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PubMed2005

Functional specialization within the dorsolateral prefrontal cortex: a review of anatomical and physiological studies of non-human primates.

The dorsolateral prefrontal cortex (DLPFC) possesses cortico-cortical connections with the parietal and premotor cortices that are involved in visuomotor control of actions. Studies have shown that the DLPFC, especially the caudal part, has a crucial role in cognitive control of motor behavior, and that it uses spatial information in conjunction with information such as object identity, behavioral rules, and rewards. Current anatomical and physiological studies indicate that the DLPFC may not be a single entity. Anatomical studies show that preferential anatomical connections exist between subregions of the DLPFC and the parietal/premotor cortices. Physiological studies based on data obtained from monkeys performing a variety of cognitive tasks report region-specific neuronal activity within the DLPFC. In this article, I review evidence for functional segregation within the DLPFC and postulate that at least two distinct subregions, i.e., the dorsal and ventral parts, can be identified.

Animals↗

PubMed1999

Dopaminergic correlates of sensory-specific satiety in the medial prefrontal cortex and nucleus accumbens of the rat.

Changes in dopamine (DA) efflux in the medial prefrontal cortex and nucleus accumbens of rats were monitored using in vivo microdialysis during sensory-specific satiety experiments. Rats consumed significant amounts of a palatable food during an initial meal but ate little when the same food was available as a second meal. In contrast, rats given a different palatable food ate a significant quantity during the second meal. DA efflux in both brain regions reflected this difference in food intake, indicating that DA activity is influenced by changes in the deprivation state of animals and sensory incentive properties of food. Given the proposed role of DA in motivated behaviors, these findings suggest that DA efflux may signal the relative incentive salience of foods and thus is a determinant of the pattern of food consumption observed in sensory-specific satiety.

Animals↗

PubMed2006

The role of short-term depression in sustained neural activity in the prefrontal cortex: a simulation study.

Recent experimental researches have suggested that sustained neural activity in the prefrontal cortex is a process of memory retention in decision making. Previous theoretical studies indicate that a balance between recurrent excitation and feedback inhibition is important for sustaining the activity. To investigate a plausible balancing mechanism, we simulated a biophysically realistic network model. Our model shows that short-term depression (STD) enables the network to sustain its activity despite the presence of long-term inhibition by GABA(B) receptors and that the sustained firing rates have a bell-shaped dependence on the degree of STD. By analyzing the neural network dynamics, we show that the bell-shaped dependence on STD is formed by destabilizing the balance with either excessive or insufficient STD. We also show that the optimal degree of STD has a linear relationship with the neural network size. These results suggest that STD provides a balancing mechanism and controls levels of sustained activities of various size networks.

Action Potentials↗

PubMed2006

The presence of background dopamine signal converts long-term synaptic depression to potentiation in rat prefrontal cortex.

Executive functions of the brain are believed to require tonic dopamine inputs to the prefrontal cortex (PFC). It is unclear, however, how this background dopamine activity controls synaptic plasticity in the PFC, a possible underlying mechanism of executive functions. Using PFC slices, we show that pairing of dopamine with weak tetanic stimulation, a maneuver that otherwise induces NMDA receptor-independent long-term depression (LTD), induces long-term potentiation (LTP) when "primed" with dopamine. This "priming" occurs through the combined activation of D1 and D2 receptors and requires 12-40 min to develop. Moreover, concurrent synaptic activation of NMDA receptors during priming is necessary for this novel form of LTP. We suggest that a role of background dopamine signals in the PFC is to prevent high-frequency synaptic inputs from abnormally inducing LTD and to secure the induction of LTP.

Animals↗

PubMed2003

Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia.

Anatomical and molecular abnormalities of excitatory neurons in the dorsolateral prefrontal cortex (DLPFC) are found in schizophrenia. We hypothesized that brain-derived neurotrophic factor (BDNF), a protein capable of increasing pyramidal neuron spine density and augmenting synaptic efficacy of glutamate, may be abnormally expressed in the DLPFC of patients with schizophrenia. Using an RNase protection assay and Western blotting, we detected a significant reduction in BDNF mRNA (mean=23%) and protein (mean=40%) in the DLPFC of patients with schizophrenia compared to normal individuals. At the cellular level, BDNF mRNA was expressed at varying intensities in pyramidal neurons throughout layers II, III, V, and VI of DLPFC. In patients with schizophrenia; neuronal BDNF expression was decreased in layers III, V and VI. Our study demonstrates a reduction in BDNF production and availability in the DLPFC of schizophrenics, and suggests that intrinsic cortical neurons, afferent neurons, and target neurons may receive less trophic support in this disorder.

Adolescent↗

PubMed2002

The role of the dorsolateral prefrontal cortex: evidence from the effects of contextual constraint in a sentence completion task.

Although the prefrontal cortices, in particular the dorsolateral prefrontal cortex (DLPFC), have been examined in numerous imaging and neuropsychological studies, it has proved difficult to assign a specific function to this brain region. The aim of this study was therefore to delineate the function of the DLPFC first by using positron emission tomography with a word generation task and second by comparing these findings with a series of different circumstances in which the DLPFC is activated in association with response selection. Six healthy volunteers were presented with a sentence completion task based on the Hayling test. In each of two conditions, (A) response initiation and (B) response suppression, volunteers saw a sentence with the final word omitted. In condition A they had to provide a word that fitted at the end of the sentence and in condition B they had to provide a word that did not fit. The corpus of sentences used varied systematically in their level of contextual constraint, ranging from low to high. With all levels of constraint combined, significant greater activation was observed in the left DLPFC (BA46/9) under the suppression condition and in the medial orbitofrontal cortex (BA11) under the initiation condition. Under the high-constraint condition with both tasks combined, significant right middle temporal activity (BA21) was observed, whereas under low constraint, the left DLPFC was significantly activated. An interaction of task and constraint revealed that the left DLPFC was significantly more active in the suppression task at all levels of constraint, but only under the low-constraint conditions in the initiation task. The reaction time analyses mirrored the pattern of activity observed, with slower reaction times under conditions of suppression and under conditions of initiation with low constraint. By comparing these findings with other studies of response selection, we argue that the most likely single cognitive function of the DLPFC is to specify a set of responses suitable for a given task and to bias these for selection (sculpting the response space). This function resembles the biasing of competition between stimuli in the model of Desimone and Duncan and is analogous to the component of the Supervisory Attentional System that modulates the contention scheduling system.

Adult↗

PubMed2004

Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: involvement of serotonin and GABA.

Serotonin is involved in psychiatric disorders exhibiting abnormal prefrontal cortex (PFC) function (e.g. major depression, schizophrenia). We examined the effect of the stimulation of the dorsal and median raphe nuclei (DR and MnR, respectively) on the activity of PFC neurons. Electrical stimulation of DR/MnR inhibited 66% (115/173) of pyramidal neurons in the medial PFC (mPFC). The rest of the cases exhibited orthodromic excitations, either pure (13%) or preceded by short-latency inhibitions (20%). Excited neurons had a lower pre-stimulus firing rate than those inhibited. Excitations evoked by MnR stimulation had a shorter latency than those evoked by DR stimulation. WAY-100635 [a 5-hydroxytryptamine1A (5-HT1A) antagonist] and the selective gamma aminobutyric acidA (GABAA) antagonist picrotoxinin partially antagonized DR/MnR-evoked inhibitions, suggesting the involvement of 5-HT1A- and GABAA-mediated components. The presence of a direct DR/MnR-mPFC GABAergic component is suggested by the short latency of evoked inhibitions (9 +/- 1 ms), faster than those evoked in the secondary motor area (20 +/- 3 ms), and that of antidromic spikes evoked by DR/MnR stimulation in mPFC pyramidal neurons (15 +/- 1 ms). Stimulation of the DR/MnR with paired pulses enhanced the duration of inhibitions and turned some excitations into inhibitions. Thus, the DR/MnR control the activity of mPFC pyramidal neurons in vivo in a complex manner, involving 5-HT-mediated excitations and GABA- and 5-HT-mediated inhibitions.

Animals↗

PubMed2002

Neuronal activity representing visuospatial mnemonic processes associated with target selection in the monkey dorsolateral prefrontal cortex.

To investigate how visuospatial mnemonic and target selection processes are represented in the dorsolateral prefrontal cortex (PFC), we studied neuronal attributes of the dorsolateral PFC while monkeys were performing oculomotor delayed visual search (ODVS) and oculomotor delayed-response (ODR) tasks. In the ODVS task, the subject made a memory-guided saccade to a remembered target location that had been presented along with distractors before a delay period; in the ODR task, the target was presented without any distractors. A total of 252 neurons in the dorsolateral PFC showed directional delay-period activity and were divided into two groups; neurons that showed directional delay-period activity predominantly in the ODVS task (n=112), and those that showed such activity similarly in both the ODVS and ODR tasks (n=140). These neuronal groups shared similar temporal properties (i.e. onset latency, peak time of delay-period activity) and spatial tuning. Our findings suggest that the dorsolateral PFC contains a particular visuospatial memory system for information selected by target selection (selective attention), and this attention-memory system (or 'memory system for special use') appears to be represented in the dorsolateral PFC, in parallel with a more 'general' memory system that is not specifically associated with target selection.

Action Potentials↗

PubMed2003

Decisional role of the dorsolateral prefrontal cortex in ocular motor behaviour.

Three patients with a unilateral cortical lesion affecting the dorsolateral prefrontal cortex (DLPFC), i.e. Brodmann area 46, were tested using different paradigms of reflexive saccades (gap and overlap tasks), intentional saccades (antisaccades, memory-guided and predictive saccades) and smooth pursuit movements. Visually guided saccades with gap and overlap, latency of correct antisaccades and memory-guided saccades and the gain of smooth pursuit were normal, compared with controls. These results confirm our anatomical data showing that the adjacent frontal eye field (FEF) was unimpaired in these patients. The specific pattern of abnormalities after a unilateral DLPFC lesion, compared with that of the FEF lesions previously reported, consists mainly of: (i) a bilateral increase in the percentage of errors in the antisaccade task (misdirected reflexive saccades); (ii) a bilateral increase in the variable error in amplitude, without significant decrease in the gain, in the memory-guided saccade task; and (iii) a bilateral decrease in the percentage of anticipatory saccades in the predictive task. Taken together, these results suggest that the DLPFC plays a crucial role in the decisional processes, preparing saccades by inhibiting unwanted reflexive saccades (inhibition), maintaining memorized information for ongoing intentional saccades (short-term spatial memory) or facilitating anticipatory saccades (prediction), depending upon current external environmental and internal circumstances.

Adult↗

PubMed2005

Subgenual prefrontal cortex of child and adolescent bipolar patients: a morphometric magnetic resonance imaging study.

The subgenual prefrontal cortex (SGPFC) plays an important role in emotional processing. We carried out a magnetic resonance imaging (MRI) study comparing the volume of the SGPFC in child and adolescent bipolar patients and healthy controls. The sample consisted of 15 children and adolescents who met DSM-IV criteria for bipolar disorder (mean age +/- S.D.=15.5 +/- 3.5 years) and 21 healthy adolescents (mean age +/- S.D.=16.9 +/- 3.8 years). MR images were obtained with a 1.5 T GE Signa Imaging System with Signa 5.4.3 software. SGPFC volumes were measured with the semi-automated software MedX (Sensor Systems, Sterling, VA, USA). ANCOVA was performed to compare SGPFC volumes between groups, using age, gender and intra-cranial volume (ICV) as covariates. The volumes (mean +/- S.D.) of the right and left SGPFC for bipolar patients were 291.27 +/- 88.70 mm(3) and 284.86 +/- 83.98 mm(3), respectively. For healthy controls, the right and left SGPFC volumes were 284.95 +/- 73.33 mm(3) and 307.55 +/- 73.67 mm(3), respectively. There were no statistically significant differences between groups regarding right or left SGPFC volumes. We found no evidence of volumetric abnormalities in the SGPFC of bipolar children and adolescents.

Adolescent↗

PubMed2004

Repeated injections of sulpiride into the medial prefrontal cortex induces sensitization to cocaine in rats.

RATIONALE: Recent studies have suggested that the medial prefrontal cortex (mPFC) plays an important role in the development of sensitization to cocaine. In particular, a recent report proposed that sensitization is associated with a decreased dopamine D(2) receptor function in the mPFC. The present study was designed to further examine the involvement of mPFC dopamine D(2) receptors in cocaine sensitization. OBJECTIVES: The experiments described below sought to determine the effects of acute or repeated intra-mPFC injections of the dopamine D(2) antagonist sulpiride on subsequent motor-stimulant and nucleus accumbens dopamine responses to cocaine. METHODS: Rats received bilateral cannulae implants above the ventral mPFC for microinjections and above the nucleus accumbens for in vivo microdialysis. Initial studies examined the effects of intra-mPFC sulpiride pretreatment on the acute motor-stimulant and nucleus accumbens dopamine responses to cocaine. Follow-up studies determined the effects of repeated intra-mPFC sulpiride injections on subsequent behavioral and nucleus accumbens dopamine responses to a cocaine challenge. RESULTS: Intra-mPFC sulpiride enhanced the cocaine-induced increases in motor activity and dopamine overflow in the nucleus accumbens. Repeated intra-mPFC sulpiride induced behavioral and neurochemical cross-sensitization to cocaine. CONCLUSIONS: The data support previous findings that sensitization is associated with a decrease in dopamine D(2) receptor function in the mPFC.

Animals↗

PubMed2005

Morphometric characterization of synapses in the primate prefrontal cortex formed by afferents from the mediodorsal thalamic nucleus.

The main thalamic afferentation of the prefrontal cortex (PFC) originates in the mediodorsal nucleus (MD). Although it is suggested that this pathway is affected in schizophrenia, there is a lack of functional and structural data regarding its synaptic organization. The scope of this study was to characterize the ultrastructural features of thalamocortical synapses formed by afferents from the MD by applying anterograde tract tracing, immunohistochemical detection of parvalbumin (PV, a probable marker of thalamocortical endings), and quantitative electron microscopic techniques to the PFC of the macaque monkey. Our findings indicate that anterogradely-labeled and PV-immunoreactive boutons exhibit similar ultrastructural properties, characterized by their larger size, higher incidence of release sites and a higher occurrence of mitochondria when compared to non-labeled, excitatory-like endings in the middle layers of the PFC. Although most of the contacts were made on spines in both cases, PV-immunopositive axon terminals apparently targeted dendritic shafts at about twice the frequency found for anterogradely-labeled afferents from the MD (20.5% and 9.5%, respectively). This result suggests diversity among thalamocortical and/or PV-immunoreactive axon terminals of the PFC. In accordance with studies in other cortical areas, our findings suggest that corollary discharge through the mediodorsal thalamocortical projection is also adapted to synaptic transmission with high efficacy and probably exhibits marked short-term temporal dynamics in the PFC.

Animals↗

PubMed2006

Efferent association pathways originating in the caudal prefrontal cortex in the macaque monkey.

The efferent association fibers from the caudal part of the prefrontal cortex to posterior cortical areas course via several pathways: the three components of the superior longitudinal fasciculus (SLF I, SLF II, and SLF III), the arcuate fasciculus (AF), the fronto-occipital fasciculus (FOF), the cingulate fasciculus (CING F), and the extreme capsule (Extm C). Fibers from area 8Av course via FOF and SLF II, merging in the white matter of the inferior parietal lobule (IPL) and terminating in the caudal intraparietal sulcus (IPS). A group of these fibers turns ventrally to terminate in the caudal superior temporal sulcus (STS). Fibers from the rostral part of area 8Ad course via FOF and SLF II to the IPS and IPL and via the AF to the caudal superior temporal gyrus and STS. Some fibers from the rostral part of area 8Ad are conveyed to the medial parieto-occipital region via FOF, to the STS via Extm C, and to the caudal cingulate gyrus via CING F. Fibers from area 8B travel via SLF I to the supplementary motor area and area 31 in the caudal dorsal cingulate region and via the CING F to cingulate areas 24 and 23 and the cingulate motor areas. Fibers from area 9/46d course via SLF I to the superior parietal lobule and medial parieto-occipital region, via SLF II to the IPL. Fibers from area 9/46v travel via SLF III to the rostral IPL and the frontoparietal opercular region and via the CING F to the cingulate gyrus.

Amino Acids↗

PubMed2005

Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia.

Patients with schizophrenia have reduced neurotrophin levels in their dorsolateral prefrontal cortex (DLPFC) compared to normal unaffected individuals. The tyrosine kinase-containing receptors, trkB and trkC, mediate the growth-promoting effects of neurotrophins and respond to changes in growth factor availability. We hypothesized that trkB and/or trkC expression would be altered in the DLPFC of patients with schizophrenia. We measured mRNA encoding the tyrosine kinase domain (TK+)-containing form of trkB and measured pan trkC mRNA in schizophrenics (N=14) and controls (N=15) using in situ hybridization. TrkB and trkC mRNAs were detected in large and small neurons in multiple cortical layers of the human DLPFC. We found significantly diminished expression of trkB(TK+) mRNA in large neurons in multiple cortical layers of patients as compared to controls, while small neurons also showed reductions in trkB(TK+) mRNA that did not reach statistical significance. In normals, strong positive correlations were found between trkB(TK+) mRNA levels and brain-derived neurotrophic factor (BDNF) mRNA levels among various neurons, while no correlation between BDNF and trkB(TK+) was found in patients with schizophrenia. TrkC mRNA was also reduced in the DLPFC of schizophrenics in large neurons in layers II, III, V and VI and in small neurons in layer IV. Since neurons in the DLPFC integrate and communicate signals to various cortical and subcortical regions, these reductions in growth factor receptors may compromise the function and plasticity of the DLPFC in schizophrenia.

Adolescent↗

PubMed1995

Influence of lipid peroxidation on [3H]ketanserin binding to 5-HT2 prefrontal cortex receptors.

The influence of lipid peroxidation on 5-HT2 receptor binding was examined in prefrontal cortex membranes from sheep brain. Lipid peroxidation was induced with ascorbic acid and ferrous sulphate and measured by the thiobarbituric acid method. In lipid-peroxidized membranes, [3H]ketanserin specific binding was inhibited. The Bmax values decreased by 80%, from 50.1 +/- 3.5 fmol/mg protein in control membranes to 10.1 +/- 2.0 fmol/mg protein in peroxidized membranes, indicating a decrease in the number of 5-HT2 binding sites. However, the KD values for the [3H]ketanserin specific binding did not significantly change. In order to further characterize [3H]ketanserin binding, the inhibition potency (IC50 values) of antagonists or agonists of serotonin and dopamine receptors for [3H]ketanserin specific binding was determined. In control membranes, the order of inhibition potency of the drugs tested was the following: ketanserin (-log[IC50]=8.56 +/- 0.70] > ritanserin (-log [IC50]=8.13 +/- 0.30)>methysergide (-log[IC50]= 7.42 +/- 0.50)> spiperone (-log[IC50]=7.23 +/- 0.18 > serotonin (-log [IC50] = 6.99 +/- 0.65)> haloperidol (-log[IC50]= 6.95 +/- 0.65) > dopamine (-log [IC50] = 5.82 +/- 0.76). After membrane lipid peroxidation, the IC50 value for ritanserin was significantly increased, suggesting a decreased capacity for displacing [3H]ketanserin specific binding. Other antagonists of 5-HT2 receptors showed apparent increases in IC50 values upon peroxidation, whereas spiperone was shown to be the most potent drug (-log[IC50]= 7.19 +/- 1.06) in inhibiting [3H]ketanserin specific binding. A decrease in polyunsaturated fatty acids, namely docosahexaenoic acid (22:6) was also observed in peroxidized membranes. These results indicate a modulating role of the surrounding lipids and of the physical properties of the membranes on the binding activity of 5-HT2 receptors upon the lipid peroxidation process, which can be involved in the tissue impairment that occurs during the aging process and in post-ischemic situations.

Animals↗

PubMed1985

Excitotoxin lesions suggest an aspartatergic projection from rat medial prefrontal cortex to ventral tegmental area.

High affinity D-[3H]aspartate uptake and amino acid concentrations were examined in synaptosome-enriched preparations of microdissected rat ventral tegmental area 6-7 days following N-methyl-D-aspartate lesions confined to medial prefrontal cortex. Specific reductions were observed in the high affinity uptake of D-[3H]aspartate (59% of control, P less than 0.005) and concentrations of L-aspartate (79% of control, P less than 0.05) in the ventral tegmental area suggesting the presence of an aspartatergic projection from medial prefrontal cortex to this area.

Animals↗

PubMed1999

Relationships between the prefrontal cortex and the basal ganglia in the rat: physiology of the cortico-nigral circuits.

The prelimbic/medial orbital areas (PL/MO) of the rat prefrontal cortex are connected to substantia nigra pars reticulata (SNR) through three main circuits: a direct nucleus accumbens (NAcc)-SNR pathway, an indirect NAcc-SNR pathway involving the ventral pallidum (VP) and the subthalamic nucleus (STN), and a disynaptic cortico-STN-SNR pathway. The present study was undertaken to characterize the effect of PL/MO stimulation on SNR cells and to determine the contribution of these different pathways. The major pattern of responses observed in the SNR was an inhibition preceded by an early excitation and followed or not by a late excitation. The inhibition resulted from the activation of the direct NAcc-SNR pathway because it disappeared after acute blockade of the glutamatergic cortico-striatal transmission by CNQX application into the NAcc. The late excitation resulted from the activation of the indirect NAcc-VP-STN-SNR pathway via a disinhibition of the STN because it disappeared after either CNQX application into the NAcc or blockade of the GABAergic striato-pallidal transmission by bicuculline application into the VP. The early excitation, which was markedly decreased after blockade of the cortico-STN transmission by CNQX application into the STN, resulted from the activation of the disynaptic cortico-STN-SNR pathway. Finally, the blockade of the cortico-STN-VP circuit by CNQX application into STN or VP modified the influence of the trans-striatal circuits on SNR cells. This study suggests that, in the prefrontal cortex-basal ganglia circuits, the trans-subthalamic pathways, by their excitatory effects, participate in the shaping of the inhibitory influence of the direct striato-nigral pathway on SNR neurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1986

An excitatory amino acid projection from rat prefrontal cortex to periaqueductal gray.

High affinity D-[3H]aspartate and [3H]GABA uptake, and amino acid concentrations were examined in synaptosome-enriched preparations of rat periaqueductal gray matter 6-7 days following N-methyl-D-aspartate lesions confined to medial prefrontal cortex. Specific reductions were observed in the high affinity uptake of D-[3H]aspartate (78% of control, p less than 0.025), but not of [3H]GABA. Concentrations of glutamate, aspartate, GABA, glycine and alanine were not significantly reduced in lesioned animals. These results suggest the presence of glutamatergic and/or aspartatergic projections from medial prefrontal cortex to periaqueductal grey matter.

Animals↗