the present perceptual context, and the temporal episode in which stimuli occur, respectively. The results support an unified modular model of cognitive control that describes the overall functional organization of the human lateral PFC and has basic methodological and theoretical implications.

Adult↗
PubMed2005

Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex.

The prefrontal cortex (PFC) plays an important role in higher cognitive processes, and in the regulation of stress-induced hypothalamic-pituitary-adrenal (HPA) activity. Here we examined the effect of repeated restraint stress on dendritic spine number in the medial PFC. Rats were perfused after receiving 21 days of daily restraint stress, and intracellular iontophoretic injections of Lucifer Yellow were carried out in layer II/III pyramidal neurons in the anterior cingulate and prelimbic cortices. We found that stress results in a significant (16%) decrease in apical dendritic spine density in medial PFC pyramidal neurons, and confirmed a previous observation that total apical dendritic length is reduced by 20% in the same neurons. We estimate that nearly one-third of all axospinous synapses on apical dendrites of pyramidal neurons in medial PFC are lost following repeated stress. A decrease in medial PFC dendritic spines may not only be indicative of a decrease in the total population of axospinous synapses, but may impair these neurons' capacity for biochemical compartmentalization and plasticity in which dendritic spines play a major role. Dendritic atrophy and spine loss may be important cellular features of stress-related psychiatric disorders where the PFC is functionally impaired.

Animals↗