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PubMed1997

Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy.

BACKGROUND: Positron emission tomographic and postmortem studies comparing schizophrenic patients with healthy control subjects have found medial prefrontal cortical and anterior cingulate abnormalities that suggest dysfunction in glutamatergic neurons. The glutamate used for nerve signal transduction is predominantly derived from glutamine. After signal transduction, glutamate released into the synapse is converted to glutamine in glial cells, transported back to the presynaptic neuron, and reconverted to glutamate for reuse. In this study, levels of glutamate and glutamine were examined by means of in vivo proton (1H) magnetic resonance spectroscopy. METHODS: Localized in vivo 1H spectra were acquired from a 4.5-cm3 volume in the left medial prefrontal cortex encompassing portions of Brodmann areas 24, 32, and 9 in 10 never-treated schizophrenic subjects and 10 healthy controls of comparable age, sex, handedness, education, and parental education. From each spectrum, metabolite levels were estimated for glutamate and glutamine, as well as 10 other metabolites and 3 macromolecules, by means of a noninteractive computer program that combined modeled in vitro spectra of every metabolite to reconstruct each in vivo spectrum. RESULTS: A significant increase in glutamine level was found in the medial prefrontal cortex of the schizophrenic patients compared with controls. N-acetylaspartate and other measured metabolites and macromolecules were not significantly changed in schizophrenics. CONCLUSION: Increased glutamine levels in the medial prefrontal region most likely reflect decreased glutamatergic activity in this region in never-treated schizophrenic patients compared with healthy controls.

Adolescent↗

PubMedDate not supplied

Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons.

A series of electron microscopic immunocytochemical studies was performed to analyze subcellular sites for noradrenergic modulation in monkey prefrontal cortex. One out of 12 noradrenergic varicosities, identified by dopamine beta-hydroxylase immunocytochemistry within single ultrathin sections, forms morphologically identifiable junctions with small dendrites and spines. Accordingly, alpha2-adrenergic receptors, almost all of which are of the A-subtype, that occur in spines are localized discretely over postsynaptic membranes. alpha2-Adrenergic receptors are also found at sites along axons, dendritic shafts and astrocytic processes lacking morphologically identifiable synaptic junctions, suggesting that these receptors are activated by volume transmission. In particular, axonal alpha2-adrenergic receptors occur mostly at pre-terminal regions, suggesting that axo-axonic interactions may mediate reduction of neurotransmitter release at sites other than axo-spinous junctions by closing voltage-dependent calcium channels. These results indicate that noradrenergic modulation of prefrontal cortex involves synaptic interactions at spines of pyramidal neurons and nonsynaptic volume transmission to glia, dendritic shafts and axons.

Animals↗

PubMed1999

Pathological laughing and crying in multiple sclerosis: a preliminary report suggesting a role for the prefrontal cortex.

As part of a wide ranging study investigating the prevalence, demographic and disease related characteristics of pathological laughing and crying (PLC) in multiple sclerosis (MS), a putative role for the prefrontal cortex was also explored. Eleven multiple sclerosis (MS) patients with carefully defined PLC were compared to a control group of 13 MS patients without PLC on various cognitive indices known to be sensitive to frontal lobe dysfunction. Although the two groups did not differ with respect to age, sex, physical disability, disease course, duration of MS, years of education, premorbid IQ, and depression, the PLC group performed more poorly on the Stroop test and a measure of verbal fluency. They also showed a trend to make more total errors on the Wisconsin Card Sort Test. The relevance of these findings to the pathogenesis of PLC is discussed, in particular whether the syndrome is, in part, mediated by dysfunction of the prefrontal cortex.

Adult↗

PubMed2006

Ovariectomized rats show decreased recognition memory and spine density in the hippocampus and prefrontal cortex.

Effects of ovariectomy (OVX) on performance of the memory tasks, Object Recognition (OR) and Object Placement (OP), and on dendritic spine density in pyramidal neurons in layer II/III of the prefrontal cortex and the CA1 and CA3 regions of the hippocampus were determined. OVX was associated with a significant decline in performance of the memory tasks as compared to intact rats beginning at 1 week post OVX for OR and 4 weeks post OVX for OP. Golgi impregnation at 7 weeks post OVX showed significantly lower spine densities (17-53%) in the pyramidal neurons of the medial prefrontal cortex and the CA1, but not the CA3, region of the hippocampus in OVX compared to intact rats. These results suggest that cognitive impairments observed in OVX rats may be associated with morphological changes in brain areas mediating memory.

Animals↗

PubMed1996

Effect of ethanol on extracellular 5-HT and glutamate in the nucleus accumbens and prefrontal cortex: comparison between the Lewis and Fischer 344 rat strains.

The present study investigated the impact of systemic (i.p.) ethanol administration on extracellular levels of serotonin and glutamate in the prefrontal cortex and the nucleus accumbens in Lewis and Fischer 344 rat strains using in vivo microdialysis. At 1.0 g/kg, ethanol elicited a significant increase in nucleus accumbens-dialysate levels of both 5-HT (44% +/- 16, P = 0.002) and glutmate (90% +/- 43, P = 0.009) in Lewis rats. In Fischer rats, there was no increase in 5-HT (6% +/- 7: P = 0.5), and a trend toward an increase in glutamate (88% +/- 46: P = 0.1). The 0.5 and 2.0 g/kg doses did not result in any significant change in extracellular 5-HT or glutamate in the nucleus accumbens or prefrontal cortex of either strain. The basal levels of glutamate, in both brain regions, were significantly lower in Lewis than in Fischer 344 rats. The basal levels of 5-HT were also lower in the nucleus accumbens of Lewis rats. These findings suggest that enhanced sensitivity of the mesoaccumbens 5-HT or glutamate systems to ethanol and/or inherent low basal levels of 5-HT or glutamate activity may be associated with the predisposition to alcohol-drinking behavior seen in Lewis rats.

Alcohol Drinking↗

PubMed2004

GABA transporters GAT-1 and GAT-3 in the human dorsolateral prefrontal cortex in schizophrenia.

This study aimed to investigate the binding affinity of [3H]GABA and [3H]beta-alanine to GABA transporters GAT-1 and GAT-3 in the human dorsolateral prefrontal cortex (Brodmanns' area 9) in schizophrenia. Using post mortem tissue from individuals diagnosed with schizophrenia (n=6) and control subjects (n=6), the density of GAT-1 was established by displacing [3H]GABA with muscimol, and for GAT-3 [3H]beta-alanine was used. Data analysis showed a significant decrease of GAT-1 levels (45%), and a significant increase of GAT-3 density (23%) within the dorsolateral prefrontal cortex of individuals diagnosed with schizophrenia when compared to age- and sex-matched controls. The observed decrease of GAT-1 could be explained as a consequence of the GABA hypo-function or the result of volumetric shrinkage of the cerebral cortex previously reported in this disease. The observed elevation of GAT-3 levels could be due to a compensatory effect for any functional loss of GABA re-uptake by the decreased GAT-1 levels.

Adult↗

PubMed2001

Phencyclidine-induced dysregulation of dopamine response to amphetamine in prefrontal cortex and striatum.

Phencyclidine (PCP) administration in rodents has been used to model aspects of schizophrenia. One aspect of such treatment has been the enhancement of amphetamine-induced increase of dopamine in the prefrontal cortex and striatum. To further characterize this mechanism rats were treated for 2 weeks with continuous PCP (15 mg/kg per day via Alzet minipump). Rats were implanted with a microdialysis probe into the prefrontal cortex (PFC) or striatum. Amphetamine was administered locally via the dialysis probe during one collection period and changes in extracellular dopamine were monitored. The effect of local administration of the dopamine uptake blocker nomifensine was also measured. Amphetamine (10 microM) and nomifensine (10 microM) increased the level of dopamine in both the PFC and striatum. PCP administration did not alter the response to amphetamine or nomifensine in the PFC, but reduced this response about 2-fold in striatum. To examine effects of continuous PCP administration on dopamine autoreceptor function, release of [3H]dopamine in response to electrical stimulation and in the presence of a dopamine agonist or antagonist was tested in striatal and prefrontal cortical tissue. Autoreceptor responses were similar in control and PCP-treated tissues. We conclude that the brain region-specific enhancement of dopamine release by peripheral amphetamine administration in rats after PCP is not likely mediated by alterations in the dopamine autoreceptors or changes in the dopamine transporter. The selective local responses of amphetamine indicates heterogeneous regional effects of continuous PCP on NMDA receptor function; effects that influence both regional excitatory responses and the overall dynamics of tonic excitatory/inhibitory inputs to the PFC and striatum.

Amphetamines↗

PubMed2002

Decision-making heterogeneity in obsessive-compulsive disorder: ventromedial prefrontal cortex function predicts different treatment outcomes.

Certain clinical aspects of patients with Obsessive-Compulsive Disorder (OCD) appear similar to those of patients with damage to the ventromedial sector of the prefrontal cortex. The hypothesis for the involvement of the frontal region in OCD is also supported by neuropsychological findings. Building on this evidence, we assessed the performance of a group of 34 OCD patients on a measure indexing with orbitofrontal cortex functioning and compared it with the performance of two other subject groups, one consisting of 34 healthy control subjects and the other 16 patients with panic disorder. All study subjects performed a neuropsychological task, which is sensitive to frontal lobe dysfunction and simulating real-life decision-making. Significant differences were found between the neuropsychological profiles of the OCD and of other groups, pointing to a possible specificity of decision-making deficit in OCD. Comparison of the performance of the OCD patients grouped according to response to antiobsessive drug treatment showed that poor neuropsychological task performance predicted poor outcome of pharmacological treatment. Task behavior did not correlate with severity of illness or demographic characteristics of the subjects. Results support the role of the ventromedial prefrontal cortex in OCD.

Adult↗

PubMed1996

Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects.

Recent investigations have reported a reduced density of interneurons and an increase of GABAA receptor binding occurring preferentially in layer II of the anterior cingulate cortex of schizophrenic subjects [Benes F.M. et al. (1992) J. Neurosci. 12, 924-929]. Since a reduction in the density of interneurons has also been found in layer II of the prefrontal cortex, this study has sought to determine whether an un-regulation of the GABAA receptor binding activity might also be found in this region of schizophrenics. A high-resolution autoradiographic analysis of bicuculline-sensitive [3H]muscimol (GABAA) receptor binding on individual neuron cell bodies in layers II, III, IV and VI has been applied to Brodmann area 10 from normal controls (n = 16) and schizophrenic (n = 7) subjects. A computer-assisted technique has been used under strictly blind conditions to determine whether differences in binding occur in the schizophrenic group. A significant increase of GABAA receptor binding activity has been observed in layers II, III, V and VI in the schizophrenic group. When the binding is expressed as a density with respect to neuronal cell size, there is a gradient of binding across layers II, III, V and VI, with neuronal cell bodies in layer II having the greatest density of grains. When different subpopulations of neurons distinguished according to size criteria are examined separately, large (pyramidal) neurons show significantly higher binding, particularly in layer II, where it was increased by 90% in schizophrenics. Small (non-pyramidal) cells do not show significant differences in binding in schizophrenics, except in layer VI, where there was a 135% increase. Potential confounding effects from age and post mortem interval do not explain the differences between the two groups, because both young and old schizophrenics, as well as schizophrenics with long and short post mortem intervals, showed increased GABAA receptor binding activity when compared to control cases distinguished in a corresponding fashion. These data suggest that there may be a preferential reduction of inhibitory GABAergic inputs to pyramidal neurons, particularly in layer II of the preferential cortex, in schizophrenia. This change could potentially result in an increased excitatory outflow from the prefrontal area to other cortical regions of the schizophrenic brain. Overall, these results are consistent with the idea that reduced amounts of GABAergic activity in the prefrontal cortex could be related to a perinatal disturbance and could be a potentially important component of the pathophysiology of psychosis.

Adult↗

PubMed2002

Information processes in the primate prefrontal cortex in relation to working memory processes.

Working memory is a mechanism for short-term active storage of information as well as for processing stored information. Although evidence for neuronal mechanisms of temporary storage of information has accumulated for the prefrontal cortex, little is known about neuronal mechanisms for processing information. To understand how information is processed by prefrontal neurons, we first need to know what information is represented by single-neuron activity, and then examine how information represented by single-neuron activity or a population of activities changes along the temporal sequence of the trial. By examining task-related single-neuron activities while monkeys performed various working memory tasks, delay-period activity observed in the prefrontal cortex is considered to be a neuronal correlate of the mechanism for temporary active storage of information. Delay-period activity represents a variety of information including the spatial position and the physical feature of the stimulus, the forthcoming behavioral response, the quality of reward that the subject would receive, the difference of the task, or the rule of the task. Although delay-period activity could represent this variety of information, the information represented by delay-period activity is only the information relevant for task performance. In addition, using complex conditional tasks, delay-period activity has been shown to represent several kinds of information simultaneously. Based on these results, we examined how information represented by a population of prefrontal activities changes along the temporal sequence of the trial. Using two kinds of oculomotor delayed-response tasks, we first identified what information each task-related activity represents. Then, using population vector analysis, we could not only visualize information represented by a population of prefrontal activities, but also demonstrate the temporal change of information represented by a population of prefrontal activities. These attempts are important to understand information processes for working memory.

Animals↗

PubMed2003

Apolipoprotein D levels are elevated in prefrontal cortex of subjects with Alzheimer's disease: no relation to apolipoprotein E expression or genotype.

BACKGROUND: Apolipoprotein E (apoE) has been implicated in the pathology of AD ever since inheritance of the epsilon4 allele was shown to be an important risk factor for the development of AD. Apolipoprotein D (apoD) is elevated in association with several central nervous system disorders, including Alzheimer's disease (AD), and has been proposed to be an especially robust marker for brain regions specifically affected by particular neuropathologies. Progressive cognitive decline is the core clinical feature of AD and is associated with disturbances in the prefrontal cortex. METHODS: We measured apoD levels in prefrontal cortex samples obtained postmortem from 20 autopsy-confirmed AD subjects and 40 control subjects. RESULTS: Enzyme-linked immunosorbent assay analysis revealed a significant increase in apoD expression in AD subjects compared with control subjects (.218+/-.029 microg/mg protein vs.117+/-.011 microg/mg protein; p=0003). There was no significant difference in apoD expression between early-onset and late-onset Alzheimer's subjects. Apolipoprotein D expression levels were not correlated with apoE levels, nor were they correlated with inheritance of the APOE epsilon4 allele. CONCLUSIONS: These findings suggest that apoD may be related to the cognitive decline observed in AD patients and that apoD and apoE likely play different roles in the pathogenesis of AD.

Aged↗

PubMed2006

Enhancement of conditioned fear extinction by infusion of the GABA(A) agonist muscimol into the rat prefrontal cortex and amygdala.

In auditory fear conditioning, repeated presentation of the tone in the absence of the shock leads to extinction of the acquired fear response. Both the infra limbic prefrontal cortex (IL) and the basolateral amygdala (BLA) are involved in extinction. In this study, we examine the involvement of these two regions in extinction by manipulating the gamma-aminobutyric acid (GABA)ergic system, in the Sprague-Dawley rat. We microinfused a low dose of the GABA(A) agonist muscimol into the IL or BLA. Muscimol infused to IL before extinction training, but not after either a short (five-trials) or long (15-trials) extinction training, resulted in long-term facilitation of extinction. Infusion of muscimol to the BLA following a short (five-trial) extinction session facilitated extinction at least 48-h post-drug infusion. The differences in the temporal parameters of the effects of muscimol in the IL or BLA, suggest differential involvement of these structures in long-term extinction of fear memory. We propose a facilitating role for GABA(A) neurotransmission in the IL in triggering the onset of fear extinction and its maintenance, whereas in the BLA, GABA(A) neurotransmission facilitates extinction consolidation. The involvement of GABA(A) receptors in fear extinction in the prefrontal cortex and amygdala is of particular interest, because of the role of these areas in emotional processes, and the role of the GABA(A) receptors in anxiety states.

Acoustic Stimulation↗

PubMed2001

Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia.

BACKGROUND: Previously we proposed that dorsolateral prefrontal cortex (PFC) supports a specific working memory (WM) subcomponent: the ability to represent and maintain context information necessary to guide appropriate task behavior. By context, we mean prior task-relevant information represented in such a form that it supports selection of the appropriate behavioral response. Furthermore, we hypothesized that WM deficits in schizophrenia reflect impaired context processing due to a disturbance in dorsolateral PFC. We use functional magnetic resonance imaging to examine PFC activation in medication-naive, first-episode patients with schizophrenia during a WM, task-isolating context processing. METHODS: Fourteen first-episode, medication-naive patients with schizophrenia and 12 controls similar in age, sex, and parental education underwent functional magnetic resonance imaging during performance of an A-X version of the Continuous Performance Test. RESULTS: Patients with schizophrenia demonstrated deficits in dorsolateral PFC activation in task conditions requiring context processing but showed intact activation of posterior and inferior PFC. In addition, patients demonstrated intact activation of the primary motor and somatosensory cortex in response to stimulus processing demands. CONCLUSIONS: These results demonstrate selectivity in dorsolateral PFC dysfunction among medication-naive first-episode patients with schizophrenia, suggesting that a specific deficit in PFC function is present at illness onset, prior to the administration of medication or the most confounding effects of illness duration. Furthermore, these results are consistent with the hypothesis that WM deficits in patients with schizophrenia reflect an impairment in context processing due to a disturbance in dorsolateral PFC function.

Adult↗

PubMed2004

Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in elderly depressed patients: an MRI-based parcellation of the prefrontal cortex.

OBJECTIVE: To examine structural abnormalities in subregions of the prefrontal cortex in elderly patients with depression, the authors explored differences in gray matter, white matter, and CSF volumes by applying a parcellation method based on magnetic resonance imaging (MRI). METHOD: Twenty-four elderly patients with major depression and 19 group-matched comparison subjects were studied with high-resolution MRI. Cortical surface extraction, tissue segmentation, and cortical parcellation methods were applied to obtain volume measures of gray matter, white matter, and CSF in seven prefrontal subregions: the anterior cingulate, gyrus rectus, orbitofrontal cortex, precentral gyrus, superior frontal cortex, middle frontal cortex, and inferior frontal cortex. RESULTS: Highly significant bilateral volume reductions in gray matter were observed in the anterior cingulate, the gyrus rectus, and the orbitofrontal cortex. Depressed patients also exhibited significant bilateral white matter volume reductions and significant CSF volume increases in the anterior cingulate and the gyrus rectus. Finally, the depressed group showed significant CSF volume reductions in the orbitofrontal cortex relative to the comparison subjects. None of the other regions examined revealed significant structural abnormalities. CONCLUSIONS: The prominent bilateral gray matter deficits in the anterior cingulate and the gyrus rectus as well as the orbitofrontal cortex may reflect disease-specific modifications of elderly depression. The differential pattern of abnormalities detected in the white matter and CSF compartments imply that distinct etiopathological mechanisms might underlie the structural cortical changes in these regions.

Aged↗

PubMed1990

Amygdalar interaction with the mediodorsal nucleus of the thalamus and the ventromedial prefrontal cortex in stimulus-reward associative learning in the monkey.

Cynomolgus monkeys (Macaca fascicularis) were assessed for their ability to associate visual stimuli with food reward. They learned a series of new 2-choice visual discriminations between colored patterns displayed on a monitor screen. The feedback for correct choice was the delivery of food. In order to promote associative learning between the visual stimuli and the incentive value of the food reward, reward delivery was not accompanied by any distinctive visual feedback on the display screen. The rate of learning new problems was assessed before and after surgery in a total of 16 monkeys. Three groups of 3 monkeys received bilaterally symmetrical ablations in either the amygdala, the mediodorsal nucleus of the thalamus, or the ventromedial prefrontal cortex. All these groups showed a severe postoperative learning impairment. Seven other animals were given a unilateral ablation in 1 of those 3 structures and a second unilateral ablation, in each case contralateral to and different from the first, in order to produce 2 groups in which a putative amygdalo-thalamo-prefrontal pathway had been disconnected by crossed unilateral lesions. One disconnection group had lesions in the amygdala and ventromedial prefrontal cortex; the other had lesions in the amygdala and the mediodorsal nucleus of the thalamus. The disconnection groups showed a significant impairment, but the effect of the disconnection surgeries was significantly milder than the effect of any of the 3 bilaterally symmetrical lesions. Therefore, symmetrical bilateral lesions in either the amygdala, the mediodorsal nucleus, or the ventromedial prefrontal cortex produce similar impairments in the present task, implying that these structures are functionally related to each other; but the relatively mild effect of disconnecting these structures from each other argues against the hypothesis that they are serial stages in a single, tightly linked functional pathway.

Amygdala↗

PubMed1999

Ovarian hormones differentially influence immunoreactivity for dopamine beta- hydroxylase, choline acetyltransferase, and serotonin in the dorsolateral prefrontal cortex of adult rhesus monkeys.

Recent studies have shown that ovariectomy reduces, and subsequent hormone replacement restores the density of axons immunoreactive for tyrosine hydroxylase in the dorsolateral prefrontal cortex of adult female rhesus monkeys. The present study indicates that three additional extrathalamic frontal lobe afferents are also sensitive to changes in the ovarian hormone environment. Specifically, the combination of hormone manipulation with qualitative and quantitative analysis of immunocytochemistry for dopamine beta-hydroxylase, choline acetyltransferase, and serotonin in the primate prefrontal cortex revealed quantitative responses in both cholinergic and monoaminergic axons to changing ovarian hormone levels. However, whereas ovariectomy produced a modest net decrease in the density of fibers immunoreactive for choline acetyltransferase, this same treatment markedly increased the density of axons immunoreactive for dopamine beta-hydroxylase and for serotonin. Further, the effects of ovariectomy on these afferent systems were differentially attenuated by estrogen verses estrogen plus progesterone hormone replacement. Estrogen was as effective as estrogen plus progesterone in stimulating normal prefrontal immunoreactivity for choline acetyltransferase and dopamine beta-hydroxylase. The dual replacement of estrogen plus progesterone, however, was a much more potent influence than estrogen alone for serotonin immunoreactivity. Thus, ovarian hormones appear to provide stimulation that differentially affects each of four chemically identified extrathalamic prefrontal afferent systems examined to date, and may have roles in maintaining the normal balance and functional interactions between these neurotransmitter systems.

Acetylcholine↗

PubMed1986

Prefrontal cortex excitability in early postnatally malnourished rats.

The effect of early postnatal malnutrition on the responsiveness of the rat prefrontal cortex was studied by determining excitability thresholds and fatigability to direct cortical stimulation. Malnutrition imposed during the period of rapid brain growth caused a significant increase of cortical chronaxie values as well as increased fatigability of direct cortical responses, indicating a detrimental effect on the axodendritic synapses. Since the prefrontal cortex plays an important role in the temporal organization of behavior, a dysfunction of this cortical area could be a causal link between nutritional and behavioral deficits.

Animal Population Groups↗

PubMed2005

Electrophysiological correlates of reward prediction error recorded in the human prefrontal cortex.

Lesion and functional imaging studies have shown that the ventromedial prefrontal cortex is critically involved in the avoidance of risky choices. However, detailed descriptions of the mechanisms that underlie the establishment of such behaviors remain elusive, due in part to the spatial and temporal limitations of available research techniques. We investigated this issue by recording directly from prefrontal depth electrodes in a rare neurosurgical patient while he performed the Iowa Gambling Task, and we concurrently measured behavioral, autonomic, and electrophysiological responses. We found a robust alpha-band component of event-related potentials that reflected the mismatch between expected outcomes and actual outcomes in the task, correlating closely with the reward-related error obtained from a reinforcement learning model of the patient's choice behavior. The finding implicates this brain region in the acquisition of choice bias by means of a continuous updating of expectations about reward and punishment.

Choice Behavior↗