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PubMed1998

Evidence for the involvement of the rat prefrontal cortex in sustained attention.

Previous studies suggest that, in both humans and rats, the prefrontal cortex (PFC) is involved in both selective and divided attention. We have also shown that the PFC is involved in response selection and that its involvement is modulated by the cognitive effort required by the task. However, the role of the PFC is much less clear when no response selection is required. The purpose of the present experiments was to assess the role of the PFC in attentional functions with a low response-selection demand. We used two tasks in which information processing was effortful but where the demand on a response selection process is low. Moreover, we assessed two different types of visual attentional functions: selective attention (Experiment 1) and sustained attention (Experiment 2). The results showed a differential involvement for the PFC in the two tasks. Selective attention was not impaired by prefrontal lesions when the number of possible positions for the stimulus on which the subjects must focus was restricted to two (Experiment 1). In contrast, prefrontal rats were unable to sustain their attention long enough to detect, and react to, subtle variations in brightness (Experiment 2). This results suggests a dissociation between different types of attentional functions depending upon the integrity of the PFC. More specifically, results in Experiment 2 suggest an involvement of the PFC in sustained attention. Finally, the overall results show that even in tasks involving low demands on response selection the PFC is involved in attentional functions.

Animals↗

PubMed1995

Effects of 6-hydroxydopamine lesions of the medial prefrontal cortex on local cerebral blood flow and D1 and D2 dopamine receptor binding in rats: a quantitative autoradiographic study.

The effects of lesions of the dopamine (DA) nerve terminals in the medial prefrontal cortex (MPFC) on local cerebral blood flow (LCBF) and DA receptor binding in rats were investigated. 4 micrograms of 6-hydroxydopamine (6-OHDA) was infused stereotaxically into the area of the bilateral MPFC of rats pretreated with desmethylimipramine, and control rats received a vehicle solution. Twenty-four days after the operation LCBFs of 23 brain regions were measured using the quantitative autoradiographic N-isopropyl-p-[125I]iodoamphetamine technique D1 and D2 DA receptor binding in various brain regions was also quantified autoradiographically using [3H]SCH 23390 and [3H]YM 09151-2 as the respective ligands. 6-OHDA lesions of MPFC produced significant increases in LCBF of the nucleus accumbens, the dorsolateral portion of the caudate-putamen and the anterior cingulate cortex. The lesioned animals did not show decreased LCBF in MPFC per se. D1 and D2 DA receptor binding was not affected in any brain region examined. These results suggest that lesions of the DA nerve terminals in MPFC induce an enhancement of functional activity in the terminal regions of the subcortical DA systems, and that hypofunction of the mesocortical dopamine system does not elicit reduced metabolic activity in the prefrontal cortex.

Animals↗

PubMed2002

Spatial and nonspatial Morris maze learning: impaired behavioral flexibility in mice with ectopias located in the prefrontal cortex.

About half of BXSB/MpJ-Yaa (BXSB) mice have neocortical ectopias (misplaced clusters of neurons located in layer I of cortex). Previous behavioral studies have suggested that ectopic mice have superior spatial, but equivalent nonspatial, reference memory learning. However, since spatial and nonspatial learning were not assessed in the same apparatus and with the same testing procedure, it is unclear if this conclusion is accurate. We have created a new nonspatial Morris maze for mice that differs from the spatial task only in the type of cues that must be utilized to efficiently locate the platform (intra-maze black/white patterns vs. extra-maze room cues) and does not differ in the level of task complexity or the presence of objects within the maze. Ectopic mice were very good in utilizing extra-maze cues when learning the spatial version and in utilizing intra-maze cues when learning the nonspatial version of the Morris maze, while non-ectopics were not, suggesting that ectopics have superior spatial and nonspatial reference memory. Ectopias in BXSB mice are usually located in prefrontal and/or motor cortex. The prefrontal cortex is involved in behavioral flexibility (e.g. being able to easily switch from using spatial to nonspatial cues). Only ectopic mice with ectopias specifically located in the prefrontal region of cortex demonstrated difficulty switching from using extra-maze to intra-maze cues and vice versa. Thus, the presence of one or more ectopias in the prefrontal region of cortex disrupted one of the normal functions of the prefrontal cortex.

Animals↗

PubMed1997

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

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

Animals↗

PubMed2000

[(3)H]PNU-101958, a D(4) dopamine receptor probe, accumulates in prefrontal cortex and hippocampus of non-human primate brain.

The D(4) dopamine receptor has been investigated for its potential role in neuropsychiatric disorders, "novelty-seeking" behaviors, and effects produced by some psychostimulants. An accurate map of D(4) distribution and density in brain is essential to clarify the role of this receptor subtype in normal brain function and in neuropsychiatric disorders. We investigated the autoradiographic distribution of D(4) receptors in non-human primate (Macaca mulatta) brain (N = 3) with the novel D(4) receptor probe [(3)H]PNU-101958. Quantification of [(3)H]PNU-101958 binding sites in 77 brain regions revealed dense levels of D(4) receptors in several cortical areas, especially in prefrontal cortex, uncus, hypothalamic median eminence, hippocampal formation, and distinct thalamic nuclei, but were significantly lower in striatum. The results correspond well with previous reports of brain distribution of D(4) receptors using other radiolabeled probes, and of D(4) mRNA localization (with some exceptions). Overall, this study reveals that [(3)H]PNU-101958 binding sites in non-human primate brain appear to reflect D(4) dopamine receptor distribution. The significance of a dense localization of D(4) receptors in prefrontal cortex and hippocampus, and broad distribution in other brain areas, allows for investigation of the relationship of these receptors to specific neuropsychiatric disorders and effects produced by psychostimulants.

Aminopyridines↗

PubMed2001

Noradrenergic dysfunction in the prefrontal cortex in depression: an [15O] H2O PET study of the neuromodulatory effects of clonidine.

BACKGROUND: Noradrenergic dysfunction has been consistently implicated in depression. Much of the evidence, though, has been indirect, such as an attenuated growth hormone response to the alpha2-adrenoceptor agonist clonidine. To more directly examine central functioning of the noradrenergic system in depression, we have used [15O] H2O positron emission tomography (PET) to measure cerebral blood flow (rCBF) in combination with clonidine as a neuromodulatory probe. METHODS: Subjects were six depressed and six healthy women, medication free and matched for age and phase of menstrual cycle. Two PET scans were acquired at baseline and two scans at 20 and 35 min following an intravenous clonidine infusion of 1.4 microg/kg while subjects performed a sustained attention task. RESULTS: The growth hormone response did not show a significant difference between groups. However, PET results revealed a difference in the right superior prefrontal cortex that was resolved as an interaction from decreased rCBF in healthy control subjects but increased rCBF in the depressed group, which was not accounted for by differences in task performance. CONCLUSIONS: This differential effect of clonidine in the right prefrontal cortex provides in vivo evidence of noradrenergic dysfunction in depression, which we postulate arises from functionally impaired presynaptic alpha2-adrenoceptors as well as regionally "supersensitive" postsynaptic cortical alpha2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1995

Co-localisation of NADPH diaphorase activity and GABA immunoreactivity in local circuit neurones in the medial prefrontal cortex (mPFC) of the rat.

This study provides evidence that neurones in the medial prefrontal cortex of the rat (mPFC areas 24b, 25, and 32) containing strong NADPH diaphorase reactivity also contain GABA immunoreactivity. Also demonstrated is the co-localisation of NADPH diaphorase activity with immunoreactivity for the neuronal isoform of nitric oxide synthase (nNOS) in mPFC neurones. Qualitative and quantitative analyses in the light and electron microscopes indicate that strongly NADPH diaphorase reactive cells are a subpopulation of GABAergic local circuit neurones and constitute a very small proportion (0.6-1.1%) of neurones in rat mPFC. These results suggest that NADPH diaphorase reactive cells in rat mPFC can influence neural activity via GABA-mediated and NO-mediated mechanisms.

Animals↗

PubMed2000

Laterality effects in selective attention to threat after repetitive transcranial magnetic stimulation at the prefrontal cortex in female subjects.

Recently, several experiments have indicated that the left and right prefrontal cortex (PFC) are differently involved in emotional processing. The aim of this study was to investigate the role of the left and right PFC in selective attention to angry faces by using a pictorial emotional Stroop task. Slow repetitive transcranial magnetic stimulation (rTMS) was applied to the left and right PFC of 10 female subjects for 15 min on separate days. Results showed a significant effect of stimulation position: right PFC rTMS resulted in selective attention towards angry faces, whereas left PFC rTMS resulted in selective attention away from angry faces. This finding is in accordance with theoretical accounts of the neural implementation of approach and withdrawal systems.

Adult↗

PubMed1996

Effects of lesions in the medial prefrontal cortex on the activity of midbrain dopamine neurons.

To determine whether lesions in the prefrontal cortex (PFC) alter the activity of midbrain dopamine (DA) neurons, single unit recordings were made from DA neurons in control and lesioned rats. PFC lesions, obtained by local injection of ibotenic acid into the medial PFC, had no effect on either firing rate or bursting activity of DA neurons in the ventral tegmental area (VTA). However, the number of spontaneously active DA neurons in the VTA was significantly decreased. In the substantia nigra (SN), the same lesions increased the firing rate and had no effect on either the bursting activity of the number of active DA cells. These results suggest that PFC lesions alter the activity of DA neurons. However, VTA and SN DA neurons may respond differently to PFC lesions.

Animals↗

PubMed1981

Intrahemispheric cortico-cortical afferent connections of the prefrontal cortex in the cat.

Ipsilateral cortical projections to the prefrontal cortex of the cat were investigated by means of the retrograde axonal transport of horseradish peroxidase technique. Labeled neurons were identified in frontal, insular, parietal and temporal regions, as well as in cingular, retrosplenial and perirhinal areas. These intrahemispheric cortical connections can be compared to those described in the rhesus monkey.

Afferent Pathways↗

PubMed1984

Properties and distribution of auditory neurons in the dorsolateral prefrontal cortex of the alert monkey.

In alert monkeys, some prefrontal neurons located in the superior dorsolateral area were activated to acoustic stimuli delivered in a restricted range of directions with respect to the animal's head. The effective direction was usually contralateral to the animal. The function of the auditory neurons in connection to that of the visual ones, which are commonly found in the prefrontal cortex, is discussed.

Acoustic Stimulation↗

PubMed1986

Distinct substrates influence the acquisition of self-stimulation of the hippocampus and the prefrontal cortex.

Self-stimulation (SS) of both the medial prefrontal cortex (MPFC) and the dorsolateral hippocampus (HPC) is known to develop slowly, over a period of days. In both cases, the acquisition of bar-pressing can be markedly hastened by delivery of noncontingent electrical stimulation for several days prior to SS training. The similarity of these effects suggests that there might be a common substrate mediating the acquisition process. However, in the present experiment, pre-training noncontingent electrical stimulation of the MPFC had no effect on how rapidly rats acquired the bar-pressing response for HPC stimulation, or vice versa. A further dissociation of the elements governing the acquisition process for these two SS sites was suggested by the observation that pre-training noncontingent stimulation of the entorhinal cortex facilitated the speed of acquisition of SS of the HPC but not of the MPFC. It seems that the HPC and entorhinal cortex can be excluded from the subset of neural structures which are known to influence the acquisition process governing MPFC SS. These and other data suggest that the development of SS of the MPFC and HPC can be regarded, at least in part, as involving a process rooted in distinct substrates.

Animals↗

PubMed2005

Thiopental sodium reduces glutamate extracellular levels in rat intact prefrontal cortex.

To investigate the effect of thiopental sodium on glutamate extracellular levels in the prefrontal cortex (PFC) of rats, a microdialysis probe was inserted into the PFC, the perfusate was collected every 10 min throughout the experiment with thiopental sodium ip or perfused into the PFC locally. The concentrations of glutamate in the perfusate were determined by reversed-phase high performance liquid chromatography. Thiopental sodium 30 mg kg(-1) ip significantly decreased glutamate levels in the perfusate after 10, 20, 30, and 40 min; glutamate levels in the perfusate were also decreased from 10 to 90 min after thiopental sodium 50 mg kg(-1) ip. Thiopental sodium with concentrations of 30, 100, or 300 microM perfused into the PFC also decreased glutamate levels in the perfusate significantly. The results suggest that thiopental sodium decreases glutamate extracellular levels in rat intact PFC.

Animals↗

PubMed2001

Adult sex differences on a decision-making task previously shown to depend on the orbital prefrontal cortex.

Monkeys and children show sex differences on tasks that depend on the orbital prefrontal cortex. To determine whether similar sex differences exist across the life span, adults were tested on an orbital-dependent decision-making task, the Iowa Card Task, as well as on a control task, the California Weather Task. In addition, estradiol, progesterone, and testosterone were assayed. The 6 groups of participants were college-age men, older men, young low-hormone (menstruating) women, young high-hormone (midluteal) women, older postmenopausal women on estrogen replacement therapy (ERT), and older postmenopausal women not on ERT. Results showed a male superiority on the Iowa Card Task. Among college-age men there was a negative correlation between performance and testosterone levels. There were no significant differences among groups of women on the card task. There were no significant sex differences or hormone correlations on the California Weather Task.

Adult↗

PubMed2001

Differences in the laminar origin of projections from the medial prefrontal cortex to the nucleus accumbens shell and core regions in the rat.

The medial prefrontal cortex (mPFC) projects to the nucleus accumbens shell, core and rostral pole. In this retrograde tract-tracing study of rat mPFC to nucleus accumbens projection neurons, the advantages of Neurobiotin are utilised in order to reveal the detailed morphology of labelled projection cells, and to permit an examination of the laminar projections to shell and core compartments The retrogradely transported Neurobiotin was found in somata, proximal and distal dendrites of neurons that project from the mPFC to the nucleus accumbens. The morphology of these projection neurons was revealed in great detail and confirmed that the projection arises wholly from pyramidal cells. Interestingly, it was also found that retrogradely labelled neurons were exclusively located in prelimbic and infralimbic regions in layers V and VI, after shell injections, but also in layer II following core sites. This observation may reflect possibly different roles for cortical laminae on the nucleus accumbens.

Animals↗

PubMed2004

A 68930 and dihydrexidine inhibit locomotor activity and d-amphetamine-induced hyperactivity in rats: a role of inhibitory dopamine D(1/5) receptors in the prefrontal cortex?

The behavioral and biochemical effects of the full dopamine D(1/5) receptor agonists, dihydrexidine and (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl (A 68930), were examined in rats. Both A 68930 (0-4.6 mg kg(-1), s.c.) and dihydrexidine (0-8.0 mg kg(-1), s.c.) caused a dose-dependent suppression of locomotor activity, as assessed in an open-field. This locomotor suppression was dose-dependently antagonized by the selective dopamine D(1/5) receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (SCH 23390; 0-5.0 microg kg(-1), s.c.), but not by the selective dopamine D(2/3) receptor antagonist raclopride (0-25.0 microg kg(-1), s.c.). Furthermore, A 68930 and dihydrexidine did not cause any locomotor activity in habituated rats that displayed a very low base-line activity. Neither did A 68930 nor dihydrexidine produce any excessive stereotypies that could possibly interfere with and mask ambulatory activity. In fact, both A 68930 and dihydrexidine potently blocked hyperactivity produced by d-amphetamine (0-4.0 mg kg(-1), s.c.). Such findings traditionally would be interpreted as a sign of potential antipsychotic properties of A 68930 and dihydrexidine. Examination of neuronal activation, as indexed by the immediate early gene c-fos, showed that A 68930 and dihydrexidine caused a highly significant expression of c-fos in the medial prefrontal cortex. This c-fos expression was sensitive to treatment with SCH 23390, but not with raclopride. The effects of A 68930 and dihydrexidine on c-fos expression in caudate putamen or nucleus accumbens were less marked, or undetectable. The results indicate that stimulation of dopamine D(1/5) receptors, possibly in the medial prefrontal cortex, is associated with inhibitory actions on locomotor activity and d-amphetamine-induced hyperactivity. Assuming an important role of prefrontal dopamine D(1/5) receptors in schizophrenia, such inhibitory actions of dopamine D(1/5) receptor stimulation on psychomotor activation may have interesting clinical implications in the treatment of schizophrenia.

Animals↗

PubMed2006

Dopamine increases inhibition in the monkey dorsolateral prefrontal cortex through cell type-specific modulation of interneurons.

Dopaminergic modulation of the dorsolateral prefrontal cortex (DLPFC) plays an important role in cognitive functions, including working memory. At optimal concentrations, dopamine (DA) enhances pyramidal cell (PC) firing to increase task-related activity. However, spatial and temporal "tuning" of the persistent firing that underlies this mnemonic activity requires inhibitory control from gamma-aminobutyric acidergic (GABAergic) interneurons. How DA modulates the inhibitory control provided by different types of interneurons in the primate cortex is not known. We studied the effects of DA and DA receptor-specific agonists and antagonists on GABAergic inhibition and interneuron excitability in slices from primate DLPFC. Using whole-cell voltage-clamp recordings from layer 2/3 pyramidal neurons, we examined the effects of DA on spontaneous (action potential dependent) and miniature (action potential independent) inhibitory postsynaptic currents. We found that DA can increase inhibition via a presynaptic, action potential-dependent mechanism. In current-clamp recordings from physiologically and morphologically identified interneurons, we investigated the pharmacology and cell type specificity of this effect. DA increased the excitability of fast-spiking (FS), nonadapting interneurons via activation of D1- but not D2-type receptors. In contrast, DA had no effect on interneurons with adapting firing patterns. Thus, DA and D1 receptor activation affect local recurrent circuits by selectively modulating FS interneurons that control the firing of PCs through perisomatic innervation.

Animals↗

PubMed1995

Effects of sigma receptor ligands on the extracellular concentration of dopamine in the striatum and prefrontal cortex of the rat.

The extracellular concentration of dopamine in the striatum and medial prefrontal cortex of the rat was determined following the systemic administration of sigma receptor ligands. The (+)-benzomorphan, (+)-pentazocine, significantly increased the extracellular concentration of dopamine in the striatum also was produced by the (+)-, but not the (-)-, enantiomer of N-allylnormetazocine, as well as by the non-benzomorphans 1-(cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoothyl-piper idi ne (DUP 734) and (-)-butaclamol. In contrast, the dopamine concentration was unaffected by di-o-tolylguanidine and markedly suppressed by (+)-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine (3-PPP). Finally, the (+)-pentazocine-induced elevation of the extracellular concentration of dopamine was not suppressed by an inhibitor of the dopamine transporter, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine (GBR 12909). Thus, benzomorphan, e.g., (+)-pentazocine and (+)-N-allylnormetazocine, and non-benzomorphan, e.g., DUP 734 and (-)-butaclamol, sigma receptor ligands appear to facilitate dopamine release from nigrostriatal, and presumably mesocorticolimbic, neurons through a non-transporter-mediated mechanism.

Animals↗