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PubMed2006

A proteomics approach to identify long-term molecular changes in rat medial prefrontal cortex resulting from sucrose self-administration.

The medial prefrontal cortex (mPFC) is involved in the processing and retrieval of reward-related information. Here, we investigated long-lasting changes in protein composition of the mPFC in rats with a history of sucrose self-administration. Protein levels were analyzed using 2-D PAGE and MALDI-TOF sequencing. From approximately 1500 spots, 28 regulated proteins were unambiguously identified and were involved in cytoskeleton organization, energy metabolism, oxidative stress, neurotransmission, and neuronal outgrowth and differentiation. For several proteins, this change was also found as a long-lasting alteration in gene expression. We show that self-administration of sucrose produces long-lasting molecular neuroadaptations in the mPFC that may be involved in reward-related information processing.

Animals↗

PubMed2006

Apparent encoding of sequential context in rat medial prefrontal cortex is accounted for by behavioral variability.

Simple sequences can be represented via asymmetrically linked neural assemblies, provided that the elements of the sequence are unique. When elements repeat, however (e.g., A-B-C-B-A), the same element belongs to two separate "sequential contexts," and a more complex encoding mechanism is required. To enable correct sequence performance, some neural structure must provide a disambiguating signal that differentiates the two sequential contexts (i.e., B as an element of "A-B" as opposed to "C-B"). The disambiguating signal may derive from a form of working memory, or, in some cases, a simple timing mechanism may suffice. To investigate the possible role of medial prefrontal cortex in complex sequence encoding, rats were trained on a spatial sequence containing two adjacent repeated segments (e.g., A-B-C-D-B-C-E). The double-repeat procedure minimized behavioral differences in the second leg (C) of the repeat subsequence that arise in the first leg (B) because of differences in the entry point (e.g., A-B vs D-B). Far more cells were context sensitive along the first leg than along the second (36 vs 9%), and most of the differences were accounted for by systematic variations in the rat's trajectory, which were much larger along the first leg. There is thus little evidence for sequential context-discriminative activity in the medial prefrontal cortex that cannot plausibly be accounted for by context-dependent behavior. The finding that the rodent medial prefrontal cortex is highly sensitive to sensory-behavioral variables raises doubts about previous experiments that purport to show working memory-related activity in this region.

Action Potentials↗

PubMed2005

[Neuropsychological assessment of the prefrontal cortex in major depressive disorder].

The pathology of the prefrontal cortex (PFC) may play an important role in the development of the symptoms of major depressive disorder. In this study, the authors used the Wisconsin Card Sorting Test (WCST) and the Iowa Gambling Test (IGT) to investigate PFC functions in depression. The WCST investigates cognitive set-shifting abilities, whereas the IGT is sensitive for the cumulative effect of reward and punishment on decision-making. Participants were 20 patients with DSM-IV major depressive disorder and 20 age-, gender-, and education-matched healthy control subjects. The depressed patients showed significant impairment in both tests, but the WCST and IGT scores did not correlate. There was no significant correlation between the test results and the severity of depressive and anxiety symptoms. Our results suggest a global impairment of the PFC in depression, which includes the dorsolateral and ventromedial regions.

Adult↗

PubMedDate not supplied

Regulation of GABAergic inhibition by serotonin signaling in prefrontal cortex: molecular mechanisms and functional implications.

Serotonergic neurotransmission in prefrontal cortex (PFC) plays a key role in regulating emotion and cognition under normal and pathological conditios. Increasing evidence suggests that serotonin receptors are involved in the complex regulation of GABAergic inhibitory transmission in PFC. Activation of postsynaptic 5-HT2 receptors in PFC pyramidal neurons inhibits GABAA-receptor currents via phosphorylation of GABAA receptor gamma2 subunits by RACK1-anchored PKC. In contrast, activation of postsynaptic 5-HT4 receptors produces an activity-dependent bi-directional regulation of GABA-evoked currents in PFC pyramidal neurons, which is mediated through phosphorylation of GABAA-receptor beta subunits by anchored PKA. On the presynaptic side, GABAergic inhibition is regulated by 5-HT through the activation of 5-HT2, 5-HT1, and 5-HT3 receptors on GABAergic intereneurons. These data provide a molecular and cellular mechanism for serotonin to dynamically regulate synaptic transmission and neuronal excitability in the PFC network, which may underlie the actions of many antidepressant and antipsychotic drugs.

Animals↗

PubMed1996

Medullary sympathoexcitatory neurons are inhibited by activation of the medial prefrontal cortex in the rat.

Electrical stimulation of the medial prefrontal cortex (MPFC) reduces arterial blood pressure. To investigate the mechanism of this response, the effects of electrical and chemical stimulation of the MPFC on splanchnic and lumbar sympathetic nerve discharge and on the discharges of barosensitive neurons of the rostral ventrolateral medulla (RVLM) were studied in halothane-anesthetized rats. Electrical stimulation (20 Hz, 1 ms, 100 and sympathoinhibitory responses (reduced discharge of the splanchnic sympathetic nerve). Microinjection of glutamate (10 nmol/100 nl) into the MPFC also reduced arterial blood pressure and sympathetic discharge. Electrical stimulation (0.5 Hz, 1-ms pulse pairs, 3-ms interval, 150-300 microA) produced distinct patterns of splanchnic and lumbar sympathetic nerve discharge. A clear sympathoinhibitory phase with an onset latency of 146 +/- 14 ms was observed only in the case of the splanchnic sympathetic nerve activity. Electrical stimulation at depressor sites within the MPFC also inhibited the discharge of 10 of 21 RVLM barosensitive neurons tested. RVLM neurons were never excited by MPFC stimulation. These results indicate that the MPFC contains neurons that form part of a central sympathoinhibitory pathway.

Animals↗

PubMed2001

Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex.

BACKGROUND: The increase in glutamate efflux in the prefrontal cortex by the psychotomimetic drugs phencyclidine (PCP) and ketamine may produce the dopaminergic and some of the behavioral effects of these drugs. Here, we examined whether antipsychotic drugs influence this increase. METHODS: The effect of haloperidol, clozapine or the 5-HT(2A) antagonist, M100907, on PCP-induced increase in cortical glutamate efflux was examined by microdialysis. Because previous studies had suggested that M100907 attenuates some behavioral effects of PCP, we also examined the effect of M100907 on PCP-induced cortical and accumbal dopamine activation while making concomitant measures of locomotion and stereotypy. RESULTS: Haloperidol, clozapine or M100907 did not significantly block hyperglutamatergic effects of PCP. M100907 was ineffective in inhibiting the dopaminergic and motoric effects of PCP. CONCLUSIONS: These results contrast previous findings with glutamatergic drugs, such as AMPA antagonists or group II metabotropic glutamate agonists, that blocked glutamatergic and motoric effects of PCP. Thus, the PCP glutamate activation model lacks predictive validity for conventional antipsychotics; however, this model may be useful for design of novel classes of drugs that target those symptoms of schizophrenia that are not generally treated with monoamine-based antipsychotics.

Animals↗

PubMed1994

Glutamatergic control of dopamine release during stress in the rat prefrontal cortex.

In vivo microdialysis was used to assess the hypothesis that the stress-induced increase in dopamine release in the prefrontal cortex is mediated by stress-activated glutamate neurotransmission in this region. Local perfusion of an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, blocked the stress-induced increase in dopamine levels, whereas an NMDA receptor antagonist, 2-amino-5-phosphonopentanoic acid, at the dose tested, was not able to alter this response significantly. These data indicate that the effect of stress on dopamine release in the prefrontal cortex is mediated locally by activation of AMPA/kainate receptors, which modulate the release of dopamine in this region.

2-Amino-5-phosphonovalerate↗

PubMed1998

Neonatal raphe lesions increase dopamine fibers in prefrontal cortex of adult rats.

In order to characterize how the dopamine (DA) and serotonin (5HT) systems may be interacting in medial prefrontal cortex (mPFC) during postnatal development, the specific toxin 5,7-dihydroxytryptamine (5,7-DHT) was used to induce lesions of the nucleus raphe dorsalis (NRD) in neonatal rats and the density of tyrosine hydroxylase-immunoreactive varicosities (TH-IRv) was assessed. During the early adult period, lesioned rats showed a significant increase in the density of the TH-IR fibers in layers V and VI when compared with sham-treated animals. These results suggest that postnatal development in medial prefrontal cortex may be associated with a competitive interaction between cortical monoaminergic systems, such that an early disturbance in the development of the 5HT innervation can potentially induce a hyperinnervation of DA fibres.

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PubMed2005

Inhibitory control by an integral feedback signal in prefrontal cortex: a model of discrimination between sequential stimuli.

The prefrontal cortex (PFC) is known to be critical for inhibitory control of behavior, but the underlying mechanisms are unclear. Here, we propose that inhibitory control can be instantiated by an integral signal derived from working memory, another key function of the PFC. Specifically, we assume that an integrator converts excitatory input into a graded mnemonic activity that provides an inhibitory signal (integral feedback control) to upstream afferent neurons. We demonstrate this scenario in a neuronal-network model for a temporal discrimination task. The task requires the working memory of the vibrational frequency (f1) of an initial stimulus (stimulus 1), followed by comparison of the frequency (f2) of a second stimulus (stimulus 2) with the stored f1 and a binary decision (f2 > f1 or f2 < f1). The integral feedback signal generated by stimulus 1 gates the later inputs based on the amplitude difference (f2 - f1). The feedback control signal enables a subset of neurons to reverse their tuning to f1 between stimulus 1 and stimulus 2, when they become tuned to the difference, f2 - f1. These neurons maintain a lower firing rate during the delay compared with their peak rate during stimulus 1. A second subset of neurons, tuned to f1 during the delay, reaches a rate during stimulus 2 that depends on the maximum of f1 and f2. Our work suggests a circuit mechanism for discrimination across time and predicts neuronal behavior that can be tested experimentally.

Discrimination, Psychological↗

PubMed2001

Coding specificity in cortical microcircuits: a multiple-electrode analysis of primate prefrontal cortex.

Neurons with directional specificities are active in the prefrontal cortex (PFC) during tasks that require spatial working memory. Although the coordination of neuronal activity in PFC is thought to be maintained by a network of recurrent connections, direct physiological evidence regarding such networks is sparse. To gain insight into the functional organization of the working memory system in vivo, we recorded simultaneously from multiple neurons spaced 0.2-1 mm apart in monkeys performing an oculomotor delayed response task. We used cross-correlation analysis and characterized the effective connectivity between neurons in relation to their spatial and temporal response properties. The majority of narrow (<5 msec) cross-correlation peaks indicated common input and were most often observed between pairs of neurons within 0.3 mm of each other. Neurons recorded at these distances represented the full range of spatial locations, suggesting that the entire visual hemifield is represented in modules of corresponding dimensions. Nearby neurons could be activated in any epoch of the behavioral task (stimulus presentation, delay, response). The incidence and strength of cross-correlation, however, was highest among cells sharing similar spatial tuning and similar temporal profiles of activation across task epochs. The dependence of correlated discharge on the functional properties of neurons was observed both when we analyzed firing from the task period as well as from baseline fixation. Our results suggest that the coding specificity of individual neurons extends to the local circuits of which they are part.

Action Potentials↗

PubMed1997

Spatial delayed alternation of rats in a T-maze: effects of neurotoxic lesions of the medial prefrontal cortex and of T-maze rotations.

The medial prefrontal cortex (mPFC) is usually considered to be a brain area important for working memory processes. In rats this statement is evidenced by their diminished performance in delay-type tasks following mPFC damage, notably in spatial delayed alternation (SDA) in a T-maze. This study has addressed two questions. First, to examine whether the functional deficiency in SDA, observed in rats with (usually large) mPFC damage, can be ascribed to an anatomically defined subarea of mPFC, the dorsal anterior cingulate area (ACd). Small, bilateral, NMDA-induced lesions were made, restricted to the dorsal part of mPFC. The performance of such animals in a T-maze paradigm, using delays of 0 and 15 s, was compared with sham-operated animals. Although these small lesions resulted in an increased number of perseverative errors, this effect was not delay-dependent, and, moreover, by the end of the training group differences had disappeared. The second aim was to study whether or not spatial (extra-maze) cues are important for the performance of this task. This was achieved by subjecting the well-trained sham-operated animals to a series of systematic trial-to-trial variations in the position of the maze in the experimental room. These spatial manipulations severely impaired the performance of the SDA task, indicating that extra-maze information is required to solve this task. In animals with ACd lesions, subjected to the same manipulations, the deficiency was comparable to that of the sham-operated animals.

Animals↗

PubMed2005

Comparative behavioral changes in postpubertal rats after neonatal excitotoxic lesions of the ventral hippocampus and the prefrontal cortex.

The neonatal ventral hippocampal (nVH) and the neonatal prefrontal cortex (nPFC) lesions in rats have been used as models to test the hypothesis that early neurodevelopmental abnormalities lead to behavioral changes putatively linked to schizophrenia. We investigated the role of the nVH and the nPFC lesions on behavioral characteristics related to locomotor behaviors, social interaction, and grooming. Bilateral ibotenic acid lesions of the VH, the PFC, or both were made in neonatal Sprague-Dawley rats (postnatal day 7, P7) and their behaviors studied at P35 and P60. No significant differences in any of the behaviors were observed between sham animals and rats with ibotenic acid lesions at P35. Postpubertally (at P60), the spontaneous locomotor activity of nVH-lesioned rats was significantly enhanced compared to the sham controls; however, this hyperactivity was reversed by nVH and nPFC double lesions. Neonatal PFC lesion alone did not alter spontaneous activity, although a trend of increased activity was observed. The duration of grooming was significantly decreased in rats with neonatal lesions of the VH. Similar to the data on locomotion, nVH plus nPFC lesion normalized the grooming behavior. Lesion of the PFC alone was without any significant effect on grooming behavior. Neonatal VH-lesioned animals spent less time in active social interaction, and this effect persisted even in nVH plus nPFC-lesioned animals. By itself, nPFC lesion did not alter social behavior. These data suggest that subtle developmental aberrations within PFC caused by nVH lesions, rather than the lesion of PFC itself, may contribute to some of the behavioral changes seen in the nVH-lesioned rats.

Animals↗

PubMed2003

Dopamine D1-class receptors selectively modulate a slowly inactivating potassium current in rat medial prefrontal cortex pyramidal neurons.

The dopamine (DA) innervation of medial prefrontal cortex (mPFC) regulates cognitive activity in a complex manner. Alterations of DA function, particularly via the DA D1 receptor class (D1R), are implicated in both schizophrenia and drug addiction, yet the precise roles of DA in modulating mPFC excitability remain unclear. We focused on DA modulation of voltage-gated K(+) current (VGKC) in acutely dissociated rat mPFC pyramidal neurons. We defined three components of the whole-cell VGKC according to biophysical and pharmacological properties. The A-type current (I(A)), with rapid activation and inactivation kinetics, was completely inactivated by prolonged holding of the membrane potential at -40 mV and was sensitive to the K(+) channel blocker 4-aminopyridine (4-AP) but not tetraethylammonium (TEA) or dendrotoxin (DTX). The slowly inactivating K(+) current (I(D)), with rapid activation but relatively slow inactivation, was the major contributor to VGKC and was completely inactivated at -40 mV and sensitive to TEA and DTX but less so to 4-AP. The very slowly inactivating K(+) current (I(K)) was elicited by command steps to more depolarized potentials from a prolonged holding potential of -40 mV and was sensitive to all three blockers. Stimulation of DA D2 receptors failed to alter any component of whole-cell VGKC. Stimulation of DA D1Rs selectively suppressed I(D), an effect mimicked by the adenylyl cyclase activator forskolin, the active cAMP analog Sp-cAMP, and the protein phosphatase inhibitor okadaic acid. Inhibition of protein kinase A (PKA) with either PKI or Rp-cAMP abolished D1R modulation. Thus, the DA D1R/cAMP/PKA signaling pathway mediates modulation of I(D) by DA in rat mPFC pyramidal neurons.

4-Aminopyridine↗

PubMed2000

Dopamine increases excitability of pyramidal neurons in primate prefrontal cortex.

Dopaminergic modulation of neuronal networks in the dorsolateral prefrontal cortex (PFC) is believed to play an important role in information processing during working memory tasks in both humans and nonhuman primates. To understand the basic cellular mechanisms that underlie these actions of dopamine (DA), we have investigated the influence of DA on the cellular properties of layer 3 pyramidal cells in area 46 of the macaque monkey PFC. Intracellular voltage recordings were obtained with sharp and whole cell patch-clamp electrodes in a PFC brain-slice preparation. All of the recorded neurons in layer 3 (n = 86) exhibited regular spiking firing properties consistent with those of pyramidal neurons. We found that DA had no significant effects on resting membrane potential or input resistance of these cells. However DA, at concentrations as low as 0.5 microM, increased the excitability of PFC cells in response to depolarizing current steps injected at the soma. Enhanced excitability was associated with a hyperpolarizing shift in action potential threshold and a decreased first interspike interval. These effects required activation of D1-like but not D2-like receptors since they were inhibited by the D1 receptor antagonist SCH23390 (3 microM) but not significantly altered by the D2 antagonist sulpiride (2.5 microM). These results show, for the first time, that DA modulates the activity of layer 3 pyramidal neurons in area 46 of monkey dorsolateral PFC in vitro. Furthermore the results suggest that, by means of these effects alone, DA modulation would generally enhance the response of PFC pyramidal neurons to excitatory currents that reach the action potential initiation site.

Action Potentials↗

PubMed2000

Horizontal synaptic connections in monkey prefrontal cortex: an in vitro electrophysiological study.

In monkey dorsolateral prefrontal cortex (PFC), long-distance, horizontally oriented intrinsic axon collaterals interconnect clusters of pyramidal neurons in the supragranular layers. In order to study the electrophysiological responses mediated by these long-distance projections, an in vitro slice preparation of monkey PFC was used to obtain whole-cell patch clamp recordings from layer 3 pyramidal neurons. Using in vivo tracer injections, we found that long-distance projections were well preserved in PFC slices cut in the coronal plane. Postsynaptic currents were evoked by low-intensity electrical extracellular stimulation applied successively to 20-30 discrete sites located up to 2200 micron lateral to the recorded cell. Several criteria were applied to discriminate between mono- and polysynaptic responses. Long-distance monosynaptic connections were mediated by fibers with relatively slow conduction velocity (0.14 m/s). Excitatory postsynaptic currents (EPSCs) evoked by stimulation of short- or long-distance horizontal connections did not differ in kinetic properties. The majority (77%) of the 35 layer 3 PFC neurons studied were monosynaptic targets of long-distance connections. EPSCs mediated by long-distance connections had amplitudes that were similar or even larger than short-distance EPSCs, suggesting that excitatory input provided by the former was relatively robust. For most neurons (87.5%) in which a full complement of monosynaptic EPSCs was evoked by multisite stimulation, the EPSC amplitude as a function of stimulation distance from the recorded cells exhibited statistically significant peaks. The spacing between peaks was similar to the spacing between interconnected clusters of neurons observed in previous anatomical studies. The results show that long-distance excitatory connections constitute a significant intrinsic pathway of synaptic communication in layer 3 of monkey PFC.

Animals↗

PubMed1999

Rule-dependent neuronal activity in the prefrontal cortex.

We studied single-neuron activity in the prefrontal cortex (PF) while a monkey performed a task according to two different rules, termed conditional and spatial. The monkey viewed a video screen, and its task required a hand movement in response to the dimming of a light spot. There were four light spots on the screen: right, left, up, and down from the center. Only one of the four spots dimmed, and the degree of dimming was slight. Accordingly, the monkey needed to foveate the "correct" light spot to detect the dimming. A visual cue indicated which of the four light spots would be deemed correct and, thus, would dim on each trial. The sequence of events was as follows: a fixation spot appeared at the center of the screen; then, a cue appeared twice at one of the four potential target locations; then, the four target spots appeared; and, finally, one of them dimmed. Except for the color of an initial fixation point, the cues, their locations, and other events were identical for the conditional and spatial rules. The rules differed in one essential way. For the conditional rule, nonspatial attributes of the visual cue indicated which of the four light spots would dim, and the cue's location was irrelevant. For the spatial rule, the cue's location determined the correct target on that trial. The light spot at the location of the cue always dimmed, regardless of which cue appeared there. Our sample included 221 PF neurons showing significant task-related activity modulation, distributed among dorsal, dorsolateral, and ventral PF regions. Between one-third and one-half of the sample in each of those regions showed statistically significant activity differences that could be attributed to the rule. Selectivity for cues and/or their locations was common. However, there was no significant regional segregation of such selectivity. These data support the hypothesis that PF plays a role in the guidance of behavior according to previously learned rules.

Animals↗

PubMed1996

Patterns of intrinsic and associational circuitry in monkey prefrontal cortex.

Both local and long-range connections are critical mediators of information processing in the cerebral cortex, but little is known about the relationships among these types of connections, especially in higher-order cortical regions. We used quantitative reconstructions of the label arising from discrete (approximately 350 microns diameter) injections of biotinylated dextran amine and cholera toxin B to determine the spatial organization of the axon collaterals and principal axon projections furnished by pyramidal neurons in the supragranular layers of monkey prefrontal cortex (areas 9 and 46). Both terminals and cell bodies labeled by transport along axon collaterals in the gray matter formed intrinsic clusters which were arrayed as a series of discontinuous stripes of similar size and shape. The co-registration of anterograde and retrograde transport confirmed that these convergent and divergent intrinsic connections also were reciprocal. Transport from the same injection sites along principal axons through the white matter formed associational clusters which were also arrayed as a series of discontinuous stripes. The dimensions of the anterogradely- and retrogradely-labeled associational stripes were very similar to each other and to the intrinsic stripes. These findings demonstrate that divergence, convergence, and reciprocity characterize both the intrinsic and associational excitatory connections in the prefrontal cortex. These patterns of connections provide an anatomical substrate by which activation of a discrete group of neurons would lead to the recruitment of a specific neuronal network comprised of both local and distant groups of cells. Furthermore, the consistent size of the intrinsic and associational stripes (approximately 275 by 1,800 microns) suggests that they may represent basic functional units in the primate prefrontal cortex.

Animals↗

PubMedDate not supplied

The effects of haloperidol and clozapine on extracellular GABA levels in the prefrontal cortex of the rat: an in vivo microdialysis study.

Recent electrophysiological and pharmacological data indicate that dopamine enhances the activity of interneurons in the prefrontal cortex (PFC) and induces the release of GABA from these cells. We used in vivo microdialysis to examine the effects of two dopamine receptor antagonists on GABA release in the prefrontal cortex of awake, freely moving rats. Depolarization accomplished by local perfusion of potassium chloride or veratradine markedly increased extracellular GABA levels in the PFC. In contrast, local perfusion of TTX reduced extracellular GABA levels in the PFC. These data indicate that extracellular GABA is derived in part from neurons, and that extracellular levels of the inhibitory amino acid are impulse dependent. The acute administration of haloperidol weakly but significantly decreased extracellular GABA levels in the PFC; no effect of haloperidol on striatal extracellular GABA levels was observed. Systemic administration of the atypical antipsychotic drug clozapine markedly reduced extracellular GABA levels in the PFC, but did not alter striatal GABA levels. Thus, release of GABA from interneurons in the PFC is inhibited by two antipsychotic drugs. These data may suggest that different D2-like dopamine receptors are localized to pyramidal and nonpyramidal neurons in the cortex.

Animals↗