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PubMed1987

Dissociation of item and order spatial memory in rats following medial prefrontal cortex lesions.

In order to test whether there is a correspondence in function of prefrontal cortex in rats and humans, rats with medial prefrontal cortex lesions were tested for item and order memory for a list of items (spatial locations in a maze). Results indicate that for order memory rats with medial prefrontal cortex lesions cannot remember the order of presentation of four or eight specific spatial locations. This inability to remember order information can be seen even when animals with lesions have to remember only two spatial locations, can self-order the sequence of four or eight spatial locations, or have been presented with the same study phase on every trial. In contrast, for item memory animals with medial prefrontal cortex lesions retain the first item of the list in the variable study phase situation and remember all the items of the list in a constant study phase situation. However, there are also deficits for the last items within a list in the variable study phase situation for both win-stay and win-shift procedures. This deficit might be a function of an impairment in the utilization of appropriate temporal strategies, which normally would facilitate recognition memory in the win-stay and win-shift tasks. In general, the data suggest a partial, but not complete, dissociation of item-order memory. Furthermore, the data suggest that the medial prefrontal cortex is involved in temporal structuring of information.

Animals↗
PubMed2000

Plasticity at hippocampal to prefrontal cortex synapses: dual roles in working memory and consolidation.

The involvement of the hippocampus and the prefrontal cortex in cognitive processes and particularly in learning and memory has been known for a long time. However, the specific role of the projection which connects these two structures has remained elusive. The existence of a direct monosynaptic pathway from the ventral CA1 region of the hippocampus and subiculum to specific areas of the prefrontal cortex provides a useful model for conceptualizing the functional operations of hippocampal-prefrontal cortex communication in learning and memory. It is known now that hippocampal to prefrontal cortex synapses are modifiable synapses and can express different forms of plasticity, including long-term potentiation, long-term depression, and depotentiation. Here we review these findings and focus on recent studies that start to relate synaptic plasticity in the hippocampo-prefrontal cortex pathway to two specific aspects of learning and memory, i.e., the consolidation of information and working memory. The available evidence suggests that functional interactions between the hippocampus and prefrontal cortex in cognition and memory are more complex than previously anticipated, with the possibility for bidirectional regulation of synaptic strength as a function of the specific demands of tasks.

Animals↗
PubMed2000

Segregation of working memory functions within the dorsolateral prefrontal cortex.

It is now widely accepted that the prefrontal cortex (PFC) plays a critical role in the neural network subserving working memory (WM). At least three related questions are still under debate: (1) is the PFC critical for all constituent processes of WM (i.e., short-term storage, manipulation, and utilization of mental representations) or only in one or a few of them? (2) Is there segregation of function among different cytoarchitectonic subdivisions of the PFC? (3) If this be the case, is this segregation based on the nature of the information being processed or on the type of cognitive operation performed? The present review article describes findings in the monkey supporting a modular "domain-specific" model of PFC functional organization with respect to WM operations. In this model, the dorsolateral prefrontal cortex (DLPFC) is composed of several subregions, based primarily on the nature of the information being processed in WM. Storage and processing functions are integrally related in each area. Future studies designed to map as yet uncharted areas of prefrontal cortex with refined anatomical and physiological approaches may provide a critical test of the model and evaluate the extent to which it applies generally or, instead, mainly to visual domains or only to dorsolateral convexity areas.

Animals↗
PubMed2006

BDNF Val66Met polymorphism and GAD67 mRNA expression in the prefrontal cortex of subjects with schizophrenia.

OBJECTIVE: In the prefrontal cortex of subjects with schizophrenia, decreased signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase (TrkB) appears to contribute to the reduced expression of mRNA encoding the 67-kilodalton isoform of glutamate decarboxylase (GAD(67)), an enzyme for GABA synthesis. The authors examined in subjects with schizophrenia the effect in the human BDNF gene of a single nucleotide polymorphism (Val66Met), which reduces the trafficking and secretion of BDNF protein, on the expression of GAD(67) mRNA. METHOD: BDNF Val66Met genotyping was performed in 27 matched pairs of schizophrenia and comparison subjects. The impact of this polymorphism on prefrontal cortex GAD(67) mRNA expression in schizophrenia subjects was assessed by comparing within-pair differences in GAD(67) mRNA expression between schizophrenia subjects with versus without the Met66 allele after the level of BDNF mRNA expression was controlled. RESULTS: In contrast to expectations, the within-pair reduction in GAD(67) mRNA expression was not greater in schizophrenia subjects who were hetero- or homozygous for the Met66 allele. These subjects did tend to exhibit less marked within-pair reductions in both GAD(67) and BDNF mRNA expression compared with schizophrenia subjects homozygous for the Val allele. CONCLUSIONS: The presence of the BDNF Met66 allele does not contribute to the decreased level of GAD(67) mRNA expression in the prefrontal cortex of subjects with schizophrenia.

Brain-Derived Neurotrophic Factor↗
PubMed1994

Event-related theta rhythms in cat hippocampus and prefrontal cortex during an omitted stimulus paradigm.

In a recent study on human subjects which performed a time prediction task in an omitted stimulus paradigm we found an increase in the amplitudes of evoked potentials (EPs) for the stimulus preceding the omitted stimuli, probably due to expectancy and focused attention. The amplitude increases were dominant over frontal and parietal association areas and were mainly reflected in enhancements of the theta (3-6 Hz) components. In the present study we analyse the responses of the auditory cortex (GEA, gyrus ectosylvianus anterior), different parts of hippocampus (CA1, CA3), reticular formation (RF), and motor cortex (MC) of the cat brain using a similar paradigm. Similar theta component increases of the EPs were obtained in various parts of the hippocampus, which were dominant in pyramidal cell layers (CA3, CA4), and in motor cortex. The results are interpreted as signs of a diffuse theta response system in the brain including mainly the hippocampus and frontal and parietal association areas. The diffuse theta system is probably involved in general attention and expectancy processes.

Acoustic Stimulation↗
PubMed1996

Age-related modifications on the GABAA receptor binding properties from Wistar rat prefrontal cortex.

In the present communication we have investigated the pharmacological properties of the GABAA receptor from adult (3 months old) and aged (24 months old) Wistar rat prefrontal cortex. The prefrontal cortex is implicated in cognitive functions and stress and both processes seem to be altered during aging. These changes could be mediated by modifications in the GABAA receptor properties. Our results indicated the absence of generalized age-related modifications on the pharmacological properties of the GABAA receptor from prefrontal cortical membranes. Saturation experiments using the non-selective benzodiazepine [3H]flunitrazepam revealed that neither the Kd values or the Bmax were modified during aging. Moreover, Cl 218 872 displacement of [3H]flunitrazepam showed no age-related modifications on either the Kis or the relative proportion between the Type I and Type II benzodiazepine binding sites. Therefore, the benzodiazepine binding sites are well preserved in aged prefrontal cortex. On the other hand, saturation experiments using the GABA agonist [3H]muscimol demonstrated in the Bmax of the low affinity [3H]muscimol binding sites in aged rats (4.3 +/- 0.8 pmol/mg protein vs. 2.3 +/- 0.2 pmol/mg protein in adult and aged rats, respectively). However, no age-dependent modifications were observed in the allosteric interaction between GABA and benzodiazepine binding sites. These results demonstrate that the benzodiazepine binding sites and the GABA binding sites of the GABAA receptor complex from rat prefrontal cortical membranes are differentially affected by the aging process.

Aging↗
PubMed1980

Behavioural and biochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat.

The effects of 6-hydroxydopamine (6-OHDA) lesions of catecholamine terminals within the medial prefrontal cortex on spontaneous motor activity, dopamine (DA)-dependent stereotyped behaviour and subcortical dopamine turnover were investigated in the rat. Two types of lesions were examined, bilateral injection of 6-OHDA into the medial prefrontal cortex of untreated rats (6-OHDA alone), and bilateral injection of 6-OHDA into the medial prefrontal cortex of animals pretreated with the noradrenaline (NA) uptake blocking agent desmethylimipramine (6-OHDA/-DMI). Ten days after surgery the 6-OHDA lesions produced no significant change in spontaneous motor activity and had no overall effects on stereotyped behaviour induced by apomorphine or (+)-amphetamine. This lesion caused gross depletion of NA within the medial prefrontal cortex and curiously, elevated DA concentrations within this site. No changes in DA concentration were recorded within subcortical sites, although concentrations of DA metabolites within striatum and nucleus accumbens were reduced. In contrast, the 6-OHDA/DMI lesion of the medial prefrontal cortex significantly enhanced spontaneous motor activity and amphetamine-induced stereotyped behaviour. Apomorphine-induced stereotypy, on the other hand, was significantly reduced. Biochemically the lesion caused a large depletion of DA with relatively little loss of NA within the medial prefrontal cortex. In addition, from this and another study (ref. 33), increases in DA and its metabolite concentrations were measured in striatum and nucleus accumbens, together with an apparent increase in DA turnover within these subcortical sites. It is thus apparent that in the absence of a substantial portion of the DA innervation of the medial prefrontal cortex, with a largely intact NA innervation, there is an increase in motor activity and amphetamine-induced stereotypy which may be related to functional changes in DA activity within subcortical telencephalic structures. Such a finding might suggest that DA within the frontal cortex has a behaviourally inhibitory role in the rat, although further work is required to substantiate this.

Animals↗
PubMed1984

Collateral innervation of the medial and lateral prefrontal cortex by amygdaloid, thalamic, and brain-stem neurons.

The distribution of the afferents to the rat's prefrontal cortex originating in the thalamic mediodorsal nucleus and the amygdala was investigated with two fluorescent tracers. Special emphasis was laid on detecting the loci of neurons which project via axonal collaterals into both lateral and medial portions of the prefrontal cortex. It was found that a high number of neurons of the anterior portion of the basolateral amygdaloid nucleus terminate via collaterals in both the medial and lateral subfields of the prefrontal cortex. On the other hand, only a small number of mediodorsal thalamic cells were found to project to both sides of the prefrontal hemisphere via bifurcating axonal collaterals. These cells were situated exclusively in the lateral part of the medial segment of the mediodorsal nucleus. The majority of both thalamic and amygdaloid neurons with bifurcating axons originate from subregions whose cells innervate primarily the medial prefrontal cortex. In brain-stem, neurons of the nucleus raphé dorsalis also project via collaterals to the medial and lateral prefrontal regions. Furthermore, neurons of the dorsal and ventral premamillary nuclei, the lateral mamillary nucleus, the ventral tegmental area of Tsai, and the ventral tegmental nucleus of Gudden were found to project to the medial prefrontal cortex. Our results indicate a differential collateral organization of thalamic and amygdaloid afferents to prefrontal cortical fields. The anterior basolateral amygdala (which innervates via collaterals both the medial and lateral prefrontal subfields) may add a common input to either subfield, such as information on the significance of incoming stimuli to the animal's behavior, while the mediodorsal nucleus (whose segments are principally connected to only one prefrontal subfield) may add segment-specific information, for example, of a spatial-cognitive nature for the lateral segment and of an emotional nature for the central and medial segments. The existence of a basolateral limbic circuit, composed of the amygdala, the thalamic mediodorsal nucleus, and the prefrontal cortex, is confirmed and knowledge on its interconnectivity is extended. From an anatomical point of view these data provide arguments for both unitary and diverging functions of the prefrontal cortex.

Amygdala↗
PubMed1998

Ceruletide inhibits phencyclidine-induced dopamine and serotonin release in rat prefrontal cortex.

Phencyclidine (PCP; 5.0 mg/kg, i.p.) produced a greater increase in extracellular dopamine (DA) levels in the prefrontal cortex than in the striatum, while PCP increased the extracellular 5-hydroxytryptamine (serotonin; 5-HT) levels in the prefrontal cortex but not the striatum, as determined by in vivo microdialysis in awake, freely moving rats. The cholecystokinin (CCK)-related decapeptide ceruletide (120 and 400 microg/kg, i.p.), administered 60 min prior to PCP, significantly attenuated the PCP-induced increase in the extracellular levels of DA and 5-HT in the prefrontal cortex, but not in the striatum. These effects were reversed by PD 135,158, a selective CCK-B receptor antagonist (0.1 mg/kg, s.c.), administered 5 min prior to ceruletide. When administered alone, ceruletide (400 microg/kg, i.p.) significantly increased basal extracellular DA levels only in the prefrontal cortex. The selective N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (0.5 mg/kg, i.p.) also increased extracellular DA levels in the prefrontal cortex, but this effect was unaffected by ceruletide pretreatment. These results suggest that ceruletide may differentially modulate basal and PCP-induced release of DA and 5-HT in the prefrontal cortex.

Animals↗
PubMed2003

Prefrontal cortex: procedural sequence learning and awareness.

Activation of the prefrontal cortex has been linked to awareness during sequence-learning tasks. A recent study, however, finds activation of the prefrontal cortex during such tasks regardless of awareness. So what is the neurophysiological basis of awareness, and what is the role of the prefrontal cortex in sequence learning?

Awareness↗
PubMed2004

Visual activation in prefrontal cortex is stronger in monkeys than in humans.

The prefrontal cortex supports many cognitive abilities, which humans share to some degree with monkeys. The specialized functions of the prefrontal cortex depend both on the nature of its inputs from other brain regions and on distinctive aspects of local processing. We used functional MRI to compare prefrontal activity between monkey and human subjects when they viewed identical images of objects, either intact or scrambled. Visual object-related activation of the lateral prefrontal cortex was observed in both species, but was stronger in monkeys than in humans, both in magnitude (factors 2-3) and in spatial extent (fivefold or more as a percentage of prefrontal volume). This difference was observed for two different stimulus sets, at two field strengths, and over a range of tasks. These results suggest that there may be more volitional control over visual processing in humans than in monkeys.

Animals↗
PubMed1992

Cholecystokinin- and dopamine-containing mesencephalic neurons provide distinct projections to monkey prefrontal cortex.

Retrograde transport and immunohistochemical techniques were utilized to determine if cholecystokinin (CCK)-containing neurons of the primate ventral mesencephalon project to prefrontal cortex, and to examine what relation the CCK innervation of prefrontal cortex bears to the dopaminergic projection to this region. Following injections of Fast blue into monkey prefrontal cortex, retrogradely labeled, CCK-positive neurons were observed predominantly in rostromedial portions of the ventral mesencephalon; these CCK-containing projection neurons were not immunoreactive for tyrosine hydroxylase. Furthermore, dual-labeling studies in the prefrontal cortex revealed that CCK and tyrosine hydroxylase were present in separate populations of axons. These results demonstrate that the CCK innervation of monkey prefrontal cortex arises from both intrinsic and extrinsic sources; in contrast to the rat, the extrinsic CCK innervation of monkey prefrontal cortex is distinct from the dopaminergic mesocortical projection.

Animals↗
PubMed1987

Effects of neonatal thermal lesioning of the mesocortical dopaminergic projection on the development of the rat prefrontal cortex.

The role of dopamine (DA) in the development of the prefrontal cortex (PFC) was investigated by depleting the dopaminergic innervation of the PFC. A new stereotaxic procedure made it possible to produce small lesions in 1-day-old rats confined to the A10 group of dopaminergic cell bodies in the ventral tegmentum, from which the dopaminergic projection to the PFC originates. The variety in the lesions revealed a clear topographical organization of the efferent connections of the ventral tegmental area (VTA) to the prefrontal cortex. As far as we know from the literature the data presented in this study are a first direct indication of a neurotrophic role for dopamine in the development of the prefrontal cortex. When the prefrontal cortex was depleted of the dopaminergic innervation from birth on, by lesioning the cells of origin on postnatal day 1, the cortical thickness in the medial PFC was reduced by about 6%. Although coagulative lesions in the ventral tegmentum cause also a depletion of cortical serotonin, cortical reduction seems to be rather the result of the absence of dopamine during its development. This is indicated by the absence of a significant cortical thickness reduction in the dysgranular part of the first somatosensory cortex, which receives a serotonergic but no dopaminergic innervation.

Animals↗
PubMed2004

Plasticity at hippocampal to prefrontal cortex synapses is impaired by loss of dopamine and stress: importance for psychiatric diseases.

The direct hippocampal to prefrontal cortex pathway and its changes in synaptic plasticity is a useful framework for investigating the functional operations of hippocampal-prefrontal cortex communication in cognitive functions. Synapses on this pathway are modifiable and synaptic strength can be turned up or down depending on specific patterns of activity in the pathway. The objective of this review will be to summarize the different studies carried out on this topic including very recent data and to underline the importance of animal models for the development of new and effective medications in psychiatric diseases. We have shown that long-term potentiation (LTP) of hippocampal-prefrontal synapses is driven by the level of mesocortical dopaminergic (DA) activity and more recently that stress is also an environmental determinant of LTP at these cortical synapses. Stimulation of the ventral tegmental area at a frequency known to evoke DA overflow in the prefrontal cortex produces a long-lasting enhancement of the magnitude of hippocampal-prefrontal cortex LTP whereas a depletion of cortical DA levels generates a dramatic decrease in this LTP. Moreover, hippocampal stimulation induces a transient but significant increase in DA release in the prefrontal cortex and an optimal level of D1 receptor activation is essential for LTP expression. We recently investigated the impact of stress on hippocampal-prefrontal LTP and demonstrated that exposure to an acute stress causes a remarkable and long-lasting inhibition of LTP. Furthermore, we demonstrated that tianeptine, an antidepressant which has a unique mode of action, and clozapine an atypical antipsychotic when administered at doses normally used in human testing are able to reverse the impairment in LTP. Stressful life events have a substantial causal association with psychiatric disorders like schizophrenia and depression and recent imaging studies have shown an important role of the limbic-cortical circuit in the pathophysiology of these illnesses. Therefore, we proposed that agents capable of reversing the impairment of plasticity at hippocampal to prefrontal cortex synapses have the potential of becoming new therapeutic classes of antidepressant or antipsychotic drugs.

Animals↗
PubMed2003

Medial prefrontal cortex suppression of the hypothalamic-pituitary-adrenal axis response to a physical stressor, systemic delivery of interleukin-1beta.

Previous studies have shown that the medial prefrontal cortex can suppress the hypothalamic-pituitary-adrenal axis response to stress. However, this effect appears to vary with the type of stressor. Furthermore, the absence of direct projections between the medial prefrontal cortex and corticotropin-releasing factor cells at the apex of the hypothalamic-pituitary-adrenal axis suggest that other brain regions must act as a relay when this inhibitory mechanism is activated. In the present study, we first established that electrolytic lesions involving the prelimbic and infralimbic medial prefrontal cortex increased plasma adrenocorticotropic hormone levels seen in response to a physical stressor, the systemic delivery of interleukin-1beta. However, medial prefrontal cortex lesions did not alter plasma adrenocorticotropic hormone levels seen in response to a psychological stressor, noise. To identify brain regions that might mediate the effect of medial prefrontal cortex lesions on hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1beta, we next mapped the effects of similar lesions on interleukin-1beta-induced Fos expression in regions previously shown to regulate the hypothalamic-pituitary-adrenal axis response to this stressor. It was found that medial prefrontal cortex lesions reduced the number of Fos-positive cells in the ventral aspect of the bed nucleus of the stria terminalis. However, the final experiment, which involved combining retrograde tracing with Fos immunolabelling, revealed that bed nucleus of the stria terminalis-projecting medial prefrontal cortex neurons were largely separate from medial prefrontal cortex neurons recruited by systemic interleukin-1beta, an outcome that is difficult to reconcile with a simple medial prefrontal cortex-bed nucleus of the stria terminalis-corticotropin-releasing factor cell control circuit.

Adrenocorticotropic Hormone↗
PubMed1994

Local pharmacological manipulation of extracellular dopamine levels in the dorsolateral prefrontal cortex and caudate nucleus in the rhesus monkey: an in vivo microdialysis study.

The prefrontal cortex, caudate nucleus, and their dopaminergic innervations have been implicated in complex information processing. The present study utilized the in vivo microdialysis technique to characterize the extracellular dopamine levels in the prefrontal cortex and the caudate nucleus in the rhesus monkey. Basal levels of dopamine were consistently found in the caudate nucleus, while levels in the prefrontal cortex were less reliably measured. Manipulation of dopamine levels using tetrodotoxin and high potassium demonstrated that dopamine measured was dependent on neuronal firing. Administration of indirect dopamine agonists d-amphetamine and cocaine into the prefrontal cortex and the caudate nucleus increased extracellular dopamine levels 250% and 5000%, respectively. Amphetamine and cocaine had greater effects on dopamine levels in the caudate than in the prefrontal cortex. Cocaine induced increases appeared to be less than that of amphetamine and the actions of cocaine lasted longer than amphetamine. This study demonstrates the feasibility of using in vivo microdialysis in monitoring neurochemicals in different regions of the rhesus monkey brain.

Animals↗
PubMed1996

Formation and retrieval of inhibitory avoidance memory: differential roles of glutamate receptors in the amygdala and medial prefrontal cortex.

This study investigated the roles of NMDA and AMPA receptors in the amygdala and medial prefrontal cortex in formation and retrieval of affective memory. In a one-trial step-through inhibitory avoidance task, groups of rats with cannulae implanted into these two regions received infusion of 2.5 micrograms APV or 0.3 micrograms CNQX 5 min before training, shortly after training or 5 min prior to the 1-day or 21-day retention test. Results showed that pre- or posttraining intra-amygdala infusion of APV or CNQX induced a persistent retention deficit with the pretraining treatment causing a greater effect. Pre- or posttraining infusion of CNQX into the medial prefrontal cortex also induced a persistent retention deficit with the posttraining treatment causing a greater effect. Pre- or posttraining infusion of APV into the medial prefrontal cortex impaired 21-day retention but not 1-day retention. Pretraining infusion of lidocaine into either structure caused a retention deficit, which was not attenuated by activating the other structure with glutamate. Pretest intra-amygdala infusion of CNQX impaired memory expression in the 1-day test, while infusion of CNQX into the medial prefrontal cortex impaired memory expression in the 21-day test. Pretest APV infusion into either structure had no effect on memory expression. These findings suggest that the amygdala and medial prefrontal cortex may be contained in a circuitry responsible for formation of affective memory. The consolidation process involves the NMDA and AMPA receptors in both structures. Further, retrieval of recent affective memory engages amygdala AMPA receptors, whereas retrieval of remote affective memory engages AMPA receptors in the medial prefrontal cortex.

2-Amino-5-phosphonovalerate↗
PubMed1998

Amphetamine infusions into the prefrontal cortex attenuate the sensitization to amphetamine.

1. Adult male rats were implanted with chronic medial prefrontal cortex cannulae. 2. On each of 5 consecutive days, rats received bilateral 0.5 ml intra-prefrontal cortex injections of either 5 mg d-amphetamine or saline, followed by a subcutaneous injection of either 1 mg/kg d-amphetamine or saline. 3. Immediately after the drug treatments each rat was placed into a photocell equipped locomotor activity chamber for 60 min. 4. Administration of d-amphetamine into the prefrontal cortex did not block the acute locomotor response to subcutaneous d-amphetamine nor did it in itself produce an increase in locomotor activity. However, prefrontal cortex amphetamine treatments did attenuate the sensitized locomotor effects of subcutaneous amphetamine that developed over trials/days. 5. Dopamine in the prefrontal cortex may be involved in the development of amphetamine-induced behavioral sensitization.

Animals↗