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PubMed2004

Different representation of forthcoming reward in nucleus accumbens and medial prefrontal cortex.

We recorded single units in the rat nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) to investigate activity related to reward mediation and anticipation during execution of an alternating reward task. NAcc and mPFC neurons showed increased activity differently during an interposed delay preceding reward delivery. Some NAcc neurons increased their activity specifically during the delay period before reward presentation, discriminating forthcoming food or water presentation. A subset of neurons in the mPFC similarly discriminated between food and water reward during the delay; however, about half did not discriminate reward qualities. These results show that the NAcc and the mPFC contribute differently to the organization and execution of goal-directed behavior.

Action Potentials↗

PubMed2004

Phasic alterations in dopamine and serotonin release in striatum and prefrontal cortex in response to cocaine predictive cues in behaving rhesus macaques.

The ability of environmental cues associated with cocaine availability to cause relapse may result from conditioned activation of dopamine (DA) release. We examined this hypothesis in macaque monkeys by conducting microdialysis studies in animals during exposure to a cocaine predictive compound cue. In addition to studying DA release in mesolimbic and sensorimotor striatum, both DA and serotonin levels were determined in the prefrontal cortex (medial orbitofrontal and anterior cingulate). The compound cue employed visual, auditory, and olfactory components, and was salient to the animals as demonstrated by anticipatory lever pressing in the absence of cocaine. During a 10-min period of exposure prior to cocaine availability, there was no significant increase in striatal or cortical DA. The addition of a DA uptake inhibitor to the striatal perfusate to reduce the potential interference of neuronal uptake did not alter the results. In contrast to the lack of any change in striatal DA, a significant decrease in extracellular serotonin in the prefrontal cortex during the 10 min of cue exposure was observed.

Animals↗

PubMed2005

Prefrontal cortex activity related to abstract response strategies.

Many monkeys adopt abstract response strategies as they learn to map visual symbols to responses by trial and error. According to the repeat-stay strategy, if a symbol repeats from a previous, successful trial, the monkeys should stay with their most recent response choice. According to the change-shift strategy, if the symbol changes, the monkeys should shift to a different choice. We recorded the activity of prefrontal cortex neurons while monkeys chose responses according to these two strategies. Many neurons had activity selective for the strategy used. In a subsequent block of trials, the monkeys learned fixed stimulus-response mappings with the same stimuli. Some neurons had activity selective for choosing responses based on fixed mappings, others for choosing based on abstract strategies. These findings indicate that the prefrontal cortex contributes to the implementation of the abstract response strategies that monkeys use during trial-and-error learning.

Action Potentials↗

PubMed2003

Neural activity in prefrontal cortex during copying geometrical shapes. I. Single cells encode shape, sequence, and metric parameters.

In drawing a copy of a geometrical shape, a sequence of movements must be produced to represent the sides of the object in the proper spatial relationship. We investigated neural mechanisms of this process by training monkeys to draw (using a joystick) copies of geometrical shapes (triangles, squares, trapezoids and inverted triangles) presented on a video monitor while recording single cell activity in prefrontal cortex. The drawing trajectories monkeys produced were divided into a series of discrete segments, varying in direction and length. We performed a stepwise multiple linear regression analysis to identify those copy parameters significantly influencing cell activity. The copied shape (e.g., triangle, square) and the serial position of the segment within each trajectory were the most prevalent effects (in 46% and 43% of cells, respectively), followed by segment direction (32%) and length (16%). Effects of temporal factors (maximum segment speed and time to maximum segment speed) were less frequent. These results demonstrate that prefrontal neurons encode several spatial and sequence variables that define copy trajectories. We also found that specific groupings of significant effects tended to occur together in single neurons. Specifically, single neurons simultaneously processed the serial position of a segment within each trajectory along with the corresponding spatial (but not temporal) attributes of that segment (i.e., direction and length), as well as with the overall shape to which the segments belong. Finally, we discovered that relationships between neural activity and segment serial position were systematic in many instances, described by monotonically increasing and decreasing functions, as well as parabolic functions. These findings indicate that, within the copying task, the serial segment position is a key factor for neural activity in the periprincipalis area of the prefrontal cortex.

Action Potentials↗

PubMed1995

Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics.

BACKGROUND: Up-regulation of gamma-aminobutyric acidA (GABAA) receptors and decreased GABA uptake in the cerebral cortex of schizophrenics suggest altered GABAergic transmission, which could be caused by primary disturbance of GABA synapses or by decreased production of the transmitter. Decreased production could be due to a shutdown in GABA production or to loss of GABA neurons caused by cell death or their failure to migrate to the cortex during brain development. METHODS: To discriminate between these possibilities, we quantified levels of messenger RNA (mRNA) for the 67-kd isoform of glutamic acid decarboxylase (GAD), the key enzyme in GABA synthesis, and the number and laminar distribution of GAD mRNA--expressing neurons in the dorsolateral prefrontal cortex (DLPFC) of schizophrenics and matched controls, using in situ hybridization-histochemistry, densitometry, and cell-counting methods. These data were compared with the total number of neurons, the number of small, round or ovoid neurons 8 to 15 microns in diameter, and overall frontal lobe volume. As a control, mRNA levels for type II calcium-calmodulin-dependent protein kinase (CamIIK) were quantified. RESULTS: Schizophrenics showed a pronounced decrease in GAD mRNA levels in neurons of layer I (40%) and layer II (48%) and an overall 30% decrease in layers III to VI. There were also strong overall reductions in GAD mRNA levels. The CamIIK mRNA levels showed no significant differences between samples. No differences were found in the total number of neurons nor in small, round or ovoid neurons, which should include a majority of the GABA cells. Prefrontal gray and white matter volume did not differ significantly between controls and schizophrenics. CONCLUSIONS: The prefrontal cortex of schizophrenics shows reduced expression for GAD in the absence of significant cell loss. This may be brought about by an activity-dependent down-regulation associated with the functional hypoactivity of the DLPFC. The lack of significant alterations in cell numbers in the DLPFC and frontal lobe volume in schizophrenics also implies that overall cortical neuronal migration had not been compromised in development. Previous reports of altered neuronal distribution in the subcortical white matter of schizophrenic brains in comparison with that of controls may indicate disturbances of migration or programmed cell death in the cortical subplate, leading to altered connection formation in the overlying cortex of schizophrenics and activity-dependent down-regulation of neurotransmitter-related gene expression.

Adult↗

PubMed2000

Reciprocal information flow between prefrontal cortex and ventral tegmental area in an animal model of schizophrenia.

The medial prefrontal cortex (PFC) is anatomically and functionally connected with the ventral tegmental area (VTA), the neuronal source of mesocorticolimbic system that is pathophysiologically related to schizophrenia-like symptoms. Methamphetamine (MAP) was applied to examine the functional relationship between PFC and VTA in an animal model of schizophrenia. Hyperactivity and stereotyped behavior were observed accompanied by a distinctive direction of information flow. In hyperactivity, information flow in the direction from PFC to VTA was dominant. Contrarily, dominant information flow from VTA to PFC was found in stereotyped behavior. These results indicate that dysfunctional interaction between PFC and VTA is the neuronal basis of MAP-induced schizophrenia-like psychosis. The information flow and its direction can be useful tool to explain the neurogenesis of these abnormal behaviors.

Animals↗

PubMed1991

Acidic Amino Acids and Self-stimulation of the Prefrontal Cortex in the Rat: A Pharmacological Study.

The effects of intraventricular and intracortical microinjections of acidic amino acid antagonists on self-stimulation (SS) of the medial prefrontal cortex (MPC) were investigated. Self-stimulation was measured by depressing a lever in a standard chamber. Spontaneous motor activity of the animal and SS of the contralateral non-injected MPC were used as control for non-specific effects of the drugs. Intraventricular microinjections of gamma-d-glutamylglycine (DGG), an antagonist of NMDA, kainate and quisqualate receptors, or 2-amino-5-phosphonovalerate (AP-5), a specific antagonist of NMDA receptors, produced a dose-related decrease of SS in the MPC. Spontaneous motor activity of the animal was not significantly affected. Unilateral microinjections into the medial prefrontal cortex of DGG or AP-5 produced a decrease of SS in the ipsilateral side while no effects were found on the contralateral MPC. On the contrary, intraventricular microinjections of gamma-d-glutamyltaurine (Glu-tau), an antagonist with more relative affinity for kainate and quisqualate receptors, produced a dose-related decrease of both self-stimulation and spontaneous motor activity of the rats. Moreover, intracortical microinjections of Glu-tau had no effect on self-stimulation of this cortical area. These results suggest that acidic amino acids through NMDA, but not kainate or quisqualate, receptors could be part of the neurochemical substrate underlying SS of the MPC in the rat.

Journal Article↗

PubMed1998

Prefrontal cortex infusions of SCH 23390 cause immediate and delayed effects on ventral tegmental area stimulation reward.

A reward-relevant relationship between dopamine projection regions of the ventral tegmental area (VTA) was investigated through the use of brain stimulation reward (BSR) thresholds. Using a rate-free method, changes in VTA BSR thresholds were determined after intracranial injections of the dopamine D1 antagonist, SCH 23390 into the prefrontal cortex (PFC), or the nucleus accumbens (NAcc). Reward thresholds assessed immediately after the infusion of SCH 23390 into the NAcc (0.5 microgram/0.5 microliter/side) were significantly higher than those assessed just after saline infusions, indicating a drug-induced attenuation of the rewarding effects of the brain stimulation. The effects of this dose subsided when tested 24 h later. Conversely, intra-PFC infusions of SCH 23390 at the same dose (0.5 microgram/0.5 microliter/side) resulted in lowered BSR thresholds when rats were tested immediately after infusion. In addition, animals tested 24 h after receiving the lowest dose (0.125 microgram/0.5 microliter/side) demonstrated a robust delayed threshold-lowering effect. These immediate and delayed effects of the intra-PFC dopamine antagonist demonstrate a facilitation of VTA BSR and are consistent with the view that PFC dopamine serves a modulatory role over important reward elements within the NAcc. The deferred effects of intra-prefrontal cortex DA receptor blockade on brain stimulation reward thresholds may reflect adaptive responses of subcortical structures to changes in PFC dopamine neurotransmission. It has been suggested that neural adjustments of this type may underlie long term changes in central nervous system functioning brought about by disease, drug use or behavioral conditioning.

Analysis of Variance↗

PubMed2004

Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex.

Interactions between dopamine and N-methyl-D-aspartate receptors (NMDARs) in prefrontal cortex (PFC) and other brain regions are believed to play an important role in normal mental function and neuropsychiatric disorders. In this study, we examined the regulation of NMDAR currents by the dopamine D1 receptor in PFC pyramidal neurons. Application of the D1 receptor agonist SKF81297 caused a prominent increase of the steady-state NMDA-evoked current in acutely isolated PFC pyramidal neurons. The D1 effect on NMDARs was independent of protein kinase A or protein phosphatase 1, but was abolished by incubation of neurons in Ca2+-free medium. Intracellular application of the Ca2+ chelator, calmodulin, or calmodulin inhibitors largely prevented the D1 modulation of NMDAR currents. Moreover, inhibiting PKC activity or disrupting PKC association with its anchoring protein also significantly reduced the D1 effect on NMDAR currents. This upregulation of NMDAR activity by dopamine D1 receptors and the previous finding on up-regulation of dopamine D1 receptors by NMDAR activation provide a cellular mechanism for the reciprocal interactions between D1 and NMDARs. These interactions may play an important role in modulating synaptic plasticity and thus in cognitive and emotional processes.

Animals↗

PubMed1997

Ventral prefrontal cortex is not essential for working memory.

It is widely held that the prefrontal cortex is important for working memory. It has been suggested that the inferior convexity (IC) may play a special role in working memory for form and color (). We have therefore assessed the ability of monkeys with IC lesions to perform visual pattern association tasks and color-matching tasks, both with and without delay. In experiment 1, six monkeys were trained on a visual association task with delays of up to 2 sec. Conservative IC lesions that removed lateral area 47/12 in three animals had no effect on the task. Further experiments showed that these lesions had no effect on the postoperative new learning of a color-matching task with delays of up to 2 sec or versions of the visual association task involving delays of up to 8 sec. In experiment 2, larger lesions of both areas 47/12 and 45A were made in the three control animals. This lesion caused a profound deficit in the ability to relearn simultaneous color matching, but subsequent matching with delays of up to 8 sec was clearly unimpaired. We suggest that the IC may be more important for stimulus selection and attention as opposed to working memory.

Animals↗

PubMed2001

Stimulation of prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens.

The prefrontal cortex (PFC) is thought to provide an excitatory influence on the output of mesoaccumbens dopamine neurons. The evidence for this influence primarily arises from findings in the rat that chemical or high-intensity and high-frequency (60-200 Hz) electrical stimulations of PFC increase burst activity of midbrain dopamine neurons, and augment terminal release of dopamine in the nucleus accumbens. However, PFC neurons in animals that are engaged in PFC-dependent cognitive tasks increase their firing frequency from a baseline of 1-3 Hz to 7-10 Hz, suggesting that the commonly used high-frequency stimulation parameters of the PFC may not be relevant to the behavioral states that are associated with PFC activation. We investigated the influence of PFC activation at lower physiologically relevant frequencies on the release of dopamine in the nucleus accumbens. Using rapid (5-min) microdialysis measures of extracellular dopamine in the nucleus accumbens, we found that although PFC stimulation at 60 Hz produces the expected increases in accumbal dopamine release, the same amplitude of PFC stimulation at 10 Hz significantly decreased these levels. These results indicate that activation of PFC, at frequencies that are associated with increased cognitive demand on this region, inhibits the mesoaccumbens dopamine system.

Animals↗

PubMed2003

NMDA receptors in the rat orbital prefrontal cortex are involved in guidance of instrumental behaviour under reversal conditions.

The orbital prefrontal cortex (OPFC) might be particularly involved in adapting instrumental responses to changes of stimulus-reward contingencies. We investigated whether signals in the OPFC transmitted via N-methyl-D-aspartate (NMDA) receptors are critical for learning a reversal of stimulus-reward contingencies. Rats were trained in a reaction time (RT) task demanding conditioned lever release with discriminative stimuli signalling in advance the upcoming reward magnitude (one or five pellets). After acquisition, RT of responses with expectancy of high reward magnitude were significantly shorter. Thereafter, stimulus-reward contingencies were reversed and rats received intra-OPFC infusions of saline or of the NMDA receptor antagonist AP5. Reversal learning was tested for 6 days, with microinfusions being given on days 1, 3 and 5. Intra-OPFC blockade of NMDA receptors impaired the learning of a reversal of previously acquired stimulus-reward magnitude contingencies: (i) latencies of correct responses were generally shortened, regardless of the response-associated reward magnitude; (ii) the proportion of premature responses was increased; and (iii) responses were not guided by the current significance of the reward-predicting stimuli. These findings provide novel evidence for NMDA-receptor-dependent plasticity in the OPFC in reversal learning.

2-Amino-5-phosphonovalerate↗

PubMed1990

6-Hydroxydopamine lesion of the rat prefrontal cortex increases locomotor activity, impairs acquisition of delayed alternation tasks, but does not affect uninterrupted tasks in the radial maze.

The role of mesocortical dopamine neurons in locomotion and acquisition of various delayed and uninterrupted maze tasks was investigated in the rat. Dopaminergic terminals of the medial prefrontal cortex were lesioned by stereotaxically guided injections of the selective neurotoxin 6-hydroxydopamine (6-OHDA), while noradrenergic neurons were protected by systemically administered desipramine. 6-OHDA lesions resulted in a selective depletion of dopamine and its metabolite, dihydroxyphenylacetic acid, in the prefrontal cortex but not in subcortical structures. Prefrontal serotonin was not depleted. 6-OHDA-cloned rats performed uninterrupted alternation tasks (spontaneous and reinforced alternation) in the radial maze in the same manner as controls, whereas performance of delayed alternation in the T-maze and the radial maze was impaired in lesioned rats. In addition, locomotor activity during maze performance was increased in lesioned rats. Based on the hypothesis that increased motor activity and impaired delayed alternation performance are due to increased susceptibility to interfering stimuli, we propose tentatively that prefrontal dopamine may function to suppress interference during the delay period of certain cognitive tasks.

Afferent Pathways↗

PubMed2003

Orbital prefrontal cortex and guidance of instrumental behaviour in rats under reversal conditions.

The orbital prefrontal cortex (OPFC) is suggested to be part of a circuitry mediating the perception of reward and the initiation of adaptive behavioural responses. In the present study, we investigated in rats changes of goal-directed behaviour after bilateral OPFC-lesions by N-methyl-D-aspartate (NMDA) in more detail. A reaction time (RT) task was used which is sensitive to subtle changes in discriminative guidance of instrumental behaviour by the anticipated reward magnitudes. The task demands conditioned lever release triggered by an imperative stimulus. The upcoming reward magnitude (five or one food pellet) for each trial was randomly chosen and signalled in advance by distinct instructive stimuli. In trained rats, RTs of instrumental responses were determined by the two distinct stimulus-reward magnitude contingencies, i.e. RTs were shorter to the instructive stimulus predictive of the higher reward magnitude. Results show that lesions of the OPFC did not impair discriminative guidance of behavioural responses according to preoperatively acquired stimulus-reward magnitude contingencies. However, guidance of instrumental behaviour was altered in lesioned rats after a reversal of the stimulus-reward magnitude contingencies. The data add further support to the hypothesis that the rat OPFC is not involved in retrieval of acquired stimulus-reward magnitude contingencies but in integration of incentive information to guide behaviour after a reversal of stimulus-reward contingencies.

Adaptation, Physiological↗

PubMed2000

GABA-containing neurons in the rat ventral tegmental area project to the prefrontal cortex.

Dopamine-containing projections from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) have been extensively characterized since their discovery over 25 years ago. However, the VTA projection to the PFC also contains a substantial nondopamine component, whose neurochemical phenotype is unknown. To examine if a portion of this nondopamine VTA projection contains GABA, anterograde and retrograde tract-tracing in the rat was combined with GABA immunocytochemistry and electron microscopy. Following injections of Fluoro-Gold (FG) into the PFC, many VTA neurons were retrogradely labeled, as visualized by immunoperoxidase staining for FG. A large portion of FG-labeled somata (58%) and dendrites (33%) within the VTA also contained immunogold-silver labeling for GABA. These dually labeled profiles exhibited a morphology similar to dopamine-containing cells within the VTA. To confirm and extend these findings, anterograde transport of biotinylated dextran amine (BDA) from the VTA was combined with immunogold-silver labeling for GABA within the PFC. Consistent with the results obtained from retrograde tracing, a portion of BDA-labeled terminals in the PFC also contained immunoreactivity for GABA. These dually labeled terminals formed symmetric synapses onto small caliber dendrites and dendritic spines. Some PFC dendrites contacted by GABA-containing VTA terminals were themselves GABA-labeled. The results of this investigation have identified a substantial population of GABA-containing neurons in the VTA that send axons to the PFC where they synapse on the distal processes of both pyramidal and local circuit neurons. This GABA-containing mesocortical pathway may provide substrates for both inhibitory and disinhibitory influences on PFC neuronal activity.

Animals↗

PubMed2005

Quantitative investigation of connections of the prefrontal cortex in the human and macaque using probabilistic diffusion tractography.

The functions of prefrontal cortex (PFC) areas are constrained by their anatomical connections. There is little quantitative information about human PFC connections, and, instead, our knowledge of primate PFC connections is derived from tracing studies in macaques. The connections of subcortical areas, in which white matter penetration and hence diffusion anisotropy are greatest, can be studied with diffusion-weighted imaging (DWI) tractography. We therefore used DWI tractography in four macaque and 10 human hemispheres to compare the connections of PFC regions with nine subcortical regions, including several fascicles and several subcortical nuclei. A distinct connection pattern was identified for each PFC and each subcortical region. Because some of the fascicles contained connections with posterior cortical areas, it was also possible to draw inferences about PFC connection patterns with posterior cortical areas. Notably, it was possible to identify similar circuits centered on comparable PFC regions in both species; PFC regions probably engage in similar patterns of regionally specific functional interaction with other brain areas in both species. In the case of one area traditionally assigned to the human PFC, the pars opercularis, the distribution of connections was not reminiscent of any macaque PFC region but, instead, resembled the pattern for macaque ventral premotor area. Some limitations to the DWI approach were apparent; the high diffusion anisotropy in the corpus callosum made it difficult to compare connection probability values in the adjacent cingulate region.

Adult↗

PubMed2006

Multiple dopamine receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting.

Dopamine (DA) input to the prefrontal cortex (PFC), acting on D1 receptors, plays an essential role in mediating working memory functions. In comparison, less is known about the importance of distinct PFC DA receptor subtypes in mediating executive functions such as set-shifting. The present study assessed the effects of microinfusion of D2 and D4 receptor antagonists, and D1, D2, and D4 receptor agonists into the PFC on performance of a maze-based set-shifting task. In Experiment 1, rats were trained on a response discrimination task, and then on a visual-cue discrimination task requiring rats to suppress the use of the response strategy and approach the previously irrelevant cue to locate food. In Experiment 2, the order of training was reversed. Infusions of the D2 antagonist eticlopride, or the D4 agonist PD-168,077, impaired shifting from a response to a visual-cue discrimination strategy and vice versa, and caused a selective increase in perseverative errors. In contrast, infusions of the D4 antagonist L-745,870 improved set-shifting. Infusions of the D1 agonist SKF81297 or the D2 agonist quinpirole caused no reliable effect. These data, in combination with previous reports of impaired set-shifting following D1 receptor blockade, suggest that multiple receptors in the PFC are essential for set-shifting and that the mechanisms by which PFC DA mediates behavioral flexibility may be different from those underlying working memory. These findings may have important implications for developing novel treatments for cognitive deficits observed in disorders such as attentional deficit and hyperactivity disorder and schizophrenia.

Analysis of Variance↗

PubMed2003

Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.

Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.

Adult↗