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PubMed2000

Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons.

Cannabinoids receptors have been reported to modulate synaptic transmission in many structures of the CNS, but yet little is known about their role in the prefrontal cortex where type I cannabinoid receptor (CB-1) are expressed. In this study, we tested first the acute effects of selective agonists and antagonist of CB-1 on glutamatergic excitatory postsynaptic currents (EPSCs) in slices of rat prefrontal cortex (PFC). EPSCs were evoked in patch-clamped layer V pyramidal cells by stimulation of layer V afferents. Monosynaptic EPSCs were strongly depressed by bath application (1 microM) of the cannabinoid receptors agonists WIN55212-2 (-50.4 +/- 8.8%) and CP55940 (-42.4 +/- 10.9%). The CB-1 antagonist SR141716A reversed these effects. Unexpectedly, SR141716A alone produced a significant increase of glutamatergic synaptic transmission (+46.9 +/- 11.2%), which could be partly reversed by WIN55212-2. In the presence of strontium in the bath, the frequency but not the amplitude of asynchronous synaptic events evoked in layer V pyramidal cells by stimulating layer V afferents, was markedly decreased (-54.2 +/- 8%), indicating a presynaptic site of action of cannabinoids at these synapses. Tetanic stimulation (100 pulses at 100 Hz, 4 trains) induced in control condition, no changes (n = 7/18), long-term depression (LTD; n = 6/18), or long-term potentiation (LTP; n = 5/18) of monosynaptic EPSCs evoked by stimulation of layer V afferents. When tetanus was applied in the presence of WIN 55,212-2 or SR141716-A (1 microM) in the bath, the proportion of "nonplastic" cells were not significantly changed (n = 7/15 in both cases). For the plastic ones (n = 8 in both cases), WIN 55,212-2 strongly favored LTD (n = 7/8) at the apparent expense of LTP (n = 1/8), whereas the opposite effect was observed with SR141716-A (7/8 LTP; 1/8 LTD). These results demonstrate that cannabinoids influence glutamatergic synaptic transmission and plasticity in the PFC of rodent.

Animals↗

PubMed1989

Mamillary body in the rat: topography and synaptology of projections from the subicular complex, prefrontal cortex, and midbrain tegmentum.

The retrograde and anterograde transport of horseradish peroxidase conjugated to wheat germ agglutinin (WGA-HRP) has been used to trace afferent connections of the rat mamillary body (MB) at the light and electron microscopic levels. Injections of WGA-HRP into different parts of the MB resulted in heavy retrograde labeling in the subicular complex, medial prefrontal cortex, and dorsal and ventral tegmental nuclei. Injections of WGA-HRP into each of these brain regions, respectively, resulted in anterograde labeling with specific distributions and characteristic synaptic organizations in the MB. Projections from the rostrodorsal and caudoventral subiculum terminated in a topographically organized laminar fashion in the medial mamillary nucleus bilaterally, whereas afferent projections from the presubiculum and parasubiculum terminated only in the lateral mamillary nucleus. Labeled axon terminals which originated from the subicular complex were characterized by round vesicles and formed asymmetric synaptic junctions with small-diameter dendrites and dendritic spines in the medial and lateral mamillary nuclei. Projections from the prefrontal cortex originated mainly in the infralimbic area and to a lesser degree in the prelimbic and anterior cingulate areas. Injections of tracer into these brain regions gave rise to dense labeling of axon terminals in the medial mamillary nucleus, pars medianus, and in the anterior dorsomedial portion of the pars medialis. The labeled terminals were characterized by round vesicles and formed asymmetric synaptic junctions with small-diameter dendrites and dendritic spines. Projections from the dorsal tegmental nucleus terminated in the ipsilateral lateral mamillary nucleus, whereas afferent projections from the anterior and posterior subnuclei of the ventral tegmental nucleus terminated topographically in the medial mamillary nucleus. The ventral tegmental nucleus, pars anterior projected to the midline region of the medial nucleus and the dorsolateral and ventromedial subdivisions of the pars posterior projected to medial and lateral parts of the medial nucleus, respectively. In contrast to the synaptic morphology of subicular complex and medial prefrontal cortex axon terminals in the MB, labeled axon terminals in the MB which originated from the midbrain tegmentum were characterized by pleomorphic vesicles and formed symmetric synaptic junctions with neuronal somata and proximal dendrites as well as distal dendrites and dendritic spines.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗

PubMed2006

Involvement of the medial prefrontal cortex in central cardiovascular modulation in the rat.

The medial prefrontal cortex (MPFC) and specifically its ventral portion (vMPFC) have been reported to modulate autonomic responses. On the cardiovascular system, this modulation is characterized by an influence on arterial blood pressure, regional blood flow as well as cardiac sympathetic and parasympathetic responses. The vMPFC also modulates baroreflex activity. Several neurotransmitters are present in the vMPFC. Among them L-glutamate, acetylcholine and noradrenaline are involved with cardiovascular modulation. In the present review, we describe evidences on the mechanisms involved in the vMPFC-related cardiovascular modulation.

Acetylcholine↗

PubMed1997

Modulatory role of catecholamines in the transsynaptic expression of c-fos in the rat medial prefrontal cortex induced by disinhibition of the mediodorsal thalamus: a study employing microdialysis and immunohistochemistry.

We studied the interaction of catecholaminergic and thalamic afferents of the medial prefrontal cortex (PFC) by analyzing the effects of catecholamine depletion on thalamus-induced c-fos expression in the PFC of freely moving rats. Thalamic projections to the PFC were pharmacologically activated by perfusing the GABA-A receptor antagonist bicuculline (0.03 mM or 0.1 mM) through a dialysis probe implanted into the mediodorsal thalamic nucleus. Bicuculline perfusion induced Fos-like immunoreactivity in the thalamic projection areas, including the PFC, and in the thalamic nuclei surrounding the dialysis probe. 6-Hydroxydopamine lesions of the ventral tegmental area causing a 70-80% depletion of catecholamines in the PFC did not influence the increase in the number of Fos-like immunoreactive nuclei in the prefrontal cortex in response to thalamic stimulation. However, densitometric image analysis revealed that the intensity of Fos-like immunoreactivity in the PFC of lesioned rats perfused with 0.1 mM bicuculline was higher than in correspondingly treated controls. The behavioral activity to bicuculline perfusion, an increase of non-ambulatory activity (0.03 mM) followed by locomotion and rearing (0.1 mM), was not changed in 6-hydroxydopamine-lesioned rats. It is suggested that the thalamically induced c-fos response is directly mediated by excitatory, presumably glutamatergic, transmission and not indirectly by an activation of catecholaminergic afferents of the PFC. The increase in the intensity of Fos-like immunostaining in strongly stimulated, catecholamine-depleted rats suggests that catecholamines modulate the degree to which thalamic activity can activate the PFC of awake animals.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Focused attention modulates visual responses in the primate prefrontal cortex.

Several current models propose an important role of the prefrontal cortex (PFC) in attention. To test the effects of attention in PFC, we recorded from PFC neurons in monkeys performing a task in which they had to attend to one hemifield and wait for a single stimulus that matched a previously presented cue. Neurons exhibited a slight decrease in their initial response and an enhanced activity late in the response to a stimulus at the cued location. The data demonstrate attentional effects on the activity of PFC neurons but they also show that single visual stimuli are initially represented in the activity of PFC neurons even when they are behaviorally irrelevant.

Animals↗

PubMed1996

Evidence that conditioned stress enhances outflow of dopamine in rat prefrontal cortex: a search for the influence of diazepam and 5-HT1A agonists.

We evaluated the impact of conditioned stress on outflow of dopamine in the rat prefrontal cortex. Exposure of rats to an environment associated with aversive stimuli-foot shock enhanced outflow of dopamine in a similar way as seen during the conditioning session when foot shocks were applied. Diazepam (2.5 and 10 mg/kg) dose-dependently decreased outflow of dopamine and, when given in a dose of 10 mg/kg, but not 2.5 mg/kg, decreased enhanced dopamine outflow evoked by conditioned stress. On the other hand, ipsapirone (10 mg/kg, but not 2.5 mg/kg) and buspirone (2.5 mg/kg) enhanced basal outflow of dopamine. When ipsapirone (10 mg/kg) and buspirone (2.5 mg/kg) were given to rats exposed to conditioned stress, the stress-evoked elevation in dopamine outflow was abolished. Ipsapirone in a dose of 2.5 mg/kg was ineffective in the stress paradigm tested. It is concluded that conditioned stress in vivo enhances dopaminergic neurotransmission in the rat prefrontal cortex, this effect being attenuated by diazepam, a classic anxiolytic drug, and by such novel anxiolytics as ipsapirone and buspirone, which operate via serotonergic 5-HT1A receptors. Although ipsapirone and buspirone blocked stress-induced enhancement of dopamine outflow, this effect seems to result from their influence on the basal outflow of dopamine. Differential effects of diazepam and 5-HT1A agonists on basal and stress-induced alterations in dopamine outflow are discussed in terms of their possible effectiveness in various types of general anxiety disorders.

Animals↗

PubMed1997

Noradrenergic mechanisms in the prefrontal cortex.

There is growing evidence that noradrenergic inputs to the prefrontal cortex (PFC) play an important role in regulating its function. This paper reviews the pharmacological control of noradrenaline (NA) release in this region, with particular reference to our studies using brain microdialysis, and also describes how NA levels are modulated by antidepressant and antipsychotic drugs. The suggestion that atypical antipsychotics such as clozapine and risperidone may produce clinical benefits by their ability to increase NA release is discussed. Finally, a new class of drugs, which show selectivity for imidazoline receptors is described. These compounds are shown to similarly increase extracellular NA in the PFC. Their potential utility as clinical treatments is discussed.

Animals↗

PubMed1995

Local circuit neurons of the prefrontal cortex in schizophrenia: selective increase in the density of calbindin-immunoreactive neurons.

Schizophrenia has been reported to be associated with alterations in GABAergic local circuit neurons of the prefrontal cortex. In this study, immunocytochemical techniques and antibodies against the calcium-binding proteins calbindin (CB) and calretinin (CR) were used to determine the laminar distribution and relative density of separate subpopulations of local circuit neurons in prefrontal cortical areas 9 and 46 from five pairs of schizophrenic and control subjects, matched for age, sex, and post-mortem interval. The laminar distribution pattern of CB-immunoreactive local circuit neurons was similar in both schizophrenic and control subjects. In both prefrontal regions, however, the density of CB-labeled neurons was 50-70% greater in schizophrenic subjects compared with control subjects, with cortical layers III and V/VI being preferentially affected. In contrast, the density of CR-IR neurons did not differ significantly between schizophrenic and control subjects. These findings reveal a selective increase in the density of a subpopulation of GABAergic local circuit neurons in the prefrontal cortex. Although other explanations for these observations must be considered, they may be consistent with the hypothesis that gene expression in GABAergic neurons is altered in schizophrenia.

Adult↗

PubMed2000

A controlled trial of daily left prefrontal cortex TMS for treating depression.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a new technology for noninvasively stimulating the brain. Several studies have suggested that daily stimulation of the left prefrontal cortex with TMS for 2 weeks has probable antidepressant effects. We conducted a parallel-design, double-masked, sham-controlled study to address whether 2 weeks of daily TMS over the left prefrontal cortex has antidepressant activity greater than sham. METHODS: Thirty medication-free adult outpatients with nonpsychotic, major depressive (n = 21) or bipolar (n = 9) (depressed phase) disorder who were in a current major depression (Hamilton Rating Scale for Depression [HRSD] 21-item score of >18) were treated each weekday for 2 weeks. Subjects were randomly assigned to receive either daily active (20 subjects) or sham (10 subjects) stimulation. Additionally, the 20 active subjects were equally divided between slower (5 Hz) and faster (20 Hz) frequency treatment. Antidepressant response was defined as greater than a 50% improvement in the baseline HRSD. RESULTS: Active TMS resulted in significantly more responders (9/20) than did sham (0/10) (chi(2) = 6.42, p <.01). The number of responders did not differ significantly between the two active cells (3/10 faster and 6/10 slower). Expressed as a percent change from baseline, active TMS subjects had significantly greater improvement on the Beck Depression Inventory as well as the Hamilton Anxiety Rating Scale than did those who received sham. CONCLUSIONS: Daily left prefrontal TMS for 2 weeks significantly reduced depression symptoms greater than did sham. The two forms of active TMS treatment did not differ significantly.

Adult↗

PubMed2004

Item- and task-level processes in the left inferior prefrontal cortex: positive and negative correlates of encoding.

Activity in the left inferior prefrontal cortex (LIPC) is often thought to reflect processes that support episodic encoding. Functional magnetic resonance imaging (fMRI) was used to test whether processes subserved by LIPC could be negatively related to subsequent memory performance. Specifically, the current experiment explicitly tested the hypothesis that LIPC processing would positively impact encoding when primarily focused towards specific target items (item-level processing), whereas it would negatively impact encoding when primarily focused on the retrieval and instantiation of current task instructions (task-level processing). Two methods were used to identify regions that were sensitive to the two types of processes: a block-level manipulation of encoding task that influenced subsequent memory, and a back-sort procedure. LIPC was sensitive to item- and task-level processing, but not in a way that always facilitates encoding. LIPC was more active for subsequently remembered words than subsequently forgotten words, but it was also more active in a task that emphasized task-level processing relative to a task that emphasized item-level processing, although this former condition led to poorer subsequent memory performance. This pattern indicates that processes subserved by LIPC are not always positively correlated with episodic encoding. Rather, LIPC processes can support both the controlled semantic processing of items and the controlled retrieval of relevant semantic task context. When devoted to the latter, the diversion of LIPC processes to the task level can have a negative consequence for item-level analysis and encoding.

Adult↗

PubMed1998

Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders.

The prefrontal cortex (PFC) ventral to the genu of the corpus callosum has been implicated in the modulation of visceral responses to stressful and emotionally provocative stimuli, based upon analysis of lesion effects involving this area in humans and experimental animals. In a recent magnetic resonance imaging (MRI) study of familial mood disorders, we demonstrated that the mean grey matter volume of this cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of their treatment status or current mood state. Moreover, in preliminary histopathological assessments of subgenual PFC tissue taken post mortem from subjects with MDD and bipolar disorder we obtained results suggesting that this decrement in grey matter volume is associated with a reduction in glia without an equivalent loss of neurons. The potential functional significance of these neuroimaging and microscopic abnormalities is discussed with respect to evidence that subgenual PFC dysfunction may disturb stress-related autonomic and neuroendocrine responses and reward-related mesolimbic dopamine function. These data may thus hold important implications for the development of neural models of mood disorders that can account for the abnormal hedonic, motivational, neuroendocrine, and autonomic manifestations evident in these idiopathic conditions.

Bipolar Disorder↗

PubMed1997

Normal conditioned inhibition and extinction of freezing and fear-potentiated startle following electrolytic lesions of medical prefrontal cortex in rats.

The authors investigated the role of medial prefrontal cortex (mPFC) in the inhibition of conditioned fear in rats using both Pavlovian extinction and conditioned inhibition paradigms. In Experiment 1, lesions of ventral mPFC did not interfere with conditioned inhibition of the fear-potentiated startle response. In Experiment 2, lesions made after acquisition of fear conditioning did not retard extinction of fear to a visual conditioned stimulus (CS) and did not impair "reinstatement" of fear after unsignaled presentations of the unconditioned stimulus. In Experiment 3, lesions made before fear conditioning did not retard extinction of fear-potentiated startle or freezing to an auditory CS. In both Experiments 2 and 3, extinction of fear to contextual cues was also unaffected by the lesions. These results indicate that ventral mPFC is not essential for the inhibition of fear under a variety of circumstances.

Acoustic Stimulation↗

PubMed2001

Characterization of the role of medial prefrontal cortex dopamine receptors in cocaine-induced locomotor activity.

Medial prefrontal cortex (mPFC) dopamine (DA) modulates the motor-stimulant response to cocaine. The present study examined the specific mPFC DA receptor subtypes that mediate this behavioral response. Intra-mPFC injection of the DA D2-like receptor agonist quinpirole blocked cocaine-induced motor activity, an effect that was prevented by coadministration of the D2 receptor antagonist sulpiride. Intra-mPFC injection of the selective D4 receptor agonist PD 168,077 or the selective D1 receptor agonist SKF 81297 did not alter the motor-stimulant response to cocaine. Finally, it was found that an intermediate dose of quinpirole, which only attenuated cocaine-induced motor activity, was not altered by SKF 81297 coadministration, suggesting a lack of synergy between mPFC D1 and D2 receptors. These results suggest that D2 receptor mechanisms in the mPFC are at least partly responsible for mediating the acute motor-stimulant effects of cocaine.

Animals↗

PubMed1994

Stress-induced norepinephrine release in the rat prefrontal cortex measured by microdialysis.

Norepinephrine (NE) release in the medial prefrontal cortex (PFC) of rats was studied during immobilization using an intracerebral microdialysis technique. A series of experiments using pharmacological and physiological manipulations indicated that the NE recovered in the medial PFC dialysate was mainly derived from nerve terminals and that the dorsal noradrenergic bundle was a major source of NE in the medial PFC. Immobilization stress immediately elevated NE levels to 176.0 +/- 9.0% of basal release, and this increase continued for the entire period of stress and 20 min after termination of the stress. Preinjection of a benzodiazepine receptor agonist, diazepam (5 mg/kg ip), significantly attenuated immobilization-induced NE release, while injection of an anxiogenic compound, FG-7142 (20 mg/kg ip), facilitated NE release in an obviously nonstressed condition. These results therefore suggest that stressful stimuli activate the NE system in the medial PFC, which may be modulated by an activation of benzodiazepine receptors in the brain.

Animals↗

PubMed1995

Anatomic basis of cognitive-emotional interactions in the primate prefrontal cortex.

Recognition that posterior basal and medial parts of the prefrontal cortex belong to the cortical component of the limbic system was important in understanding their anatomic and functional organization. In primates, the limbic system has evolved along with the neocortex and maintains strong connections with association areas. Consequently, damage to limbic structures in primates results in a series of deficits in cognitive, mnemonic and emotional processes. Limbic cortices differ in their structure and connections from the eulaminate areas. Limbic cortices issue widespread projections from their deep layers and reach eulaminate areas by terminating in layer I. By comparison, the eulaminate areas receive projections from a more restricted set of cortices and when they communicate with limbic cortices they issue projections from their upper layers and terminate in a columnar pattern. Several of the connectional and neurochemical characteristics of limbic cortices are observed as a transient feature in all areas during development. Anatomic evidence suggests that limbic areas retain some features observed in ontogeny, which may explain their great plasticity and involvement in learning and memory, but also their preferential vulnerability in several psychiatric and neurologic disorders.

Animals↗

PubMed2003

Pyramidal neuron local axon terminals in monkey prefrontal cortex: differential targeting of subclasses of GABA neurons.

In monkey prefrontal cortex (PFC), approximately 50% of the local axon terminals of pyramidal neurons form synapses with the dendritic shafts of GABA neurons. Subclasses of GABA neurons can be distinguished by the presence of different calcium-binding proteins. For example, in monkey PFC, parvalbumin (PV)-containing cells comprise approximately 25% of GABA neurons and are predominantly located in layers 3b-4, whereas calretinin (CR)-containing cells, which are present in greatest density in layers 2-3a, constitute 50% of GABA neurons. Consequently, in order to determine the cell class and laminar specificity of the dendritic targets of pyramidal neuron local axon collaterals in monkey PFC area 9, we conducted ultrastructural analyses of local axon terminals labeled with the anterograde tracer, biotinylated dextran amine, and dendrites immunoreactive (IR) for PV or CR. In layer 3b, the majority of the local axon terminals targeted PV-IR dendritic shafts, whereas CR-IR dendritic shafts were targeted infrequently. This differential targeting was also present in layers 2-3a, although it was less pronounced. In addition, PV-IR dendrites had a significantly greater density of excitatory inputs than did CR-IR dendrites. These findings indicate that PV-containing interneurons, which have a potent inhibitory effect on pyramidal neurons, are selectively targeted by the excitatory local axon terminals of supragranular pyramidal neurons in monkey PFC. These connections may provide the anatomical substrate for the coordinated activity of pyramidal neurons and fast-spiking GABA neurons during working memory.

Animals↗

PubMed2005

Hypothesis: minimal changes in neural transmission in schizophrenia: decreased glutamatergic and GABAergic functions in the prefrontal cortex.

As the pathophysiology, decreased glutamatergic neurotransmission in the postmortem prefrontal cortex of schizophrenics has been suggested to underlie the condition. But consistent reproducible results have not been seen with the molecular biological studies focused on examining glutamatergic parameters in schizophrenic brains. We noticed the lack of reproducibility of these studies and hypothesized that this was caused by "minimal (functional) changes" of schizophrenic pathophysiology that cannot be detected as a robust result by investigating only one marker (i.e., receptor). The authors then investigated glutamate levels, as well as mRNA expression of glutamate receptors and transporters simultaneously for the same schizophrenic and control brain samples, in order to detect the "minimal changes" of glutamatergic neurotransmission in schizophrenic synaptic clefts. The results showed a tendency of increased mGluRs and decreased EAAT2 mRNA in all Brodmann areas examined, but no significant difference was observed between schizophrenics and controls. To make these small changes of glutamatergic neurotransmission on the synaptic clefts more apparent, the "receptors/transporters ratio" (mGluRs/EAAT2 ratio) was calculated for each case and the results showed that the mGluRs/EAAT2 ratio was significantly increased in schizophrenics compared to controls. Glutamate levels, measured by HPLC, showed a decrease in the schizophrenics, but failed to reach statistical significance. The same phenomenon was recognized in our GABAergic study of schizophrenic brain. To interpret these results as a monism, the increase in mGluRs and the decrease of EAAT2 mRNA compensate for the decrease in glutamate transmission in the schizophrenic synaptic clefts. But these changes are small and failed to be statistically significant. The "receptors/transporters ratio" for each case magnified these changes, such that they became statistically significant.

Animals↗

PubMed2003

C-fos activation patterns in rat prefrontal cortex during acquisition of a cued classical conditioning task.

The prefrontal cortex (PFC) is known to be involved in associative learning; however, its specific role in acquisition of cued classical conditioning has not yet been determined. Furthermore, the role of regional differences within the PFC in the acquisition of cued conditioning is not well described. These issues were addressed by exposing rats to either one or four sessions of a cued classical conditioning task, and subsequently examining c-fos immunoreactivity in various areas of the PFC. Differences in patterns of c-fos immunopositive nuclei were found when comparing the PFC areas examined. No significant differences were found between rats presented with a temporally contingent conditioned stimulus (CS) light and food (paired groups) and those presented with the same stimuli temporally non-contingently (unpaired groups). In lateral and orbital PFC, both the paired and unpaired groups showed more c-fos immunopositive nuclei than control groups exposed only to the behavioral setup (context exposed groups), and all groups showed a drop in c-fos immunopositive nuclei from session 1 to session 4. In dorsal medial PFC, no differences were seen between the paired, unpaired and context exposed groups. These groups did, however, differ from naive animals, an effect that was not seen in the ventral medial PFC. The results of this study do not support a role for the PFC in the acquisition of a cued classical conditioning task. The differences seen between paired, unpaired and context exposed groups in orbital and lateral PFC could be due to contextual conditioning or reward-related effects.

Analysis of Variance↗