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PubMed2005

Immunohistochemical and immunoblot analysis of gamma-aminobutyric acid B receptor in the prefrontal cortex of subjects with schizophrenia and bipolar disorder.

Immunohistochemical and immunoblot techniques were employed to examine the distribution and expression of GABA(B) receptors in the prefrontal cortex of postmortem subjects with schizophrenia and bipolar disorder. GABA(B)R1a/b immunoreactivity was observed in the neuronal soma and dendrites as well as in the neuropil in the control subjects. GABA(B)R1a/b immunolabeling in neurons from the subjects with schizophrenia and bipolar disorder was less intense than in those from the control subjects. In control subjects, the distribution of GABA(B)R2 immunoreactivity was found to be similar to that of GABA(B)R1a/b. GABA(B)R2 immunolabeling in neurons from the bipolar disorder group appeared less intense than that of the normal controls as well as that in schizophrenic groups. Immunoblot analysis demonstrated a significant decrease in GABA(B)R1a levels in schizophrenic subjects, while there was a significant decrease in GABA(B)R1a, GABA(B)R1b, and GABA(B)R2 levels in bipolar subjects compared with the controls. The present study suggests that the GABA(B) receptor is involved in the pathophysiology of schizophrenia and bipolar disorder, and further suggests that the patterns of changes in GABA(B) receptor subtypes are different between these two disorders.

Adult↗

PubMed2005

Increased action potential firing rates of layer 2/3 pyramidal cells in the prefrontal cortex are significantly related to cognitive performance in aged monkeys.

The neurobiological substrates of significant age-related deficits in higher cognitive abilities mediated by the prefrontal cortex (PFC) are unknown. To address this issue, whole-cell current-clamp recordings were used to compare the intrinsic membrane and action potential (AP) firing properties of layer 2/3 pyramidal cells in PFC slices from young and aged behaviorally characterized rhesus monkeys. Most aged subjects demonstrated impaired performance in Delayed Non-Match to Sample (DNMS) task acquisition, DNMS 2 min delay and the Delayed Recognition Span task. Resting membrane potential and membrane time constant did not differ in aged relative to young cells, but input resistance was significantly greater in aged cells. Single APs did not differ in terms of threshold, duration or rise time, but their amplitude and fall time were significantly decreased in aged cells. Repetitive AP firing rates were significantly increased in aged cells. Within the aged group, there was a U-shaped quadratic relationship between firing rate and performance on each behavioral task. Subjects who displayed either low or very high firing rates exhibited poor performance, while those who displayed intermediate firing rates exhibited relatively good performance. These data indicate that an increase in AP firing rate may be responsible, in part, for age-related PFC dysfunction.

Action Potentials↗

PubMed1996

Dopamine D1 receptor actions in layers V-VI rat prefrontal cortex neurons in vitro: modulation of dendritic-somatic signal integration.

The ionic mechanisms by which dopamine (DA) regulates the excitability of layers V-VI prefrontal cortex (PFC) output neurons (including those that project to the nucleus accumbens) were investigated in rat brain slices using in vitro intracellular recording techniques. DA or the D1 receptor agonist SKF38393, but not the D2 agonist quinpirole, reduced the first spike latency and lowered the firing threshold of the PFC neurons in response to depolarizing current pulses. This was accomplished by enhancing the duration of a tetradotoxinsensitive, slowly inactivating Na+ current and attenuating a slowly inactivating, outwardly rectifying, dendrotoxin-sensitive K+ current. Furthermore, D1 receptor stimulation attenuated high-threshold Ca2+ spike(s) (HTS) evoked primarily from the apical dendrites of these PFC neurons. Taken together, these data suggest that D1 receptor stimulation on layers V-VI pyramidal PFC neurons: (1) restricts the effects of inputs to the apical dendrites of these neurons by attenuating the dendritic HTS-mediated amplification of such inputs; and (2) potentiates the influence of local inputs from neighboring deep layers V-VI neurons by enhancing the slowly inactivating Na+ current and attenuating the slowly inactivating K+ current. By influencing the input/output characteristics of PFC-->NAc neurons, DA may play an important role in the processes through which PFC signals are translated into action.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2002

Medial prefrontal cortex and pavlovian conditioning: trace versus delay conditioning.

Pavlovian eyeblink (EB) conditioning was studied in both trace and delay paradigms in rabbits (Oryctolagus cuniculus) with either medial prefrontal cortex (mPFC) lesions or sham lesions. mPFC lesions of prelimbic cortex (Brodmann's Area 32) retarded EB conditioning in the trace but not the delay paradigm. However, this effect was significant only when the conditioned stimulus (CS) was 500 rather than 100 ms in duration. Lesions of the anterior cingulate cortex (Area 24) did not affect EB conditioning in a trace paradigm. Accompanying CS-evoked heart rate slowing was attenuated under all conditions by the mPFC lesions, although this result was not always statistically significant.

Animals↗

PubMed2003

Group II metabotropic glutamate receptors enhance NMDA receptor currents via a protein kinase C-dependent mechanism in pyramidal neurones of rat prefrontal cortex.

The action of glutamate in CNS is mediated by the activation of metabotropic and ionotropic receptors. The metabotropic glutamate receptors (mGluRs) are highly enriched in prefrontal cortex (PFC) - a brain region critically involved in the regulation of cognition and emotion. Emerging evidence has suggested that mGluRs are viable drug targets for neuropsychiatric disorders associated with PFC dysfunction. However, the mGluR-mediated signalling in PFC remains unclear. To understand the physiological functions of postsynaptic group II mGluRs (mGluR2/3) in PFC neurones, we investigated the molecular and cellular mechanisms underlying the regulation of NMDA receptor channels by group II mGluRs. We found that APDC, a highly selective and potent group II mGluR agonist, reversibly increased NMDAR currents in acutely dissociated PFC pyramidal neurones. Selective group II mGluR antagonists, but not group I mGluR antagonists, blocked APDC-induced enhancement of NMDAR currents, suggesting the mediation by mGluR2/3 receptors. The APDC effect on NMDAR currents was independent of Mg(2+) block or membrane voltages, and primarily targeted NR2A subunits containing NMDARs. While changing protein kinase A levels was without effect, inhibiting protein kinase C (PKC) or dialysis with Ca(2+) chelators largely blocked the mGluR2/3 modulation of NMDAR currents. In contrast, inhibiting protein tyrosine kinases, cyclin-dependent kinase 5, Ca(2+)/calmodulin-dependent kinase II or the Ca(2+)/calmodulin-dependent phosphatase calcineurin failed to do so. Moreover, treatment of PFC slices with APDC significantly increased the PKC activity and PKC phosphorylation of NMDA receptors. These findings suggest that activation of mGluR2/3 receptors potentiates NMDAR channel functions in PFC through a PKC-dependent mechanism. This modulation may be relevant for developing novel mGluR-related pharmacological agents for the treatment of mental illnesses.

Animals↗

PubMed2004

Hemispheric specialization of the lateral prefrontal cortex for strategic processing during spatial and shape working memory.

OBJECTIVE: We investigated whether spatial working memory (WM) is associated with functional specialization of the right prefrontal cortex (PFC) relative to WM for shapes. We designed spatial and shape WM tasks that are relatively easy to perform and that minimize both task-switching and manipulation demands. The tasks use identical stimuli and require the same motor response. METHODS: We presented 12 subjects with target shapes that appeared in particular locations. Subjects maintained either the location or the shape of the targets in WM and responded to each probe by indicating whether it was a target. During a non-WM control task, subjects indicated whether the probe appeared on the right or left side of the screen. Subjects were scanned with a 3.0 T Siemens scanner and data were analyzed using SPM99. The WM tasks were compared to identify PFC activation that was different for spatial versus shape WM. Each WM task was also compared to the control task. RESULTS: compared with shape WM, spatial WM performance was faster and more accurate and was associated with increased right ventrolateral and frontopolar PFC activation. In contrast, compared to spatial WM, shape WM was associated with increased left ventrolateral PFC activity. CONCLUSIONS: These findings demonstrate hemispheric specialization for spatial versus shape WM in the ventrolateral PFC. The increased activity in the right PFC for spatial WM cannot be attributed to increased task difficulty, the stimuli used, or the response requirements. Rather, we propose that differences in performance and activation reflect the use of configural processing strategies for spatial WM.

Adult↗

PubMed2003

Serotonin induces tonic firing in layer V pyramidal neurons of rat prefrontal cortex during postnatal development.

The effects of serotonin (5-HT) on neuronal activity were examined during postnatal development in layer V pyramidal neurons of the rat prefrontal cortex (PFC) in vitro. Whole-cell patch-clamp recordings were made in slices obtained from rats aged between postnatal day (P) 6 and P31. In P14 or younger neurons, bath application of 5-HT (10 microM) induced a large depolarization followed by tonic firing at 2-5 Hz. The excitatory effects of 5-HT decreased rapidly after P14, so that by P21, 5-HT produced a small depolarization or hyperpolarization without cell firing. The excitatory effects of 5-HT at younger ages were attributed to 5-HT2A receptors because the effects were mimicked by the 5-HT2 agonist alpha-methyl-5-HT but not by the 5-HT3 agonist 1-(m-chlorophenyl)-biguanide, nor by the 5-HT2B/2C agonist 1-(3-chlorophenyl)piperazine, and were blocked by the 5-HT2A antagonists ketanserin and alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol. The excitatory responses persisted in 0 [Ca2+]o and high [Mg2+]o in the presence of TTX or blockers of ionotropic glutamate receptors, suggesting that the effects were mediated essentially by postsynaptic mechanisms. The responses to 5-HT involve a reduction of K+ conductance and an enhancement of the hyperpolarization-activated Na+/K+ current. The developmental decline of 5-HT-induced excitatory effects was associated with a downregulation of 5-HT2A receptor function and a decrease in the input resistance during early life. These results suggest that 5-HT is an important regulator of neuronal activity in the neonatal PFC and may play a role in activity-dependent developmental processes.

Age Factors↗

PubMed2002

Cholinergic receptor blockade in prefrontal cortex and lesions of the nucleus basalis: implications for allocentric and egocentric spatial memory in rats.

In this study we have examined the involvement of the prefrontal cortex (PFC) along with the Nucleus basalis magnocellularis (NBM) in two types of spatial navigation tasks. We evaluated the effects of excitotoxic (ibotenate-induced) lesions of the NBM in an allocentric and an egocentric task in the Morris water maze, using sham operations for a comparison. In both cases we also assessed the effects of local cholinergic receptor blockade in the PFC by infusing the muscarinic receptor antagonist scopolamine (4 or 20 microg). Anatomically, the results obtained showed that this lesion produced a profound loss of acetylcholinesterase (AChE) positive cells in the NBM, and a loss of AChE positive fibres in most of the neocortex, but hardly in the medial PFC. Behaviourally, such lesions led to a severe impairment in the allocentric task. Intraprefrontal infusions of scopolamine led to a short-lasting impairment in task performance when the high dose was used. In the second experiment, using the same surgical manipulations, we examined the performance in the egocentric task. Like in the allocentric task animals with NBM lesions were also impaired, but with continued training they acquired a level of performance similar to the sham-operated ones. This time, infusions of scopolamine in the medial PFC led to a severe disruption of performance in both groups of animals. We conclude that acetylcholine in the medial PFC is important for egocentric but not allocentric spatial memory, whereas the NBM is involved in the learning of both tasks, be it to a different degree.

Acetylcholinesterase↗

PubMed2004

Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression.

Magnetic resonance imaging (MRI) studies in depressed subjects report smaller volumes of amygdala, hippocampus, inferior anterior cingulate, and the orbital prefrontal cortex (OPFC), components of the limbic-cortico-thalamic circuit. Major depression occurs more commonly in women, raising the possibility of an additional psychopathological process affecting women and not men. We sought to determine whether volumetric differences related to mood disorders are dependent on sex. Eight male and 10 female depressed subjects, meeting DSM III R criteria for a major depressive episode, and eight male and 10 female healthy volunteers had MRI scans on a 1.5 T GE Signa Advantage scanner. The regions of interest included amygdala, hippocampus, inferior anterior cingulate, and OPFC. In all analyses, regional volumes were normalized for total cerebral volume. Volumetric changes in the ROIs showed a significant sex by diagnosis interaction, indicating a different pattern of volumetric changes in depressed males compared with females relative to controls. Relative to sex-matched controls, the left inferior anterior cingulate was smaller in depressed males (23%) compared with depressed females (11%). Depressed females but not depressed males had smaller amygdala compared with controls (F-value = 4.946, p = 0.033). No significant volumetric differences were noted in the hippocampus or OPFC. No volumetric correlations were noted with clinical variables, depression subtypes, or a reported history of sexual or physical abuse. Sex may affect volumetric deficits in amygdala and anterior cingulate cortex in mood disorders, but no effects were found in the hippocampus or OPFC. The biology of mood disorders in females may differ in some aspects from males, and may contribute to the higher rate of depression in women.

Adult↗

PubMed2005

Use of handheld computers for assessment of prefrontal cortex function in patients with phenylketonuria.

Assessment of prefrontal brain cortex function can be helpful in treatment monitoring in patients with phenylketonuria. We aimed to assess the usefulness of computerized neuropsychological tests developed for handheld computers for this purpose. We observed worse test performance among persons with blood phenylalanine concentrations exceeding the recommended range. Use of handheld computers was assessed by patients and by doctors as interesting, not time-consuming and convenient. This method can be helpful during routine follow-up visits.

Adolescent↗

PubMed2001

Hypoperfusion in the supplementary motor area, dorsolateral prefrontal cortex and insular cortex in Parkinson's disease.

The changes of regional cerebral blood flow (rCBF) in Parkinson's disease (PD) were investigated. Because of individual differences in brain volume and the extent of brain atrophy, previous functional imaging studies involved potential methodological difficulties. In this study, using the statistical parametric mapping technique, 99mTechnetium-labeled hexamethylpropyleneamineoxime brain single-photon emission computed tomography images from 18 patients with PD were transformed into standard brain-based stereotaxic coordinate spaces and then compared with such images for 11 control subjects matched for age and extent of brain atrophy. A rCBF decrement in the supplementary motor area (SMA) and such decrement in the dorsolateral prefrontal cortex (DLPFC) were observed in the summarized PD images as compared with controls (p<0.005). In a subgroup in the Hoehn-Yahr III/IV stage (11 cases), the rCBF decrement was demonstrated not only in the SMA, but also in the DLPFC and insular cortex (p<0.001). There was a correlation between the degree of the rCBF decrement in the DLPFC or the insular cortex and the score of the unified Parkinson's disease rating scale (p<0.05), while the rCBF decrement in the SMA showed no relationship with the severity of disease. The function of the SMA is closely associated with the nigro-striatal pathway and its impairment can explain the basic akinetic symptoms in PD, which are responsive to L-DOPA treatment. On the other hand, the DLPFC and insular cortex may play key roles in specific symptoms of impairment at advanced stages, such as impaired working memory, postural instability and autonomic dysfunction. We hypothesize that the impairment of the DLPFC and insular function is correlated with the progression of the disease and is related to DOPA-refractory symptoms, which are major problems in the care of patients with advanced PD.

Adult↗

PubMed2006

Functional connectivity of the prefrontal cortex in Huntington's disease.

BACKGROUND: Huntington's disease is a progressive neurodegenerative disorder that results in deterioration and atrophy of various brain regions. AIM: To assess the functional connectivity between prefrontal brain regions in patients with Huntington's disease, compared with normal controls, using functional magnetic resonance imaging. PATIENTS AND METHODS: 20 patients with Huntington's disease and 17 matched controls performed a Simon task that is known to activate lateral prefrontal and anterior cingulate cortical regions. The functional connectivity was hypothesised to be impaired in patients with Huntington's disease between prefrontal regions of interest, selected from both hemispheres, in the anterior cingulate and dorsal lateral prefrontal cortex. RESULTS: Controls showed a dynamic increase in interhemispheric functional connectivity during task performance, compared with the baseline state; patients with Huntington's disease, however, showed no such increase in prefrontal connectivity. Overall, patients with Huntington's disease showed significantly impaired functional connectivity between anterior cingulate and lateral prefrontal regions in both hemispheres compared with controls. Furthermore, poor task performance was predicted by reduced connectivity in patients with Huntington's disease between the left anterior cingulate and prefrontal regions. CONCLUSIONS: This finding represents a loss of synchrony in activity between prefrontal regions in patients with Huntington's disease when engaged in the task, which predicted poor task performance. Results show that functional interactions between critical prefrontal regions, necessary for cognitive performance, are compromised in Huntington's disease. It is speculated whether significantly greater levels of activation in patients with Huntington's disease (compared with controls) observed in several brain regions partially compensate for the otherwise compromised interactions between cortical regions.

Adult↗

PubMed1985

Reward related neuronal activity in monkey dorsolateral prefrontal cortex during feeding behavior.

Extracellular single neuron activity was recorded in the dorsolateral prefrontal cortex (DL) during bar pressing for food reward. Most of the reward-related neurons were located around the rostral end of the principal sulcus. Neuronal activity was diminished, abolished, or reversed when quinine adulterated food (aversive food) was given as a reinforcement. Cue-related neurons tended to be located more caudally in the DL. The activity of these neurons was not modulated by the nature of the reward as much as that of the reward-related neurons. The results suggest that DL neurons are not functionally homogeneous.

Animals↗

PubMed1985

Effects of lesions of prefrontal cortex and dorsomedial thalamus on delayed go/no-go alternation in rats.

The effect of prefrontal cortex (PFC) and/or dorsomedial thalamus (DMT) lesions on a delayed go/no-go alternation task was studied in the rat. The lesion gave rise to the impairment of smooth alternation of one response to another, resulting in the generation of some successive repetitions of either response. However, either type of response was generated in virtually equal frequencies during pre- and post-surgery sessions. These results suggest that the DMT and PFC are involved in the memory and response control process for generating the alternation response, and they do not mediate either one type of response. Furthermore, DMT or DMT/PFC lesions induced a larger behavioral impairment than PFC lesions indicating that the DMT plays a major role in generating the alternation behavior based on the memory for the previous response.

Animals↗

PubMed1986

Role of bar press-related neurons in the dorsolateral prefrontal cortex during task performance by monkey.

Extracellular single neuron activity of the dorsolateral prefrontal cortex (DL) was recorded in the monkey, during bar pressing for reward. The bar press-related neurons which exhibited excitation or inhibition during the bar press period were found to be scattered diffusely in the DL. Activity changes that arose during the bar press period also appeared when the experimenter pressed the bar for the monkey. When delivery of food was delayed for a random time after cue tone on, bar press responses were still confined to the bar press period and did not extend beyond the cue tone. These results, together with the lesion studies, suggest that bar press-related neurons are involved in the animal's concentration during the bar press period.

Action Potentials↗

PubMed1992

Spike-train analysis reveals "overshoot" in developing rat prefrontal cortex function.

A multivariate analysis of spontaneous single neuron firing in the developing prefrontal cortex (PFC) of urethane anesthetized rats has been made using selected spike-train parameters. In particular, the development of modal interspike intervals closely paralleled the volumetric 'overshoot' reported earlier by us for rat PFC. Thus, the growth phase is characterized by progressively higher firing rates associated with longer modal intervals (i.e., a change from phasic to tonic firing, suggestive of increasingly effective inhibition). In contrast, the subsequent abrupt reduction in PFC volume is accompanied by the appearance of extremely short interspike intervals with no concomitant change in overall mean discharge rates ('burst' firing). This last development could be largely due to the 'pruning' of excessive excitatory synaptic contacts.

Action Potentials↗

PubMed2006

Effect of prefrontal cortex damage on resolving lexical ambiguity in text.

The function of suppression of context-inappropriate meanings during lexical ambiguity resolution was examined in 25 adults with prefrontal cortex damage (PFCD) localized to the left (N=8), right (N=6), or bilaterally (N=11); and 21 matched Controls. Results revealed unexpected inverse patterns of suppression between PFCD and Control groups, with measures suggesting decreased interference across time in the PFCD group and increased interference in the Control group. The PFCD group, however, had significantly lower accuracy rates for the context-inappropriate condition. Results suggest a loss of the control aspects of inhibitory processes in lexical ambiguity resolution following PFCD. An aging effect on suppression function is also suggested.

Adult↗

PubMed2001

Effect of long-term potentiation induction on gamma-band electroencephalograms in prefrontal cortex following stimulation of rat hippocampus in vivo.

We examined whether long-term potentiation (LTP) affects cortical gamma-band electroencephalograms (EEG) in the hippocampo-prefrontal cortex (PFC) pathway of anesthetized rats. The LTP induction increased the evoked PFC gamma-band EEG power (40-100 Hz) to 120-135% at 500-700 ms after test stimulation. A simple increment of stimulus intensity, instead of LTP induction, did not reveal this evoked increase. Neither LTP induction nor the intensity increment changed significantly the magnitude of an evoked decrease at around 100 ms or the spontaneous prestimulation gamma-band power. These results indicate that LTP in PFC specifically increases the evoked gamma-band EEG power, which may reflect a phasic mode of plastic neurotransmission through the hippocampo-PFC pathway in vivo.

Animals↗