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PubMed2001

Recent cytoarchitechtonic changes in the prefrontal cortex of schizophrenics.

A variety of lines of converging evidence implicate the prefrontal cortex (PFC) in schizophrenia. In the past studies have focused on the various neurotransmitter systems that appear to be involved in schizophrenia such as dopamine, glutamate and serotonin. Recently, the focus of research has shifted away from systems and towards cellular morphology due partly to studies suggesting an increase in neural density in various regions of the PFC (1,2). A plethora of research has come out suggesting possible cytoarchitectural changes in pyramidal cells in the prefrontal cortex as well as alterations of certain GABAergic cells. This review examines the recent data that shows cytoarchitechtonic changes in cells of the prefrontal cortex.

Humans↗

PubMed1996

Enkephalin terminals form inhibitory-type synapses on neurons in the rat nucleus locus coeruleus that project to the medial prefrontal cortex.

Norepinephrine-containing fibres in the medial prefrontal cortex derive from the locus coeruleus, a brainstem nucleus which also receives a dense innervation of enkephalin-immunoreactive axon terminals. We combined immunogold-silver labelling of retrogradely transported FluoroGold from the medial prefrontal cortex with immunoperoxidase detection of leucine5-enkephalin in the same section of tissue through the locus coeruleus of adult rats. This dual-labelling experiment was conducted to determine whether axon terminals containing lecuine5-enkephalin target neurons in the locus coeruleus that project to the frontal cortex and, if so, what are their morphological characteristics. By light microscopy, enkephalin-labelled processes overlapped FluoroGold retrogradely labelled neurons in the locus coeruleus. By electron microscopy, retrogradely labelled perikarya and dendrites were commonly enveloped by astrocytic processes and received few afferents in the plane of section examined. However, at sites unoccupied by glial processes, abundant afferent input could be identified. In addition, some FluoroGold-labelled perikarya and dendrites lacked this glial ensheathment but were more frequently apposed by axon terminals. Of 163 FluoroGold-labelled perikarya and dendrites examined where enkephalin immunoreactivity was present in the neuropil, 42% were contacted by enkephalin-immunoreactive axon terminals. The peroxidase-labelled enkephalin terminals as well as the unlabelled terminals often contained both small, clear and large dense core vesicles. Both labelled and unlabelled terminals also formed primary symmetric synapses characteristic of inhibitory transmitters with retrogradely labelled perikarya and proximal dendrites. At times, more than one enkephalin-labelled terminal was found to converge on a common retrogradely labelled perikarya or dendrite. These results demonstrate cellular sites where enkephalin-containing afferents may directly modulate and most likely inhibit the activity of cortically projecting neurons in the locus coeruleus.

Animals↗

PubMed2002

Reduced N-acetylaspartate in prefrontal cortex of adult rats with neonatal hippocampal damage.

Previous studies in animals suggested that neonatal lesions of the ventral hippocampus disrupt development of prefrontal cortex and its regulation of dopaminergic activity. In the present study, we assayed an in vivo chemical marker of neuronal integrity (proton magnetic resonance spectroscopy signal of N-acetylaspartate, NAA) in prefrontal cortex and striatum of rats with neonatal excitotoxic lesions of the ventral hippocampus. We also measured in post-mortem tissue expression of EAAC1 mRNA, a molecular marker of intrinsic neurons. In the cohort studied at juvenile age and again at young adulthood [postnatal day (PD) 37 and 71], we found selective reductions of NAA in the prefrontal cortex only at PD 71. Emergence of neuronal pathology was temporally associated with emergence of amphetamine-induced hyperlocomotion. Reduced prefrontal NAA was confirmed in the second cohort studied at an older age (PD 120). Expression of EAAC1 mRNA was significantly reduced in prefrontal cortex of the lesioned rats. No changes in NAA were found in the striatum in either cohort and cortical area size was not changed. These results suggest that early ventral hippocampal lesions produce developmental neuronal pathology in prefrontal cortex that is temporally associated with dysregulation of dopamine behaviors and is reminiscent of the temporal profile of the onset of schizophrenia.

Age Factors↗

PubMed2002

Appetitive instrumental learning requires coincident activation of NMDA and dopamine D1 receptors within the medial prefrontal cortex.

Through its complex role in cognition, memory, and emotion, the mammalian prefrontal cortex is thought to contribute to the organization of adaptive behavioral actions. In the present studies we examined the role of dopaminergic D1 and glutamatergic NMDA receptors within the prefrontal cortex of the rat during the development of adaptive instrumental learning. Hungry rats with bilateral indwelling cannulas aimed at the medial prefrontal cortex were trained to lever-press for food. Infusion of the selective D1 antagonist SCH-23390 (0.15, 0.3, 3.0 nmol) dose-dependently impaired acquisition of this behavior. Higher doses also impaired expression of this task. Co-infusion of the lowest dose of SCH 23390 with a low dose of the NMDA antagonist AP-5 (0.5 nmol), each of which had no effect on learning when infused alone, potently reduced the ability to acquire the response. Inhibition of intracellular protein kinase A with the selective PKA inhibitor Rp-cAMPS also disrupted acquisition, suggesting that PKA is an intracellular substrate for a D1-NMDA receptor interaction. In control experiments, drug infusions that impaired learning did not affect food intake or locomotion, suggesting a specific effect on learning. We hypothesize that coincident detection of D1-NMDA receptor activation and its transcriptional consequences, within multiple sites of a distributed corticostriatal network, may represent a conserved molecular mechanism for instrumental learning.

2-Amino-5-phosphonovalerate↗

PubMed2002

The prefrontal cortex in sleep.

Experimental data indicate a role for the prefrontal cortex in mediating normal sleep physiology, dreaming and sleep-deprivation phenomena. During nonrandom-eye-movement (NREM) sleep, frontal cortical activity is characterized by the highest voltage and the slowest brain waves compared to other cortical regions. The differences between the self-awareness experienced in waking and its diminution in dreaming can be explained by deactivation of the dorsolateral prefrontal cortex during REM sleep. Here, we propose that this deactivation results from a direct inhibition of the dorsolateral prefrontal cortical neurons by acetylcholine, the release of which is enhanced during REM sleep. Sleep deprivation influences frontal executive functions in particular, which further emphasizes the sensitivity of the prefrontal cortex to sleep.

Journal Article↗

PubMed1996

Is prefrontal cortex involved in cued recall? A neuropsychological test of PET findings.

Positron emission tomography (PET) experiments have detected blood flow activations in right anterior prefrontal cortex during performance of a word stem cued recall task [3, 38]. Based on findings from a variety of PET studies, the "hemispheric encoding/retrieval asymmetry model" [44] was proposed to explain the role of the frontal lobes in episodic memory. This model asserts that left prefrontal cortex is preferentially involved in the encoding of new information into episodic memory, whereas right prefrontal cortex is more involved in episodic memory retrieval. As a neuropsychological test of this hypothesis, a group of frontal patients with lesions in areas 6, 8, 9, 10, 44, 45 and/or 46 (11 left, five right) were run on word stem cued recall under two semantic study conditions. As a group, these patients were not significantly impaired in cued recall. In the first but not the second experiment, left frontal patients recalled fewer words than controls. Right frontal patients were not impaired on either list. Right prefrontal cortex could be activated by several strategic aspects of the cued recall paradigm that were minimized in the present experiment. Brain reorganization in the lesioned patients could also account for their intact performance. The regions of prefrontal cortex activated in PET studies of young controls are not necessary for patients to perform the task.

Adult↗

PubMed1996

The role of the dorsolateral prefrontal cortex in implicit procedural learning.

We studied the role of the dorsolateral prefrontal cortex in procedural learning. Normal subjects completed several blocks of a serial reaction time task using only one hand without or with concurrent non-invasive repetitive transcranial magnetic stimulation. To disrupt their function transiently, stimulation was applied at low intensity over the supplementary motor area or over the dorsolateral prefrontal cortex contralateral or ipsilateral to the hand used for the test. Stimulation to the contralateral dorsolateral prefrontal cortex markedly impaired procedural implicit learning, as documented by the lack of significant change in response times during the task. Stimulation over the other areas did not interfere with learning. These results support the notion of a critical role of contralateral dorsolateral prefrontal structures in learning of motor sequences.

Adult↗

PubMed1985

Extent and organization of opossum prefrontal cortex defined by anterograde and retrograde transport methods.

Prefrontal cortex is commonly defined as cortex which receives afferents from the thalamic mediodorsal nucleus (MD). The extent of opossum prefrontal cortex was mapped with anterograde and retrograde axonal transport methods. The prefrontal field was found to include not only cortex on the lateral convexity of the frontal lobe as reported in earlier studies, but, in addition, cortex within the rhinal fissure and cortex on the rostral medial wall of the hemisphere. The organization of the thalamic input to the medial wall was analyzed in some detail and compared with that of the rat. The reason for this emphasis stemmed from earlier observations which suggested that a lateral, nonolfactory segment of MD, prominent in the rat and other species, may not be present in opossum MD. In the rat, the lateral segment, which constitutes approximately one-third of MD, projects to a relatively large expanse of rostral medial cortex which is also projected upon by the anteromedial nucleus. The main projection field of the lateral one-third of opossum MD is to cortex on the lateral convexity of the frontal lobe which has no input from the anteromedial nucleus and has no counterpart in the rat. Only the most lateral edge of opossum MD projects to medial cortex, to a very small field, which is also projected upon by the anteromedial nucleus. In other respects, the organization of the rostral medial cortex is similar in rat and opossum. These results suggest that, rather than being absent, an equivalent of a nonolfactory segment may be present in opossum MD but is markedly reduced in size, compared to that in rat and other species.

Animals↗

PubMed1978

Information about movements in monkeys (Macaca mulatta) with lesions of dorsal prefrontal cortex.

It is not known on what information prefrontal cortex acts. Since it has been suggested that it might operate on information about movements, rhesus monkeys were trained on a counting task testing memory for movements. They had to tap a key until a light went out and then repeat, either immediately or after a delay, the number of presses they had made. Monkeys with lesions of dorsal prefrontal cortex were impaired on this task, unlike monkeys with lesions of sulcus principalis alone. Cortex on the dorsal prefrontal convexity appears to act on information about movements.

Animals↗

PubMed1995

Effects of lesions of prefrontal cortex, amygdala, or fornix on behavioral sensitization to amphetamine: comparison with N-methyl-D-aspartate antagonists.

Behavioral sensitization to amphetamine involves the mesoaccumbens dopamine system and is accompanied by cellular changes in this system. Excitatory amino acid antagonists, when co-administered with amphetamine, prevent both behavioral sensitization and associated changes in the mesoaccumbens dopamine system. This suggests that excitatory amino acid-dependent events are critical to the initiation of sensitization. This study sought to identify excitatory amino acid projections required for sensitization, focusing on projections to the nucleus accumbens or ventral tegmental area. The major excitatory projections to the nucleus accumbens originate in the prefrontal cortex, amygdala and hippocampus. The prefrontal cortex and amygdala also send excitatory projections to the ventral tegmental area. Ibotenic acid lesions of the prefrontal cortex or amygdala and electrolytic lesions of the fornix were performed in rats. After one week of recovery, rats were treated with water or 2.5 mg/kg amphetamine for six days and challenged with amphetamine on day 8. Activity was tested in photobeam cages on days 1 and 8. On day 1, control and sham-lesioned rats exhibited stereotyped behaviors followed by a period of post-stereotypy locomotion. On day 8, sensitization was evident as an enhancement of both stereotypy and post-stereotypy locomotion. Co-administration of N-methyl-D-aspartate antagonists [MK-801 (dizocilpine maleate) or CGS 19755] with amphetamine prevented the development of sensitization of both stereotypy and post-stereotypy locomotion. Neither antagonist, however, prevented the expression of sensitization. None of the lesions completely mimicked these effects of N-methyl-D-aspartate antagonists. Lesions of hippocampal projections traveling in the fornix produced a general disinhibition of locomotor activity, but did not prevent sensitization of either stereotypy or post-stereotypy locomotion. Lesions of the prefrontal cortex failed to prevent sensitization of stereotypy was obtained following repeated amphetamine administration. However, like prefrontal cortical lesions, amygdala lesions prevented sensitization of post-stereotypy locomotion. When interpreted in the light of previous studies demonstrating the importance of the ventral tegmental area in the initiation of sensitization, the present results suggest a likely role for neuronal circuits involving the prefrontal cortex, amygdala and ventral tegmental area in the development of sensitization of post-stereotypy locomotion following repeated amphetamine administration. Such circuits may initiate sensitization through a mechanism involving excitatory amino acid regulation of the activity of mesoaccumbens dopamine neurons. Parallel circuits, involving other brain regions, may similarly contribute to sensitization of stereotyped behaviors.

Amphetamine↗

PubMed2003

Localized functional neurochemical marker abnormalities in dorsolateral prefrontal cortex in pediatric obsessive-compulsive disorder.

BACKGROUND: Neurobiological abnormalities in the prefrontal cortex have been implicated in the pathogenesis of obsessive-compulsive disorder (OCD). Although OCD commonly arises during childhood and adolescence, to our knowledge, no prior study has examined prefrontal cortex neurochemistry in pediatric patients with OCD. METHODS: A multislice spectroscopic imaging sequence with validated phantom replacement methodology was used to measure N-acetyl-aspartate (NAA), a putative neuronal marker; choline compounds (Cho); and creatine/phosphocreatine (Cr) in right and left dorsolateral prefrontal cortex (DLPFC) of 15 treatment-naïve OCD patients, 8-15 years of age, and 15 case-matched healthy comparison subjects. RESULTS: A significant increase (21% higher) in NAA was observed in left but not right DLPFC in OCD patients versus control subjects. No significant differences in Cho or Cr were observed between groups in left or right DLPFC. CONCLUSIONS: These results provide new evidence of localized functional neurochemical marker alterations in left DLPFC in pediatric OCD. Increased left DLPFC NAA may represent neuronal hypertrophy or hyperplasia, glial hypoplasia, and/or abnormal pruning of neural brain elements in DLPFC.

Adolescent↗

PubMed2003

Manipulation of dopamine d1-like receptor activation in the rat medial prefrontal cortex alters stress- and cocaine-induced reinstatement of conditioned place preference behavior.

These studies examined the ability of the dopamine D1-like agonist SKF 81297 and D1-like antagonist SCH 23390 in the medial prefrontal cortex to alter the reinstatement of cocaine-induced conditioned place preference behavior. Male Sprague-Dawley rats were fitted with bilateral cannulae over the medial prefrontal cortex and subsequently trained in a conditioned place preference task. Animals were trained in this task using four pairings of cocaine (12 mg/kg, i.p.). Conditioned place preference was demonstrated in all animals, and this behavior was then extinguished over a 5-10-day period before testing for reinstatement. Just prior to reinstatement by immobilization stress or a cocaine priming injection (5 mg/kg, i.p.), a microinjection of the D1-like receptor antagonist SCH 23390 (0.01, 0.1 or 1.0 microg/side), or the D1-like receptor agonist SKF 81297 (0.1, 0.3 or 1.0 microg/side) was given into the medial prefrontal cortex. SCH 23390 blocked both stress- and cocaine-induced reinstatement of conditioned place preference after the two higher doses were administered into the medial prefrontal cortex. The highest dose of SKF 81297 (1.0 microg/side) prevented immobilization stress- but not cocaine-induced reinstatement. The highest dose of these drugs given in the absence of stress or cocaine did not produce reinstatement. The results indicate that immobilization stress given within the place-preference chamber is capable of producing reinstatement of cocaine-seeking behavior. The microinjection studies suggest that D1-like receptor antagonism within the prefrontal cortex is sufficient to block reinstatement by stress and cocaine. Furthermore, the results from D1-like receptor activation in the medial prefrontal cortex point to utilization of different neural pathways for stress- and cocaine-induced reinstatement.

Animals↗

PubMed1993

SCH 23390 decreases self-stimulation of the medial prefrontal cortex in the rat.

We studied the effects of peripheral and central administration of SCH 23390, a selective antagonist of dopamine D1 receptors, on intracranial self-stimulation of the medial prefrontal cortex of the rat. Intraperitoneal injections of SCH 23390 produced a dose-related decrease in self-stimulation. Unilateral microinjections of SCH 23390 into the medial prefrontal cortex also produced a dose-related decrease in self-stimulation in the ipsilateral medial prefrontal cortex. However, self-stimulation of the contralateral, noninjected prefrontal cortex, used as control, was not affected. Together with previous data, the present results suggest that the dopamine neurotransmission involved in self-stimulation of the prefrontal cortex of the rat is mediated by dopamine D1 receptors.

Animals↗

PubMed2005

Chromatin alterations associated with down-regulated metabolic gene expression in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Schizophrenia is frequently accompanied by hypometabolism and altered gene expression in the prefrontal cortex. Cellular metabolism regulates chromatin structure, including covalent histone modifications, which are epigenetic regulators of gene expression. OBJECTIVE: To test the hypothesis that down-regulated metabolic gene expression is associated with histone modification changes in the prefrontal cortex of subjects with schizophrenia. DESIGN AND SUBJECTS: Histones and gene transcripts were profiled in the postmortem prefrontal cortex of 41 subjects with schizophrenia and 41 matched controls. The phosphorylation, acetylation, and methylation of 6 lysine, serine, and arginine residues of histones H3 and H4 were examined together with 16 metabolic gene transcripts using serial immunoblotting, immunohistochemical analysis, custom-made complementary DNA arrays, and quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS: Subjects with schizophrenia, as a group, showed no significant alterations in histone profiles or gene expression. In a subgroup of 8 patients with schizophrenia, levels of H3-(methyl)arginine 17, H3meR17, exceeded control values by 30%, and this was associated with the decreased expression of 4 metabolic transcripts. CONCLUSIONS: High levels of H3-(methyl)arginine 17 are associated with down-regulated metabolic gene expression in the prefrontal cortex of a subset of subjects with schizophrenia. Histone modifications may contribute to the pathogenesis of prefrontal dysfunction in schizophrenia.

Chromatin↗

PubMed1994

The induction of serotonin3-like receptor supersensitivity and dopamine receptor subsensitivity in the rat medial prefrontal cortex after the intraventricular administration of the neurotoxin 5,7-dihydroxytryptamine: a microiontophoretic study.

This study examines the effect of intraventricular administration of the neurotoxin 5,7-dihydroxytryptamine on serotonin1A, serotonin2 and serotonin3 receptors in the rat medial prefrontal cortex using in vivo extracellular single cell recording and iontophoresis. Iontophoresis of the serotonin1A, serotonin1C,2 and serotonin3 receptor agonists (+-)-8-hydroxy-(di-n-propyl)aminotetralin, (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane and 2-methylserotonin, respectively, produces a current-dependent (5-80 nA) suppression of the basal firing rate of medial prefrontal cortical cells in sham- and 5,7-dihydroxytryptamine-lesioned rats. The suppression produced by 2-methylserotonin and serotonin was significantly greater in 5,7-dihydroxytryptamine-lesioned rats than in control rats. No significant difference in the spontaneous activity of medial prefrontal cortex cells was observed between experimental and control rats after iontophoresis of (+-)-8-hydroxy-(di-n-propyl)aminotetralin or (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. There was no significant difference between the groups regarding the response of medial prefrontal cortex cells to the iontophoresis of GABA, whereas the response of medial prefrontal cortex cells to the iontophoresis of dopamine was significantly attenuated in animals pretreated with 5,7-dihydroxytryptamine compared to controls. Our results indicate that 5,7-dihydroxytryptamine-induced denervation selectively enhances the sensitivity of serotonin3-like receptors in the medial prefrontal cortex, which could, at least partially, account for the serotonin denervation supersensitivity. Moreover, the finding that the response of medial prefrontal cortical cells to the iontophoresis of dopamine is attenuated in 5,7-dihydroxytryptamine pretreated rats is consistent with the view that the inhibitory action of dopamine in the medial prefrontal cortex is dependent upon serotonin tone.

5,7-Dihydroxytryptamine↗

PubMed1993

Cocaine-sensitive and -insensitive dopamine uptake in prefrontal cortex, nucleus accumbens and striatum.

Behavioral studies have indicated that the reinforcing effects of cocaine are dependent on inhibition of dopamine uptake in nucleus accumbens and prefrontal cortex. As it has been suggested that dopamine uptake and cocaine-inhibition of dopamine uptake may differ in nucleus accumbens, prefrontal cortex and striatum, we have further characterized dopamine uptake and its susceptibility to inhibition in these three regions. Dopamine uptake was resolved into two processes, which accounts for some of the apparent reported regional differences in sensitivity of dopamine to inhibition by cocaine. One, which is probably associated with uptake into dopaminergic terminals, was sensitive to 6-hydroxydopamine lesions, cocaine, GBR 12909 or ouabain and was dependent on temperature and sodium ion concentration; this was responsible for most of the observed uptake in tissue from striatum and nucleus accumbens, but not from prefrontal cortex. There appeared to be no regional difference in susceptibility of this mode of dopamine uptake to either cocaine or GBR 12909. The other type of dopamine uptake, which represented a significant proportion of the total in prefrontal cortex, but not in striatum or nucleus accumbens, was relatively insensitive to cocaine, GBR 12909 and ouabain and was dependent on temperature, but not sodium ion concentration. In addition, the cocaine-insensitive dopamine uptake was more sensitive to inhibition by dopamine than serotonin, but did not distinguish between dopamine and norepinephrine. The occurrence of cocaine-sensitive dopamine uptake in all examined regions and its equal sensitivity to cocaine and GBR 12909 is consistent with the involvement of nucleus accumbens and/or prefrontal cortex in the reinforcing effects of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed2005

Effects of the metabotropic glutamate receptor agonist, ACPD, on the extracellular concentrations of GABA and acetylcholine in the prefrontal cortex of the rat during the normal process of aging.

The aim of the present study was to investigate the effects of activation of metabotropic glutamate receptors (mGluR) on the extracellular concentrations of GABA and acetylcholine in the prefrontal cortex of freely moving rats of different groups of age. Perfusion, through the microdialysis probe, of the agonist of mGluR, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD; 100, 500 and 1000 microM), in the prefrontal cortex of young rats produced a dose-related increase of the dialysate concentrations of GABA. The effects of perfusion of ACPD on the concentrations of GABA were attenuated in middle-aged rats. In the prefrontal cortex of aged rats, perfusion of ACPD produced no changes in dialysate concentrations of GABA at any of the doses used. Conversely, perfusion of ACPD (100, 500 and 1000 microM) in the prefrontal cortex of young, middle-aged and aged rats did not modify the dialysate concentrations of acetylcholine. Basal concentrations of acetylcholine in the prefrontal cortex of middle-aged and aged rats were significantly lower than those in young rats. In contrast, basal dialysate concentrations of GABA were not significantly different in young, middle-aged and aged rats. These results suggest that the interaction GABA-glutamate in the prefrontal cortex, mediated by mGluRs, changes with age.

Acetylcholine↗

PubMed1982

Organization of cortical afferents to the prefrontal cortex in the bush baby (Galago senegalensis).

Cortical afferents to the prefrontal cortex were studied in 10 bush babies (Galago senegalensis) by means of somatopetal transport of horseradish peroxidase. The lateral injections invariably labeled neurons in the temporal cortex and in most cases also in the insular and parietal regions. In some of these brains the cingulate and retrosplenial areas contained labeled perikarya. Injections into the medial cortex, on the other hand, consistently labeled cell bodies in the cingulate cortex, but not in the insular, temporal and parietal regions. When both lateral and medial sites of the bush baby's prefrontal cortex are considered together, apparently fewer cortical areas (as defined by Brodmann's cytoarchitectonic maps) project to the prefrontal cortex in the bush baby than in the rhesus monkey. This statement holds for both ipsi- and contralateral projections.

Afferent Pathways↗