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Neuronal correlates of classically conditioned bradycardia in the rabbit: studies of the medial prefrontal cortex.

Multiple-unit activity (MUA) in the agranular medial prefrontal cortex (PFC) was recorded in conscious rabbits during a classical conditioning procedure involving repeated pairings of a 4-s tone conditioned stimulus (CS) with eye shock. Prior to behavioral training, significant tone-evoked increases in prefrontal MUA were observed; the magnitude of this evoked cortical discharge declined with repeated presentations of the tone alone. However, the first few paired presentations of tone with eye shock served to rapidly reestablish the evoked activity, and subsequent pairings resulted in a significant enhancement of CS-evoked discharge, relative to pretraining response levels. These associative training-induced changes in prefrontal MUA appeared to parallel the development of bradycardiac conditioned responses (CRs), and, in fact, significant correlations between the neuronal and behavioral responses were observed. In contrast to these associative effects, non-associative training procedures involving either unpaired presentations of tone and eye shock or repeated presentations of the tone alone resulted in progressive attenuation of tone-evoked MUA, relative to pretraining levels. We had previously reported that bilateral destruction of the medial PFC seriously compromises the development of discriminative heart rate CRs in the rabbit. In light of this finding, our present results lend further support to the suggestion that associative training-induced changes in CS-evoked neuronal activity in this cortical region contribute, at least in part, to the development of learned cardiovascular adjustments in this animal.

Acoustic Stimulation↗

Ibotenic acid lesion of the ventral hippocampus differentially affects dopamine and its metabolites in the nucleus accumbens and prefrontal cortex in the rat.

To determine the influence of neurons of the ventral hippocampus on dopamine (DA) turnover in other limbic areas, spontaneous and amphetamine-induced locomotion as well as DA and its metabolites were assayed in nucleus accumbens, medial prefrontal cortex and anteromedial striatum, 14 and 28 days after bilateral ibotenic acid (IA) or sham lesions of the ventral hippocampus in the rat. Spontaneous locomotion was increased 28 days postoperatively, while D-amphetamine induced locomotion was augmented both 14 and 28 days postoperatively in IA lesioned animals. DA levels in the nucleus accumbens were decreased on the 14th, but increased on the 28th day after the lesion. Dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and the DOPAC/DA ratio in the medial prefrontal cortex (MPFC) were reduced 28 days postoperatively. Moreover, there was a significant negative correlation between the DOPAC/DA ratio in the MPFC and DA levels in the nucleus accumbens at this time point. These data indicate that a lesion of the ventral hippocampus can produce differential changes in cortical and limbic DA activity. Implications for an animal model of schizophrenia are considered.

Animals↗

Left prefrontal cortex activation during semantic encoding accessed with functional near infrared imaging.

OBJECTIVE: To investigate the left prefrontal lobe activation during semantic and non-semantic encoding tasks with functional near-infrared imaging (fNIRI) technique. METHOD: 22 healthy subjects were assigned semantic encoding and non-semantic encoding tasks. During semantic encoding tasks, subjects were asked to make a meaningful sentence including two unrelated Chinese word pairs, while during non-semantic encoding task they were asked to judge whether the two Chinese word pairs had the same morphological structure or not. Light intensity of two wavelengths (760 nm and 850 nm) diffused through skull and left prefrontal lobe were real-time recorded and used to reconstruct the brain activation image during the experiment. RESULT: With the fNIRI, significant activations were observed in the left inferior prefrontal cortex (Brodmann' areas 45 and 47) during the two tasks, but the evoked activations were more significant for semantic than non-semantic task. These observations were consistent with the results reported by others with functional megnetic resonance imaging (fMRI) and positron-emission tomography PET. CONCLUSION: The results suggest that fNIRI provides an important, non-invasive way to map the prefrontal activation during cognitive tasks.

Adolescent↗

Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys.

The intrinsic cortico-cortical connections within the orbital and medial prefrontal cortex (OMPFC) were demonstrated with retrograde and anterograde tracers injected into each of the architectonic areas that constitute this region. Although many of the connections linked neighboring areas, others selectively connected relatively distant areas. Most, but not all, of the connections were reciprocal. Altogether, the connections formed at least two distinct networks within the OMPFC. The "orbital" prefrontal network linked most of the areas within the orbital cortex, with very few connections to medial prefrontal areas. Areas Iam, Iapm, Ial, 12l, 12m, and 12r in the caudal and lateral parts of the orbital cortex (which received inputs from several sensory modalities) had convergent connections with areas 13l, 13m, and 13b in the central orbital cortex, with further connections to the rostral orbital area 11l. For the connections between areas Iapm, Iam, Ial, 13m, 13l, and 11l, rostrally directed fibers arose mainly in layer V, whereas caudally directed fibers originated mainly in layer III. The "medial" prefrontal network selectively involved medial areas 14r, 14c, 24, 25, 32, and 10m, rostral orbital areas 10o and 11m, and agranular insular area Iai in the posterior orbital cortex. Two orbital areas, 13a and 12o, had substantial connections to both networks and may serve as points of interaction between them; otherwise there were relatively few interconnections. The two networks also had distinct connections with other cortical regions, with limbic structures, and with the mediodorsal thalamic nucleus. Their role in guidance of affective behaviour is discussed.

Animals↗

Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia.

BACKGROUND: The neurotransmitters dopamine and glutamate have been implicated in the prefrontal dysfunction associated with schizophrenic illness. Studies suggest that the D1 subclass of dopamine receptor and the N-methyl-D-aspartate subclass of glutamate receptor are involved in this prefrontal dysfunction. These 2 receptors regulate, in opposing directions, the amount of phosphorylated activated DARPP-32, a potent inhibitor of protein phosphatase 1 that modulates the activity of several classes of receptors and ion channels. Thus, DARPP-32 occupies a key regulatory position, and may play an important role in the pathophysiological changes in dopamine and glutamate function reported in patients with schizophrenia. METHODS: The amounts of DARPP-32, synapsin I, and the alpha subunit of calcium/calmodulin-dependent protein kinase II were measured by immunoblotting in postmortem samples from 14 schizophrenic subjects and their age-, gender-, and autolysis time-matched control subjects. Possible confounding influences of neuroleptic treatment were analyzed by comparing subjects with Alzheimer disease who were and were not treated with neuroleptic agents. RESULTS: DARPP-32 was significantly reduced in the dorsolateral prefrontal cortex in more schizophrenic subjects relative to matched controls. The ratios of 2 other synaptic phosphoproteins, synapsin I and the alpha subunit of calcium/calmodulin-dependent protein kinase II, did not differ between schizophrenic and control subjects, nor between subjects with Alzheimer disease who were and were not treated with neuroleptic agents. CONCLUSIONS: Our findings are consistent with a selective reduction in DARPP-32 levels in schizophrenic subjects. This may be involved in the prefrontal dysfunction associated with schizophrenia.

Adult↗

Pathology of layer V pyramidal neurons in the prefrontal cortex of patients with schizophrenia.

OBJECTIVE: Morphological indications of abnormal circuitry have been detected in the prefrontal neuropil of patients with schizophrenia. The authors tested the hypothesis that schizophrenia is associated with smaller dendritic field size in layer V pyramidal neurons in the prefrontal cortex. METHOD: Tissue from area 10 with a mean postmortem interval of 5.7 hours was obtained from 15 subjects with chronic schizophrenia and 18 normal comparison subjects. After Golgi impregnation, basilar dendritic field size was estimated for layer V pyramidal neurons by ring intersection analysis. RESULTS: The schizophrenia subjects had 40% fewer total ring intersections per neuron than comparison subjects. Smaller basilar dendritic field size was evident in proximal and distal branches. CONCLUSIONS: These results indicate that abnormal dendritic outgrowth or maintenance contributes to reduced neuropil and prefrontal connectivity in schizophrenia. Short postmortem intervals and resulting high tissue quality suggest that these dystrophic changes reflect schizophrenia pathology rather than postmortem artifact.

Cell Count↗

Suppression of visually initiated hand movement by stimulation of the prefrontal cortex in the monkey.

Five adult monkeys (Macaca fuscata) were trained for the go/no-go hand movement task with discrimination between two different color stimuli. The go stimulus was accompanied by a reward when a monkey lifted a lever by wrist extension within the stimulus duration (500 ms). Whereas the no-go stimulus was not. The monkey revealed the potential specific to the no-go response in the prefrontal cortex, called 'no-go potential', i.e. surface-negative, depth-positive deflexions in the cortex of the dorsal bank of the principal sulcus and of the rostroventral corner of the prefrontal region. Effects of electrical stimulation of these prefrontal areas upon the go response were observed and analyzed in order to study functional significances of the no-go potential. The surface and depth (2.0-3.0 mm) electrodes chronically implanted respectively in various cortical areas of both hemispheres, originally used for recording cortical field potentials, were utilized for bipolar stimulation of the cortical area. A train of brief electrical pulses was delivered to the loci producible of the no-go potential at different times after the onset of go visual stimulus. The stimulation suppressed the go movement by cancelling and delaying. The grade of the suppressor effect depended on the timing of electrical stimulation after the onset of visual stimulus, and was maximal at around the time of appearance of the no-go potential. The suppressor effect was compared with that produced by stimulating some other areas in the prefrontal cortex and the premotor cortex, and was found rather unique in those areas producible of the no-go potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Methamphetamine causes depletion of glutathione and an increase in oxidized glutathione in the rat striatum and prefrontal cortex.

The administration of methamphetamine to experimental animals results in damage to dopaminergic neurons. The hypothesis that methamphetamine-induced neurotoxicity is mediated by reactive oxygen species was evaluated. It was found that acute administration of methamphetamine (5 and 15 mg kg(-1)) resulted in production of oxidative stress as demonstrated by decreased glutathione and increased oxidized glutathione levels in the rat striatum and prefrontal cortex. These changes in glutathione and oxidized glutathione levels were dose-dependent in striatum but not in prefrontal cortex. In conclusion, the results of present study provide further evidence in support of the notion that oxidative stress may play an important role in the methamphetamine-induced neurotoxicity.

Journal Article↗

Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat.

1. We examined the involvement of the frontal cortex in the 5-HT2A receptor-induced inhibition of 5-HT neurones in the dorsal raphe nucleus (DRN) of the anaesthetized rat using single-unit recordings complemented by Fos-immunocytochemistry. 2. Both transection of the frontal cortex as well as ablation of the medial region of the prefrontal cortex (mPFC) significantly attenuated the inhibition of 5-HT neurones induced by systemic administration of the 5-HT1A receptor agonist, 8-OH-DPAT (0.5-16 microg kg(-1), i.v.). In comparison, the response to 8-OH-DPAT was not altered by ablation of the parietal cortex. The inhibitory effect of 8-OH-DPAT was reversed by the 5-HT1A receptor antagonist, WAY 100635 (0.1 mg kg(-1), i.v.) in all neurones tested. 3. In contrast, cortical transection did not alter the sensitivity of 5-HT neurones to iontophoretic application of 8-OH-DPAT into the DRN. Similarly, cortical transection did not alter the sensitivity of 5-HT neurones to systemic administration of the selective 5-HT reuptake inhibitor, paroxetine (0.1-0.8 mg kg(-1) , i.v.). 4. 8-OH-DPAT evoked excitation of mPFC neurones at doses (0.5-32 microg kg(-1), i.v.) in the range of those which inhibited 5-HT cell firing. At higher doses (32-512 microg kg(-1), i.v.) 8-OH-DPAT inhibited mPFC neurones. 8-OH-DPAT (0.1 mg kg(-1), s.c.) also induced Fos expression in the mPFC. The neuronal excitation and inhibition, as well as the Fos expression, were antagonized by WAY 100635. 5. These data add further support to the view that the inhibitory effect of 5-HT1A receptor agonists on the firing activity of DRN 5-HT neurones involves, in part, activation of a 5-HT1A receptor-mediated postsynaptic feedback loop centred on the mPFC.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Evidence for activation of histamine H3 autoreceptors during handling stress in the prefrontal cortex of the rat.

On-line microdialysis of histamine in 10-min samples of the prefrontal cortex of the conscious rat is described. The HPLC-fluorescent assay for histamine in dialysates has been significantly simplified by using only one postcolumn reagent line instead of the three reagent lines described in earlier methods. The method is selective, sensitive (detection limit: 2-3 fmol on column), and linear over a large concentration range. Basal values of histamine decreased to about 50% of basal levels during infusion of tetrodotoxin (5 x 10(-6) M). Handling rats for 15 min increased histamine in dialysates to about 300% of basal levels. When tetrodotoxin (10(-6) M) was applied during handling the increase in histamine release was strongly (about 80%) suppressed. The handling-induced increase in histamine was used as a paradigm to investigate the functional activity of histamine H3 autoreceptors during mild stress or arousal. An H3 receptor specific agonist (alpha-methylhistamine; 10(-5) M) and antagonist (thioperamide; 10(-5) M) were infused into the frontal cortex via the microdialysis probe. The effect of handling on histamine release was potentiated during infusion of thioperamide and fully suppressed during infusion of alpha-methylhistamine. These results clearly illustrate the efficacy of the H3 autoreceptor in modulating stimulated histamine release during natural stimulatory conditions.

Animals↗

Effects of local application of dopaminergic drugs into the medial prefrontal cortex of rats on latent inhibition.

The involvement of the dopamine (DA) innervation of the medial prefrontal cortex (PFC) in attention was studied in a latent inhibition (LI) paradigm in rats. LI becomes evident by a retardation of conditioning to a stimulus after nonreinforced preexposure to that stimulus. LI is thought to reflect an animal's ability not to attend to irrelevant stimuli and is often used as an animal paradigm modeling schizophreniclike attentional deficits. In the present study the effects of bilateral infusions of the DA receptor agonist apomorphine (APO, 9.0 micrograms/side) and the DA receptor antagonist cis-flupenthixol (FLU, 12.0 micrograms/side) into the medial PFC on LI were assessed. Although in comparison with vehicle both APO and FLU infusions attenuated response suppression in nonpreexposed animals, the drugs differentially affected LI in preexposed animals. After infusions of APO animals failed to show conditioned suppression, whereas FLU-treated animals displayed as much suppression of responding as nonpreexposed animals. The abolition of LI induced by FLU infusions into the medial PFC suggests that prefrontal DA is involved in attentional processes in a way opposite to the established role of subcortical DA systems in these processes.

Animals↗

Dopamine and noradrenaline efflux in the rat prefrontal cortex after classical aversive conditioning to an auditory cue.

We used bilateral microdialysis in the medial prefrontal cortex (PFC) of awake, freely moving rats to study aversive conditioning to an auditory cue in the controlled environment of the Skinner box. The presentation of the explicit conditioned stimuli (CS), previously associated with foot shocks, caused increased dopamine (DA) and noradrenaline (NA) efflux. This conditioned response was dependent on the immediate pairing of the two stimuli; in the pseudoconditioned group that received an equal number of both stimuli, but in an unpaired fashion, no conditioned increases in efflux were observed.

Acoustic Stimulation↗

Inverse amygdala and medial prefrontal cortex responses to surprised faces.

Here we show inverse fMRI activation patterns in amygdala and medial prefrontal cortex (mPFC) depending upon whether subjects interpreted surprised facial expressions positively or negatively. More negative interpretations of surprised faces were associated with greater signal changes in the right ventral amygdala, while more positive interpretations were associated with greater signal changes in the ventral mPFC. Accordingly, signal change within these two areas was inversely correlated. Thus, individual differences in the judgment of surprised faces are related to a systematic inverse relationship between amygdala and mPFC activity, a circuitry that the animal literature suggests is critical to the assessment of stimuli that predict potential positive vs negative outcomes.

Adult↗

A mathematical model of persistent neural activity in human prefrontal cortex for visual feature binding.

A two-stage model of sustained neural activity in the prefrontal cortex is proposed in order to simulate feature binding and capacity limits in visual working memory. In the first stage, object features are stored in parallel network layers without explicit conjunctions. A second stage binds features into integrated objects consistent with the recent proposal of Wheeler and Treisman (J. Exp. Psychol. Gen. 131 (2002) 48). Model neurons have extended dendrites which are capable of active non-linear integration. Computer simulation illustrates model ability to segregate feature values of the different objects into cells with different activity amplitude and to maintain segregated feature representations for a limited number of objects. Depending on the task demands, features are retrieved in a second stage and form a unified object representation.

Models, Theoretical↗

NMDA receptor clustering in rat prefrontal cortex revealed by in vitro calcium macroimaging.

Living coronal brain slices were prepared from the rat prefrontal cortex (pFC) to determine the topographical distribution of the functional calcium-permeable N-methyl-D-aspartate (NMDA) receptor in vitro using calcium macroimage analysis with fura-2 AM. NMDA (0.25, 0.5, 1 or 2 x 10(-4) M for 30 s) bath application showed a dose-dependent [Ca2+]i increase from the steady-state level in several portions selected from the whole hemisphere slice. This regional response was suppressed by D-2-amino-5-phosphonopentanoic acid (10(-4)M) and reinforced by glycine coperfusion (5 x 10(-6) M). Image analysis showed that the cluster responsive to NMDA lay locally on the medial or lateral pFC even in the presence of tetrodotoxin.

Animals↗

Disturbing visual working memory: electrophysiological evidence for a role of the prefrontal cortex in recovery from interference.

Single cell recordings in monkeys support the notion that the lateral prefrontal cortex (PFC) controls reactivation of visual working memory representations when rehearsal is disrupted. In contrast, recent fMRI findings yielded a double dissociation for PFC and the medial temporal lobe (MTL) in a letter working memory task. PFC was engaged in interference protection during reactivation while MTL was prominently involved in the retrieval of the letter representations. We present event-related potential data (ERP) that support PFC involvement in the top-down control of reactivation during a visual working memory task with endogenously triggered recovery after visual interference. A differentiating view is proposed for the role of PFC in working memory with respect to endogenous/exogenous control and to stimulus type. General implications for binding and retention mechanisms are discussed.

Adult↗

The serotonergic modulation of synaptic plasticity in the rat hippocampo-medial prefrontal cortex pathway.

The ability of the serotonergic (5-HTergic) system to affect the hippocampo-medial prefrontal cortex (mPFC) synaptic properties was examined in rats with lesions of 5-HTergic neurons. Intracerebroventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) resulted in selective depletion of 5-HT and 5-hydroxyindoleacetic acid in the cerebral cortex, hippocampus and raphe regions. The 5,7-DHT-lesioned rat had no changes in basal synaptic transmission in the hippocampo-mPFC pathway. Conversely, we observed the augmentation of short-term synaptic plasticity, i.e. paired-pulse facilitation, when compared with sham-operated rats in this pathway. The magnitude of long-term potentiation (LTP) was significantly augmented in 5,7-DHT-lesioned rats. This augmentation of hippocampo-mPFC LTP had a significant correlation with the degree of cortical 5-HT levels. These results suggest that the 5-HTergic system may modulate plastic properties at the hippocampal-mPFC synapses in vivo.

5,7-Dihydroxytryptamine↗

Opposite effects depending on learning and memory demands in dorsomedial prefrontal cortex lesioned rats performing an olfactory task.

In this study, the functional properties of the dorsomedial prefrontal cortex (dmPFC) of the rat were examined in two olfactory tasks. In a successive cue olfactory discrimination task, dmPFC lesioned animals improved performance across sessions more rapidly than operated control animals. In an olfactory task using fixed interval training, animals with similar lesions were impaired. Both effects, although opposite, can be explained by a temporal processing deficit. The present results seem to indicate that the dmPFC is required for timing, classified as part of non-declarative memory. As reference memory improved in the lesioned animals, the finding is that the dmPFC supports non-declarative memory and thus interacts with declarative memory in the long-term formation of the associations between a particular stimulus (olfactory cue) and particular responses.

Animals↗