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PubMed1997

Single neuronal responses in medial prefrontal cortex during cocaine self-administration in freely moving rats.

Chronic single neuronal recording techniques were applied to investigate the involvement of the medial prefrontal cortex (mPFC) during cocaine self-administration in the rat. Rats were trained to press a lever for cocaine under continuous reinforcement and fixed ratio schedules. Different patterns of phasic neuronal activity changes were found to be associated with lever-pressing for cocaine. The neuronal responses could be classified into five categories: 1) increases in neuronal firing before the lever press (15 out of 121 neurons, 12.4%); 2) decreases in neuronal firing before the lever press (13 neurons, 10.7%); 3) increases in neuronal firing after cocaine infusion (4 neurons, 3.3%); 4) decreases in neuronal firing after cocaine infusion (32 neurons, 26.4%); and 5) no alteration of neuronal activity throughout the self-administration session (67 neurons, 55.4%). The anticipatory responses, i.e., neuronal activity appearing before the lever press, were observed for both the continuous reinforcement and fixed ratio schedules. In a few cases, alteration of firing rate was not observed for the first lever press but appeared before subsequent lever presses in fixed ratio schedules. Eliminating cocaine abolished the inhibitory neuronal responses observed after lever press, suggesting that these inhibitory responses after cocaine self-administration were attributable to the pharmacologic effect of cocaine. The data provide initial electrophysiological evidence that the mPFC may play a role in mediating the task sequencing which leads to cocaine self-administration.

Animals↗

PubMed2003

Excitotoxic lesions of the medial prefrontal cortex attenuate fear responses in the elevated-plus maze, social interaction and shock probe burying tests.

Previous research investigating the effects of medial prefrontal cortex (MPFC) lesions on fear- and anxiety-related behavior has yielded an inconsistent body of findings. Behavioral studies have reported increases, decreases, and no effect on anxiety. In addition, many studies are complicated by the use of lesioning techniques that destroy fibers of passage, and the use of conditioned fear tests, which may introduce the confounding effects of learning and memory. Therefore, the present study examined the effects of ibotenic acid lesions of the MPFC (including prelimbic, infralimbic and anterior cingulate) on three wide-ranging and well-validated behavioral assays of anxiety: the elevated plus maze (EPM), social interaction (SI) and the shock-probe tests (SP). In the EPM test, lesioned rats showed a significantly higher percentage of open arm entries and open arm time than controls. In a version of the SI test sensitive to anxiolytic effects, lesioned rats were found to spend a significantly greater amount of time in active interaction with a conspecific; while another version of the SI test sensitive to anxiogenic effects did not show any differences between lesioned and non-lesioned controls. In the SP test, lesioned rats exhibited significantly lower rates of burying. In contrast, retention of shock probe avoidance was not affected. No effects of lesions on measures of locomotor activity or shock reactivity were found. The concordant anxiolytic-like effects found in the three behavioral assays strongly suggests a general reduction in fear responsiveness in MPFC lesioned rats.

Animals↗

PubMed2001

Multiple effects of dopamine on layer V pyramidal cell excitability in rat prefrontal cortex.

The mechanisms underlying the inhibitory effects of dopamine (DA) on layer V pyramidal neuron excitability in the prelimbic region of the rat medial prefrontal cortex were investigated. Under control conditions, DA depressed both action potential generation (driven by somatic current injection) and input resistance (R(N)). The presence of GABA(A) receptor antagonists blocked DA-induced depression of action potential generation and revealed a delayed increase in excitability that persisted for the duration of experimental recording, up to 20 min following the washout of DA. In contrast to spike generation, disinhibition did not affect the transient depression of R(N) produced by DA, suggesting independent actions of DA on spike generation and R(N). Consistent with the hypothesis that DA acts to decrease pyramidal cell output via a GABAergic mechanism, DA increased the frequency of spontaneous inhibitory postsynaptic currents in both the absence and presence of TTX. Furthermore focal application of GABA to a perisomatic region mimicked the inhibitory effect of DA on spike production without affecting R(N). Focal application of bicuculline to the same location reversed the inhibitory effect of bath-applied DA on spike generation, while again having no effect on R(N). The depression of R(N) by DA was both occluded and mimicked by the Na(+) channel blocker TTX, suggesting the involvement of a Na(+) conductance in reducing pyramidal cell R(N) during the acute presence of DA. Together these data demonstrate that the acute presence of DA decreases pyramidal neuron excitability by two independent mechanisms. At the same time DA triggers a delayed and longer-lasting increase in excitability that is partially masked by synaptic inhibition.

Action Potentials↗

PubMed1997

Neuronal responses in prefrontal cortex and nucleus accumbens during heroin self-administration in freely moving rats.

Chronic multi-channel single unit recordings of neuronal responses in prefrontal cortex (PFC) and nucleus accumbens (NAc) were made in 9 male Sprague Dawley rats to determine patterns of neuronal activity during heroin self-administration. Up to 32 neurons were recorded simultaneously in these two brain regions while rats lever pressed on a continuous reinforcement schedule for intravenous infusion of heroin (30 microg/kg/infusion). The variety of neuronal responses observed before and after each self-administered heroin infusion can be classified according to the following categories: (1) neurons that increased or (2) decreased their activity immediately before the lever press; (3) neurons that increased or (4) decreased their activity after the heroin infusion; and, (5) neurons that did not alter their activity either before or after the lever press for heroin infusion. The majority (69% in the PFC and 65% in the NAc) of neurons sampled fell into this last category of no change, indicating that a selected fraction becomes active during this specific task. In general, NAc neurons displayed more post-heroin responses than PFC neurons while the proportion of neurons showing responses before the lever press was similar in the mPFC and the NAc. This initial description of the responses of PFC and NAc neurons during heroin self-administration suggests that the neuronal circuit of the mesocorticolimbic system is involved in heroin self-administration. This circuit appears to contribute both to the initiation of drug-seeking behavior (pre-lever press phasic neuronal responses), as well as the action of heroin infusion itself (post-infusion phasic neuronal responses) by activation of different subsets of neurons.

Analysis of Variance↗

PubMed2001

Voltage-gated sodium channels shape subthreshold EPSPs in layer 5 pyramidal neurons from rat prefrontal cortex.

The role of voltage-dependent channels in shaping subthreshold excitatory postsynaptic potentials (EPSPs) in neocortical layer 5 pyramidal neurons from rat medial prefrontal cortex (PFC) was investigated using patch-clamp recordings from visually identified neurons in brain slices. Small-amplitude EPSPs evoked by stimulation of superficial layers were not affected by the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonopentanoic acid but were abolished by the AMPA receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione, suggesting that they were primarily mediated by AMPA receptors. AMPA receptor-mediated EPSPs (AMPA-EPSPs) evoked in the apical dendrites were markedly enhanced, or increased in peak and duration, at depolarized holding potentials. Enhancement of AMPA-EPSPs was reduced by loading the cells with lidocaine N-ethylbromide (QX-314) and by local application of the Na(+) channel blocker tetrodotoxin (TTX) to the soma but not to the middle/proximal apical dendrite. In contrast, blockade of Ca(2+) channels by co-application of Cd(2+) and Ni(2+) to the soma or apical dendrite did not affect the AMPA-EPSPs. Like single EPSPs, EPSP trains were shaped by Na(+) but not Ca(2+) channels. EPSPs simulated by injecting synaptic-like current into proximal/middle apical dendrite (simEPSPs) were enhanced at depolarized holding potentials similarly to AMPA-EPSPs. Extensive blockade of Ca(2+) channels by bath application of the Cd(2+) and Ni(2+) mixture had no effects on simEPSPs, whereas bath-applied TTX removed the depolarization-dependent EPSP amplification. Inhibition of K(+) currents by 4-aminopyridine (4-AP) and TEA increased the TTX-sensitive EPSP amplification. Moreover, strong inhibition of K(+) currents by high concentrations of 4-AP and TEA revealed a contribution of Ca(2+) channels to EPSPs that, however, seemed to be dependent on Na(+) channel activation. Our results indicate that in layer 5 pyramidal neurons from PFC, Na(+), and K(+) voltage-gated channels shape EPSPs within the voltage range that is subthreshold for somatic action potentials.

2-Amino-5-phosphonovalerate↗

PubMed1993

Psychological stress increases serotonin release in the rat amygdala and prefrontal cortex assessed by in vivo microdialysis.

The effects of psychological stress on serotonin (5-HT) release were studied in the basolateral amygdaloid nucleus and the prefrontal cortex in conscious rats with in vivo microdialysis. Psychological stress, wherein emotional factors were predominantly involved, significantly increased extracellular 5-HT levels in these two areas. These findings suggest that activation of serotonergic neurons in these brain regions is involved in the emotional and/or cognitive states in animals.

Acoustic Stimulation↗

PubMed2002

Asymmetries of prefrontal cortex in human episodic memory: effects of transcranial magnetic stimulation on learning abstract patterns.

Functional neuroimaging suggests asymmetries of memory encoding and retrieval in the prefrontal lobes, but different hypotheses have been presented concerning the nature of prefrontal hemispheric specialization. We studied an associative memory task involving pairs of Kanji (Chinese) pictographs and unfamiliar abstract patterns. Subjects were ten Japanese adults fluent in Kanji, so only the abstract patterns represented novel material. During encoding, transcranial magnetic stimulation (TMS) was applied over the left and right dorsolateral prefrontal cortex (DLPFC). A significant (P<0.05) reduction in subsequent recall of new associations was seen only with TMS over the right DLPFC. This result suggests that the right DLPFC contributes to encoding of visual-object associations, and is consistent with a material-specific rather than a process-specific model of mnemonic function in DLPFC.

Adult↗

PubMed1995

In vivo stimulated dopamine release in the nucleus accumbens: modulation by the prefrontal cortex.

In vivo voltammetry was used to measure stimulated dopamine (DA) release in the nucleus accumbens following 6-hydroxydopamine (6-OHDA) lesions of the medial prefrontal cortex (PFC). Lesions of the PFC resulted in a significant potentiation of K(+)-stimulated DA release (383% of control). These data are in agreement with other studies which suggest DAergic activation of cortical sites can alter the activity of DAergic neurons at subcortical sites. Specifically these results suggest that DAergic nerve terminals in the nucleus accumbens are tonically inhibited by DAergic activity in the PFC and that alleviation of this tonic inhibition produces hyperresponsiveness in the nucleus accumbens.

Animals↗

PubMed2001

Evidence for the involvement of the ventro-medial prefrontal cortex in a short-term storage of visual images.

The purpose of this study was to clarify the role of the ventro-medial prefrontal cortex in short-term visual memory. Patients with focal lesions to the right gyrus rectus were impaired on a size judgement task, which required short-term retention of laterally presented visual patterns. The impairment was most evident when the stimuli were addressed to the damaged hemisphere (left visual field presentations) and when separated by very short (50-500 ms) intervals. The findings suggest that the ventro-medial part of the orbitofrontal cortex, like the ventro-lateral part, is involved in short-term storage of icon-like representations of visual objects, and also that there exists a right-hemispheric specialization for that function. Our study presents the first direct evidence of such specific memory effects in humans using a lesion method and points to the importance of the right gyrus rectus area in maintaining the representation of stimuli after they are removed from view.

Analysis of Variance↗

PubMed1994

Preferential activation of dopamine overflow in prefrontal cortex produced by chronic clozapine treatment.

The effect of chronic treatment with clozapine on extracellular dopamine levels in the rat striatum, nucleus accumbens and medial prefrontal cortex (mPFC) was examined using intracerebral microdialysis. Clozapine (20 mg/kg/day x 21 days in drinking water) increased basal dopamine release in the mPFC but had no effect in the striatum or nucleus accumbens. After chronic treatment, an acute dose of clozapine (20 mg/kg i.p.) produced large and long-lasting increases in extracellular dopamine in all three brain regions. The data suggest that chronic clozapine produces a sustained enhancement in dopaminergic tone in the mPFC.

Animals↗

PubMed2002

The prefrontal cortex: categories, concepts and cognition.

The ability to generalize behaviour-guiding principles and concepts from experience is key to intelligent, goal-directed behaviour. It allows us to deal efficiently with a complex world and to adapt readily to novel situations. We review evidence that the prefrontal cortex-the cortical area that reaches its greatest elaboration in primates-plays a central part in acquiring and representing this information. The prefrontal cortex receives highly processed information from all major forebrain systems, and neurophysiological studies suggest that it synthesizes this into representations of learned task contingencies, concepts and task rules. In short, the prefrontal cortex seems to underlie our internal representations of the 'rules of the game'. This may provide the necessary foundation for the complex behaviour of primates, in whom this structure is most elaborate.

Animals↗

PubMed1997

Pharmacologically induced neural plasticity in the prefrontal cortex of adult gerbils (Meriones unguiculatus).

Using a selective antibody serum against glutaraldehyde-conjugated gamma-aminobutyric acid (GABA), GABAergic neurons were identified in the medial prefrontal cortex of young adult gerbils (Meriones unguiculatus) following a single non-invasive dose of methamphetamine (25 mg/kg i.p.) applied at the age of 90 days. GABA-immunoreactive profiles were electron microscopically counted in a defined test field (0.875 mm2) covering the prefrontal prelimbic area after a single dose of either methamphetamine or saline. Within 30 days following the drug challenge the density of GABAergic innervation significantly increased by about 20%. Several lines of previous investigation indicate that a single dose of methamphetamine is an appropriate stimulus to cause selective autotoxic destruction of certain prefrontal dopamine fibres due to drug-induced hyperactivation. There is further indication of postsynaptic and transneuronal neuroplasticity since the densities of dendritic spines on prefrontal pyramidal cells went through a significant sequence of post-drug gain and loss. These structural dynamics resemble typical alterations seen after classical mechanical or chemical lesioning in other regions of the brain. The present results on drug-induced reactive neuroplasticity are discussed together with the current understanding of stimulus-induced adaptive reorganization in the mammalian central nervous system.

Animals↗

PubMed1999

Dopamine and noradrenaline release in the prefrontal cortex of rats during classical aversive and appetitive conditioning to a contextual stimulus: interference by novelty effects.

Extracellular dopamine and noradrenaline concentrations in the medial prefrontal cortex were determined using online microdialysis in freely moving rats during classical appetitive or aversive conditioning to a contextual conditioned stimulus (CS). As CS we used placement in a Skinner box where either foot shocks or food pellets were delivered as unconditioned stimuli. In the aversive conditioning group we observed a conditioned increase in noradrenaline, but not in dopamine release, upon a final exposure to CS-alone. Other conditioned effects were possibly masked by the continued presence of novelty and handling effects of the transfer to the Skinner box.

Animals↗

PubMed2006

Dynamical basis of irregular spiking in NMDA-driven prefrontal cortex neurons.

Slow N-Methyl-D-aspartic acid (NMDA) synaptic currents are assumed to strongly contribute to the persistently elevated firing rates observed in prefrontal cortex (PFC) during working memory. During persistent activity, spiking of many neurons is highly irregular. Here we report that highly irregular firing can be induced through a combination of NMDA- and dopamine D1 receptor agonists applied to adult PFC neurons in vitro. The highest interspike-interval (ISI) variability occurred in a transition regime where the subthreshold membrane potential distribution shifts from mono- to bimodality, while neurons with clearly mono- or bimodal distributions fired much more regularly. Predictability within irregular ISI series was significantly higher than expected from a noise-driven linear process, indicating that it might best be described through complex (potentially chaotic) nonlinear deterministic processes. Accordingly, the phenomena observed in vitro could be reproduced in purely deterministic biophysical model neurons. High spiking irregularity in these models emerged within a chaotic, close-to-bifurcation regime characterized by a shift of the membrane potential distribution from mono- to bimodality and by similar ISI return maps as observed in vitro. The nonlinearity of NMDA conductances was crucial for inducing this regime. NMDA-induced irregular dynamics may have important implications for computational processes during working memory and neural coding.

Action Potentials↗

PubMed2006

Fine-tuning of awake prefrontal cortex neurons by clozapine: comparison with haloperidol and N-desmethylclozapine.

BACKGROUND: Mechanisms underlying clozapine's better clinical efficacy in schizophrenia remain poorly understood. The prefrontal cortex (PFC) has been implicated as a primary site for the therapeutic effects of clozapine; however, evidence for how clozapine influences the activity of PFC neurons in behaviorally relevant contexts is lacking. METHODS: Ensemble single unit recording in awake rats was used to measure the activity of PFC neurons in response to clozapine, its main metabolite N-desmethylclozapine (DMClz), and the typical antipsychotic drug haloperidol during baseline conditions and after treatment with the N-methyl-D-aspartate antagonist MK801. Behavioral stereotypy was scored during recording. RESULTS: Clozapine and DMClz but not haloperidol had an activity-dependent influence on spontaneous firing rate of PFC cells: they increased the activity of neurons with low baseline firing rates and decreased the activity of neurons with higher firing rates. Clozapine and DMClz but not haloperidol also reversed the effect of MK801 on PFC neuronal firing. This reversal was strongly correlated with blockade of MK801-induced behavioral stereotypy. CONCLUSIONS: These findings indicate that clozapine has the capacity to fine-tune spontaneous and disrupted activity of PFC neurons. This effect might contribute, in part, to the therapeutic efficacy of clozapine in schizophrenia.

Action Potentials↗

PubMed2006

The influence of rTMS over the right dorsolateral prefrontal cortex on top-down attentional processes.

Repetitive Transcranial Magnetic Stimulation (rTMS) provides a unique opportunity to study causal relationships between activity in the dorsolateral prefrontal cortex (DLPFC) and executive functioning, by modulating brain activity in SHAM controlled designs. We devised a new Stroop task paradigm in which subjects must engage in both strategic and automatic attentional processes. In the current experiment, we manipulated subjects' expectancies for incongruent stimuli. Previous research demonstrated that when subjects have a high level of expectancy that a stimulus will be incongruent, they are able to strategically adjust the relative influence of word reading on color naming. The effect of high frequency (HF) rTMS on Stroop performance of 20 right-handed healthy female volunteers was tested using a double blind within subjects design by counterbalanced crossover sham (placebo) and active rTMS over the right DLPFC. Since mood remained unchanged after rTMS, the Stroop data could be evaluated independent of mood changes. Only in the high expectancy condition, we found a decreased response time to both congruent and incongruent trials on the Stroop task performance after HF rTMS. The SHAM placebo condition yielded no effects. We conclude that high frequency stimulation over the right DLPFC has an effect on top-down attentional processes by modulating the attentional set.

Adolescent↗

PubMed2004

Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex.

The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene affects activity of the enzyme and influences performance and efficiency of the prefrontal cortex (PFC); however, although catecholaminergic neurotransmission is implicated, the underlying mechanisms remain elusive because studies of the role of COMT in PFC function are sparse. This study investigated the effect of tolcapone, a brain-penetrant COMT inhibitor, on a rat model of attentional set shifting, which is dependent on catecholamines and the medial PFC (mPFC). Additionally, we investigated the effect of tolcapone on extracellular catecholamines in the mPFC using microdialysis in awake rats. Tolcapone significantly and specifically improved extradimensional (ED) set shifting. Tolcapone did not affect basal extracellular catecholamines, but significantly potentiated the increase in extracellular dopamine (DA) elicited by either local administration of the depolarizing agent potassium chloride or systemic administration of the antipsychotic agent clozapine. Although extracellular norepinephrine (NE) was also elevated by local depolarization and clozapine, the increase was not enhanced by tolcapone. We conclude that COMT activity specifically affects ED set shifting and is a significant modulator of mPFC DA but not NE under conditions of increased catecholaminergic transmission. These data suggest that the links between COMT activity and PFC function can be modeled in rats and may be specifically mediated by DA. The interaction between clozapine and tolcapone may have implications for the treatment of schizophrenia.

Animals↗

PubMed2002

Glia pathology in the prefrontal cortex in alcohol dependence with and without depressive symptoms.

BACKGROUND: Reductions in glial density and enlargement of glial nuclei have been reported in the dorsolateral prefrontal cortex (dlPFC) in mood disorders. In alcohol dependence, often comorbid with depression, it is unclear whether there are changes in the density and size of glial cells in the dlPFC. METHODS: The packing density and size of Nissl-stained glial cell nuclei were analyzed postmortem in the cortical layers of the dlPFC from 21 control and 17 alcohol-dependent (Alc) subjects without Wernicke or Korsakoff syndromes. Eight Alc subjects had depressive symptoms. The density of glial cells was measured with a three-dimensional cell counting method, and the areal fraction of glial fibrillary acidic protein immunoreactivity (GFAP) was also determined. RESULTS: Glial density was reduced by 11-14% in layers V and VI and in all layers combined in the Alc group. The size of glial nuclei was decreased by 3.2% in Alc subjects. The Alc subjects with depressive symptoms showed the lowest values of density and size. There was no difference in GFAP immunoreactivity, although the lowest values were in the Alc group. CONCLUSIONS: Alcohol dependence is characterized by decreases in both density and size of glia in the dlPFC. Glial pathology may be more severe in Alc subjects with depressive symptoms.

Adolescent↗