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PubMed2003

MRNA expression patterns and distribution of white matter neurons in dorsolateral prefrontal cortex of depressed patients differ from those in schizophrenia patients.

BACKGROUND: Schizophrenia, bipolar illness, and major depressive disorder have distinct presentations, but share some common symptoms. Hence, some common cellular and molecular abnormalities may be identifiable in these disorders. METHODS: We examined cell-specific markers in the dorsolateral prefrontal cortex of brains from 18 patients with bipolar or major depressive disorder, and 18 matched controls, using in situ hybridization histochemistry and staining for nicotinamide-dinucleotide phosphate-diaphorase (NADPH). The distribution of NADPH-positive interstitial cells of the white matter and the expression of the mRNA for the 67 KD form of glutamic acid decarboxylase (GAD(67)) had previously been shown to be altered in prefrontal cortex of schizophrenics. Other markers identifying glutamatergic neuronal populations were alpha-type II calcium/calmodulin dependent protein kinase (CAMKII-alpha), brain derived neurotrophic factor, (BDNF) and the putative transcription factor, T-brain-1 (TBR1). RESULTS: Expression of GAD67 and the distribution of NADPH-positive cells in the white matter were not significantly altered in the dorsolateral prefrontal cortex of depressed subjects. Expression of CAMKII-alpha and TBR1 mRNAs was significantly increased in bipolar patients but not in major depressed patients, and there was a trend toward reduced BDNF expression in both groups. Abnormal patterns of gene expression and neuronal distribution in schizophrenics are markedly different from those in depressed patients. CONCLUSIONS: The findings that TBR1 and CAMKII-alpha expression is increased only in bipolar patients suggests abnormalities of specific genes related to a major cortical cell type and its connectivity.

Adult↗

PubMed2000

Neuronal activity in the primate prefrontal cortex in the process of motor selection based on two behavioral rules.

This study examined neuronal activity in the prefrontal cortex (PF) involved in the process of motor selection in accordance with two behavioral rules. We trained two monkeys to select a target based on the integration of memorized and current sensory information. Initially, a sample cue (triangle or circle) appeared at one of three locations (top, left, or right) for 1 s. After a 3-s delay, one of two types of choice cue appeared. The first type asked the monkeys to reach for a target by matching the location (location-matching task). The second type asked the monkeys to reach for a target by matching the shape (shape-matching task). The choice cue for location matching consisted of either three circles or three triangles, and the choice cue for shape matching consisted of a circle and a triangle. When the color of the choice cue changed from red to green 1.5 s later (GO signal), the monkeys touched the correct object to obtain a reward. We found cue-, delay-, choice-, and movement-related neuronal activity in the lateral prefrontal cortex. During the sample cue presentation and delay periods, we found selective neuronal activity for the location or shape of the sample cue. Shape-selective neurons were located more anteriorly in the ventral bank of the principal sulcus and inferior convexity area, whereas location-selective neurons were more posteriorly. After the choice cue appeared, we found three main types of neuronal activity in the critical period when the subject selected the future target: 1) activity reflecting past sensory information (the location or shape of the sample cue presented 3 s earlier), 2) activity selective for the configuration of the current choice cue, and 3) activity reflecting the properties (location or shape) of the future target. During the motor-response period, we found neuronal activity selective for the location or shape of the reaching target. When muscimol was microinjected into the ventral bank of principal sulcus and inferior convexity area, the performance of both tasks was impaired. Furthermore, we found that the wealth of neuronal activity in the PF that seemed to play a role in motor selection was rarely seen in the primary motor cortex.

Animals↗

PubMed1994

Effects of dopamine depletions in the medial prefrontal cortex on DRL performance and motor activity in the rat.

Two experiments assessed the behavioral effects of dopamine depletions in the medial prefrontal cortex that were produced by injection of the neurotoxic agent 6-hydroxydopamine. In the first experiment, rats were trained to respond on a differential reinforcement of low rates of responding-30 second (DRL30) schedule. On this schedule, rats were only reinforced if they withheld responding for 30 s. Rats with prefrontal dopamine depletions were found to be impaired in the DRL task. These animals responded more than controls, received fewer reinforcers, and were less efficient in their responses. Moreover, an analysis of interresponse times (IRTs) revealed that rats with medial prefrontal dopamine depletions made more responses with short-duration IRTs, and fewer responses with long-duration IRTs. In the second experiment, rats were tested on open field activity, amphetamine-induced locomotor activity and stereotypy. No increase in spontaneous locomotor activity was found following surgery; however, increases in amphetamine-induced locomotor activity and stereotypy were observed. These results are consistent with hypothesized role for the prefrontal cortex in behavioral inhibition, and indicates that prefrontal cortical dopamine is an integral part of the system.

Animals↗

PubMed2002

Acute effect of ethanol on anxiety and 5-HT in the prefrontal cortex of rats.

The anxiolytic effect of ethanol is generally accepted to be involved in the development of alcohol dependence. Because serotonin (5-HT) is said to be involved in both anxiety and alcohol dependence, in the present study the effect of acute ethanol administration on basal 5-HT release of the medial prefrontal cortex and its effect on 5-HT release in rats submitted to an animal model of anxiety, the elevated plus maze test, were detected in two rat strains showing a different anxiety-related behavior. Ethanol had an anxiolytic-like effect and induced an increase of basal 5-HT release in the medial prefrontal cortex in the home cage in the less anxious Wistar-Harlan rats. Both effects were not seen in the more anxious Wistar-BgVV rats. The exposure to the elevated plus maze test induced an increase of extracellular 5-HT in the more anxious Wistar-BgVV rats but not in the less anxious Wistar-Harlan rats. Ethanol did not change 5-HT release during the elevated plus maze test in both rat strains. Thus, the anxiolytic-like effect of ethanol in Wistar-Harlan rats was not primarily associated with a decrease of 5-HT release in the prefrontal cortex as it is seen with other anxiolytic agents like diazepam.

Animals↗

PubMed1984

Prefrontal cortex and bulbar reticular formation and behavioral inhibition in the rat.

Electrical stimulation in the bulbar reticular formation will produce response suppression that is observably the same as that produced by stimulation in the prefrontal cortex. This includes suppression of bar-pressing for food and running in an activity wheel, but no suppression of approach and eating of food or general activity. These results, together with previous research, support the hypothesis that this inhibitory influence of the prefrontal cortex is mediated through the bulbar reticular formation. This hypothesis is not incompatible with the concept that the prefrontal cortex serves to suppress the activating influence of the rostral reticular formation.

Animals↗

PubMed2005

Emotion-modulated performance and activity in left dorsolateral prefrontal cortex.

Functional MRI (fMRI) was used to examine the relationship between processing of pleasant and unpleasant stimuli and activity in prefrontal cortex. Twenty volunteers identified the colors in which pleasant, neutral, and unpleasant words were printed. Pleasant words prompted more activity bilaterally in dorsolateral prefrontal cortex (DLPFC) than did unpleasant words. In addition, pleasant words prompted more activity in left than in right DLPFC. Response speed to pleasant words was correlated with DLPFC activity. These data directly link positive affect, enhanced performance, and prefrontal activity, providing some of the first fMRI evidence supporting models of emotional valence and frontal brain asymmetry based on electroencephalography (EEG).

Adult↗

PubMed1995

L-DOPA and psychosis: evidence for L-DOPA-induced increases in prefrontal cortex dopamine and in serum corticosterone.

L-DOPA can often induce psychotic reactions during treatment for Parkinson's disease. This study was undertaken to assess, in an animal model of Parkinson's disease, the impact of L-DOPA treatment on two potential biological risk factors for psychosis, namely, an increase in prefrontal cortex dopamine and an increase in the stress-related hormone corticosterone. Hemiparkinsonian rats with unilateral 6-hydroxydopamine (6-OHDA) lesions which resulted in severe unilateral denervation of dopamine neurons were treated with either saline or 25 mg/kg L-DOPA methyl ester (with 2 mg/kg carbidopa). Serum L-DOPA concentrations were found to be positively and highly correlated with serum corticosterone, with medial prefrontal cortex dopamine and with the dopamine metabolite homovanillic acid. Serum L-DOPA, however, was found not to be correlated with serum or brain concentrations of serotonin, 5-hydroxyindoleacetic acid, or norepinephrine. These findings support the possibility that chronic L-DOPA treatment can expose parkinsonian patients to two significant risk factors for psychosis: 1) increased levels of prefrontal cortex dopamine, and 2) increased levels of serum corticosterone.

Animals↗

PubMed1989

Effects of apomorphine on in vivo release of dopamine and its metabolites in the prefrontal cortex and the striatum, studied by a microdialysis method.

The effects of apomorphine (0.1-2.5 mg/kg) on release of endogenous dopamine and extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex and the striatum were examined in vivo by a microdialysis method. Apomorphine significantly reduced release of dopamine and the extracellular levels of dopamine metabolites, DOPAC and HVA, not only in the striatum, but also in the prefrontal cortex. These findings indicate that dopamine autoreceptors modulate in vivo release of dopamine in the prefrontal cortex.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Excitatory amino acids inhibit stimulated phosphoinositide hydrolysis in the rat prefrontal cortex.

In rat prefrontal cortical slices, the excitatory amino acids N-methyl-D-aspartate (NMDA), ibotenate, L-aspartate, quisqualate, kainate and L-glutamate inhibit carbachol-induced phosphoinositide hydrolysis as measured by the accumulation of [3H]inositol-1-phosphate ([3H]IP1). NMDA dose-dependently inhibited the carbachol response (IC50 = 14.4 microM), and this inhibition was blocked by the NMDA receptor antagonist D,L-aminophosphonovaleric acid. Lowering medium Na+ concentration to 10 mM or exposing slices to pertussis toxin alleviated the inhibitory effect of NMDA on carbachol-induced [3H]IP1 formation. Serotonin-induced stimulation of [3H]IP1 was also inhibited by NMDA; in contrast, stimulation by norepinephrine, epinephrine or dopamine was unaffected. The results suggest that excitatory amino acids, besides their traditional role as stimulatory substances, can also act to inhibit the production of 2nd messengers activated by certain neurotransmitters in the brain.

Amino Acids, Dicarboxylic↗

PubMed1989

Opposite influences of dopaminergic pathways to the prefrontal cortex or the septum on the dopaminergic transmission in the nucleus accumbens. An in vivo voltammetric study.

Modulation of dopaminergic transmission in the nucleus accumbens by the dopaminergic pathways reaching the prefrontal cortex (anteromedian and the suprarhinal parts) and the lateral septum was investigated. Changes in dopaminergic transmission in the nucleus accumbens were assessed by in vivo voltammetry using pretreated carbon fiber electrodes. This technique allows the selective detection of 3,4-dihydroxyphenylacetic acid, the main presynaptic metabolite of dopamine. Dopaminergic transmission in the prefrontal cortex (anteromedian and suprarhinal parts) and the lateral septum was altered by local injection of the dopaminergic agonist (d-amphetamine) and the dopaminergic antagonists (alpha-flupenthixol and sulpiride). Pharmacological interventions, either stimulation or blockade, in the anteromedian and suprarhinal parts of the prefrontal cortex induced, respectively, a decrease or an increase in extracellular 3,4-dihydroxyphenylacetic acid in the nucleus accumbens. The same pharmacological interventions in the lateral septum had exactly opposite effects in the nucleus accumbens. The inhibitory action of the mesocortical and mesorhinal dopaminergic projections and the facilitatory action of the mesoseptal dopaminergic projection on dopaminergic input in the nucleus accumbens were shown to rely on the activity of inhibitory fugal pathways which could be blocked by local injection of tetrodotoxin in the three structures. In a previous work, it was demonstrated that dopaminergic projections in the amygdala exert an inhibitory influence on dopaminergic transmission in the nucleus accumbens. Thus the present results suggest that functional interdependence between the different dopaminergic pathway arising in the ventral mesencephalon is a general property of this neuronal group. Data obtained after manipulation of dopaminergic transmission in these various projection areas may need to be interpret in a different light. Similarly, neurological and psychiatric observations may need to be reconsidered in view of the interdependence of the dopaminergic mesencephalic pathways.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

Ro 15-4513, like anxiogenic beta-carbolines, increases dopamine metabolism in the prefrontal cortex of the rat.

The effects of Ro 15-4513, FG 7142 and beta-CCM on the activity of the mesocortical dopaminergic system were examined by measuring the changes in the content of the principal dopamine (DA) metabolite, dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex of the rat. Ro 15-4513 increased the DOPAC content in the prefrontal cortex in a dose-dependent manner (5-40 mg/kg i.p.) but had no effect on DA concentrations. A similar increase in DOPAC content was induced by FG 7142 (40 mg/kg i.p.) and beta-CCM (8 mg/kg s.c.), two beta-carboline derivatives that interact with benzodiazepine recognition sites as partial inverse agonists. These effects of Ro 15-4513, FG 7142 and beta-CCM on DA metabolism in the prefrontal cortex are mediated via benzodiazepine recognition sites, since they were prevented by the administration of the benzodiazepine antagonists Ro 15-1788 and ZK 93426. These data indicate that Ro 15-4513 is an inverse agonist at benzodiazepine recognition sites.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

Changes in vesicular monoamine transporter (VMAT2) and synaptophysin in rat Substantia nigra and prefrontal cortex induced by psychotropic drugs.

We investigated the regulatory effect of the dopaminergic agent L-dopa, the mood stabilizer lithium and the nonselective monoamine oxidase inhibitor phenelzine on brain vesicular monoamine transporter (VMAT2) expression. Rats were treated chronically (21 days) with the three psychoactive drugs. VMAT2 gene expression at the protein level was assessed in the prefrontal cortex and striatum by autoradiography with high-affinity [(3)H]dihydrotetrabenazine ([(3)H]TBZOH) binding and at the mRNA level in the substantia nigra pars compacta by in situ hybridization. In addition, the effect of various treatments on the synaptophysin mRNA level was determined in the substantia nigra by in situ hybridization. Chronic administration of L-dopa resulted in a significant decrease (28%, p < 0.05) in the density of [(3)H]TBZOH binding in the prefrontal cortex but had no effect on VMAT2 and synaptophysin mRNA levels in the substantia nigra. Lithium treatment increased [(3)H]TBZOH-specific binding in the prefrontal cortex (23%, p < 0.05) but had no effect on VMAT2 and synaptophysin mRNA levels. Phenelzine did not modulate VMAT2 gene expression but reduced the synaptophysin mRNA level (19%, p < 0.05). The modulatory activities of these drugs, although relatively weak, may be relevant to the drug-induced synaptic and neuronal plasticity as well as to the molecular and cellular pathophysiology of monoamine-related neuropsychiatric disorders.

Animals↗

PubMed2002

Prefrontal cortex and dynamic categorization tasks: representational organization and neuromodulatory control.

We present a computational model of the intradimensional/ extradimensional (ID/ED) task (a variant of the Wisconsin card sorting task) that simulates the performance of intact and frontally lesioned monkeys on three different kinds of rule changes (Dias et al., 1997, J Neurosci 17:9285-9297). Although Dias et al. interpret the lesion data as supporting a model in which prefrontal cortex is organized into different processing functions, our model suggests an alternative account based on representational content. A key aspect of the model is that prefrontal cortex representations are organized according to different levels of abstraction, with orbital areas encoding more specific featural information and dorsolateral areas encoding more abstract dimensional information. This representational scheme of the model is integrated with two additional key elements: (i) activation-based working memory representations controlled by a dynamic gating mechanism that simulates the hypothesized phasic actions of dopaminergic neuromodulation in prefrontal cortex, which acts to stabilize or destabilize frontal representations based on success in the task; and (ii) a weight-based associative learning system simulating posterior cortex and other subcortical areas, where the stimulus-response mappings are encoded. Frontal cortex contributes to the task via top-down activation-based biasing of task-appropriate features and dimensions in this posterior cortex system - this top-down biasing is specifically important for overcoming prepotent associations after a sorting rule reverses. The ability of the model to capture the double-dissociation observed by Dias et al. with orbital versus dorsolateral lesions supports the validity of these principles, many of which have also been useful in accounting for other frontal phenomena.

Animals↗

PubMed1999

Top-down signal from prefrontal cortex in executive control of memory retrieval.

Knowledge or experience is voluntarily recalled from memory by reactivation of the neural representations in the cerebral association cortex. In inferior temporal cortex, which serves as the storehouse of visual long-term memory, activation of mnemonic engrams through electric stimulation results in imagery recall in humans, and neurons can be dynamically activated by the necessity for memory recall in monkeys. Neuropsychological studies and previous split-brain experiments predicted that prefrontal cortex exerts executive control upon inferior temporal cortex in memory retrieval; however, no neuronal correlate of this process has ever been detected. Here we show evidence of the top-down signal from prefrontal cortex. In the absence of bottom-up visual inputs, single inferior temporal neurons were activated by the top-down signal, which conveyed information on semantic categorization imposed by visual stimulus-stimulus association. Behavioural performance was severely impaired with loss of the top-down signal. Control experiments confirmed that the signal was transmitted not through a subcortical but through a fronto-temporal cortical pathway. Thus, feedback projections from prefrontal cortex to the posterior association cortex appear to serve the executive control of voluntary recall.

Animals↗

PubMed1987

Projection from the prefrontal cortex to histaminergic cell groups in the posterior hypothalamic region of the rat. Anterograde tracing with Phaseolus vulgaris leucoagglutinin combined with immunocytochemistry of histidine decarboxylase.

We investigated the projection from the infralimbic division of the prefrontal cortex (area 25) to histaminergic neurons in the posterior hypothalamic area. Phaseolus vulgaris-leucoagglutinin (PHA-L) was injected in the prefrontal cortex of rats. Frozen brain sections were subjected to combined PHA-L and histidine decarboxylase (HDC)-peroxidase immunocytochemistry, using nickel-enhanced diaminobenzidine (blue reaction product) to visualize the transported PHA-L, and diaminobenzidine (brown reaction product) to visualize simultaneously the HDC-containing neurons. PHA-L-labeled fibers could be seen coursing in the capsula interna, leaving the telencephalon via the anterior thalamic radiation and the medial forebrain bundle. In the lateral and posterior hypothalamic areas, PHA-L-labeled fibers leave the medial forebrain bundle and traverse the nuclei containing HDC-immunoreactive neurons. Varicosities on the PHA-L-labeled fibers, the majority of which occur en passant, could be observed in close association with the HDC-immunoreactive neurons. The results suggest that the hypothalamic histaminergic neurons receive afferent synaptic input from neurons of the infralimbic division of the prefrontal cortex.

Animals↗

PubMed2004

Hemispheric asymmetry in stress processing in rat prefrontal cortex and the role of mesocortical dopamine.

The prefrontal cortex (PFC) is known to play an important role not only in the regulation of emotion, but in the integration of affective states with appropriate modulation of autonomic and neuroendocrine stress regulatory systems. The present review highlights findings in the rat which helps to elucidate the complex nature of prefrontal involvement in emotion and stress regulation. The medial PFC is particularly important in this regard and while dorsomedial regions appear to play a suppressive role in such regulation, the ventromedial (particularly infralimbic) region appears to activate behavioral, neuroendocrine and sympathetic autonomic systems in response to stressful situations. This may be especially true of spontaneous stress-related behavior or physiological responses to relatively acute stressors. The role of the medial PFC is somewhat more complex in conditions involving learned adjustments to stressful situations, such as the extinction of conditioned fear responses, but it is clear that the medial PFC is important in incorporating stressful experience for future adaptive behavior. It is also suggested that mesocortical dopamine plays an important adaptive role in this region by preventing excessive behavioral and physiological stress reactivity. The rat brain shows substantial hemispheric specialization in many respects, and while the right PFC is normally dominant in the activation of stress-related systems, the left may play a role in countering this activation through processes of interhemispheric inhibition. This proposed basic template for the lateralization of stress regulatory systems is suggested to be associated with efficient stress and emotional self-regulation, and also to be shaped by both early postnatal experience and gender differences.

Animals↗

PubMed1983

Neurological reactivity during medial prefrontal cortex stimulation: effects of self-stimulation experience.

Electrical stimulation of the medial prefrontal cortex (MFC) induced a moderate behavioral suppression in a series of neurological tests that included measures of (1) open field activity (2) righting and climbing reflexes (3) somatosensory reactivity and (4) approach-withdrawal responsiveness to positive and negative stimuli. The same animals were trained to lever press for medial prefrontal cortex stimulation and after several days of self-stimulation were again tested for neurological reactivity during MFC stimulation. No habituation or lessening of behavioral suppression was evident as a result of self-stimulation experience. Therefore behavioral suppression, by itself, cannot account for the slow acquisition of MFC self-stimulation. Other data suggest that the stimulation interferes with the learning of complex operant responses and/or that the reward value of the stimulation is increased as a result of repetition.

Animals↗

PubMed2005

Involvement of rostral prefrontal cortex in selection between stimulus-oriented and stimulus-independent thought.

We used functional magnetic resonance imaging to investigate brain activity while healthy subjects performed three different tasks, each of which alternated between: (i) phases relying on stimulus-oriented thought (i.e. cognitive processes provoked by incoming sensory information); and (ii) phases relying on stimulus-independent thought (i.e. cognitive processes that were not related to any information in the immediate sensory environment). Within each task, the two phases were matched as closely as possible. In all three tasks, lateral rostral prefrontal cortex was transiently activated by a switch between stimulus-oriented and stimulus-independent thought (regardless of the direction of the switch). Medial rostral prefrontal cortex consistently exhibited sustained activity for stimulus-oriented vs. stimulus-independent thought. These results suggest the involvement of rostral prefrontal cortex in selection between stimulus-oriented and stimulus-independent cognitive processes.

Adult↗