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PubMed2001

Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin-1A, GABA(A), and glutamate receptors.

Anatomical evidence indicates that medial prefrontal cortex (mPFC) neurons project to the dorsal raphe nucleus (DR). In this study, we functionally characterized this descending pathway in rat brain. Projection neurons in the mPFC were identified by antidromic stimulation from the DR. Electrical stimulation of the mPFC mainly inhibited the activity of DR 5-HT neurons (55 of 66). Peristimulus time histograms showed a silence of 150 +/- 9 msec poststimulus (latency, 36 +/- 1 msec). The administration of WAY-100635 and picrotoxinin partly reversed this inhibition, indicating the involvement of 5-HT(1A) and GABA(A) receptors. In rats depleted of 5-HT with p-chlorophenylalanine, the electrical stimulation of mPFC mainly activated 5-HT neurons (31 of 40). The excitations (latency, 17 +/- 1 msec) were antagonized by MK-801 and NBQX. Likewise, MK-801 prevented the rise in DR 5-HT release induced by electrical stimulation of mPFC. The application of 8-OH-DPAT in mPFC significantly inhibited the firing rate of DR 5-HT neurons and, in dual-probe microdialysis experiments, reduced the 5-HT output in mPFC and DR. Furthermore, the application of WAY-100635 in mPFC significantly antagonized the reduction of 5-HT release produced by systemic 8-OH-DPAT administration in both areas. These results indicate the existence of a complex regulation of DR 5-HT neurons by mPFC afferents. The stimulus-induced excitation of some 5-HT neurons by descending excitatory fibers releases 5-HT, which inhibits the same or other DR neurons by acting on 5-HT(1A) autoreceptors. Afferents from the mPFC also inhibit 5-HT neurons through the activation of GABAergic interneurons. Ascending serotonergic pathways may control the activity of this descending pathway by acting on postsynaptic 5-HT(1A) receptors.

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

PubMed2006

Involvement of medial prefrontal cortex neurons in behavioral and cardiovascular responses to contextual fear conditioning.

To explore the ventral medial prefrontal cortex (vMPFC) involvement in behavioral and autonomic fear-conditioned responses to context, vMPFC synaptic transmission was temporarily inhibited by bilateral microinjections of 200 nL of the nonselective synapse blocker CoCl(2) (1 mM). Behavioral activity (freezing, motor activity and rearing) as well as evoked cardiovascular responses (arterial pressure and heart rate) was analyzed. Rats were pre-exposed to the footshock chamber (context) and shock stimulus was used unconditioned stimulus. During re-exposure to context, conditioned rats spent 80% of the session in freezing while non-conditioned rats (no shock group) spent less than 15% of the session time in freezing. Conditioned rats had significantly lower activity scores than non-conditioned animals. Exposure to context increased mean arterial pressure (MAP) and heart rate (HR) of both groups. MAP and HR of the conditioned animals were markedly increased and remained at a high and stable level, whereas MAP and HR increases in non-conditioned animals were less pronounced and declined during the session. CoCl(2) microinjected in the vMPFC significantly reduced freezing and attenuated MAP and HR increase of the conditioned group. Cobalt-induced vMPFC inhibition also significantly reduced MAP and HR increase observed in non-conditioned animals, without any behavioral changes. The effect of vMPFC acute ablation on MAP and HR did not seem to be specific to the fear response because they were also evident in non-conditioned animals. The results indicate that vMPFC integrity is crucial for expression of fear-conditioned responses to context, such as freezing and cardiovascular changes, suggesting that fear-conditioned responses to context involve cortical processing prior to amygdalar output. They also indicate a cardiovascular response observed during re-exposure of non-conditioned rats to the context is completely dependent on vMPFC integrity.

Analysis of Variance↗

PubMed2004

Effects of orbital prefrontal cortex dopamine depletion on inter-temporal choice: a quantitative analysis.

RATIONALE: Lesions of the orbital prefrontal cortex (OPFC) can cause pathologically impulsive behaviour in humans. Inter-temporal choice behaviour (choice between reinforcers differing in size and delay) has been proposed as a model of "impulsive choice" in animals. We recently found that destruction of the OPFC disrupted inter-temporal choice in rats. It is not known whether the dopaminergic projection to the OPFC contributes to the regulation of inter-temporal choice. OBJECTIVE: A quantitative method was used to compare inter-temporal choice in rats whose OPFC had been depleted of dopamine with that of sham-lesioned control rats. METHODS: Under halothane anaesthesia, rats received injections of 6-hydroxydopamine into the OPFC (2 microg microl(-1), 0.5 microl, two injections in each hemisphere), or sham lesions (injections of the vehicle). They were trained to press two levers (A and B) for sucrose reinforcement (0.6 M) in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of 50 microl of the sucrose solution after a delay dA; a press on B resulted in delivery of 100 microl of the same solution after a delay dB. dB was increased progressively across successive blocks of six trials in each session, while dA was manipulated systematically across phases of the experiment. The indifference delay, dB(50) (value of dB corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of dB(50) versus dA were derived, and the parameters of the function compared between the groups. Concentrations of monoamines in the OPFC were determined by high-performance liquid chromatography at the end of the experiment. RESULTS: In both groups, dB(50) increased linearly with dA (r2>0.9 in each case). The slope of the function was significantly steeper in the lesioned group than the sham-lesioned group, whereas the intercept did not differ significantly between the groups. When delays of 4 or 8 s were imposed on the smaller reinforcer, the lesioned rats showed greater tolerance of delay to the larger reinforcer (i.e. they exhibited longer values of dB(50)) than the sham-lesioned rats. Dopamine, noradrenaline and 5-hydroxytryptamine levels in the OPFC of the lesioned group were 20, 75 and 98% of those of the sham-lesioned group. CONCLUSIONS: The results indicate that dopaminergic afferents to the OPFC contribute to the regulation of inter-temporal choice behaviour due to their role in determining organisms' sensitivity both to reinforcer size and to delay of reinforcement.

Adrenergic Agents↗

PubMed1976

Dopaminergic innervation of the rat prefrontal cortex: a fluorescence histochemical study.

After the destruction of the noradrenergic ascending pathways, the localization of frontal cortical fields receiving fibers from the dopaminergic mesocortical system has been studied in rats, using a glyoxylic-paraformaldehyde method. The dopaminergic innervation was distributed in two main areas. The area of highest density was a medial field which spread in the medial cortex anterior and dorsal to the genu of the corpus callosum. It did not reach the shoulder region except in the foremost part of the frontal lobe where dopaminergic fibers were scattered in the whole cortex, including the molecular layer. A deep sulcal field was situated between the dorsal bank of the rhinal sulcus and the lateral cortex above it. In addition, a moderately dense band of dopaminergic fibers was observed between the corpus callosum and the anterior commissura, beside the accumbens nucleus. Similar data were obtained with dopamine uptake experiments on reserpine-treated but otherwise normal animals. The frontal areas receiving dopaminergic innervation coincide strikingly with the 'prefrontal cortex' as defined by neuroanatomical studies, which is assumed to be more or less equivalent to the prefrontal cortex of primates and derives direct projections from the amygdala. The functional implications of these findings are discussed.

Animals↗

PubMed1999

Dual streams of auditory afferents target multiple domains in the primate prefrontal cortex.

'What' and 'where' visual streams define ventrolateral object and dorsolateral spatial processing domains in the prefrontal cortex of nonhuman primates. We looked for similar streams for auditory-prefrontal connections in rhesus macaques by combining microelectrode recording with anatomical tract-tracing. Injection of multiple tracers into physiologically mapped regions AL, ML and CL of the auditory belt cortex revealed that anterior belt cortex was reciprocally connected with the frontal pole (area 10), rostral principal sulcus (area 46) and ventral prefrontal regions (areas 12 and 45), whereas the caudal belt was mainly connected with the caudal principal sulcus (area 46) and frontal eye fields (area 8a). Thus separate auditory streams originate in caudal and rostral auditory cortex and target spatial and non-spatial domains of the frontal lobe, respectively.

Acoustic Stimulation↗

PubMed2003

In vivo modulation of the activity of pyramidal neurons in the rat medial prefrontal cortex by 5-HT2A receptors: relationship to thalamocortical afferents.

The activation of 5-HT(2A) receptors in medial prefrontal cortex (mPFC) by the hallucinogen DOI increases the firing activity of dorsal raphe (DR) 5-HT neurons and prefrontal 5-HT release. Here we show that the i.v. administration of DOI markedly affected the firing rate of identified pyramidal neurons recorded extracellularly. DOI excited (481%) 21/56 neurons, inhibited (11%) 17/56 neurons and left the rest unaffected (overall 2.4-fold increase in firing rate). Both effects were antagonized by 5-HT(2A) receptor blockade. 5-HT(2A)-mediated orthodromic excitations were recorded in pyramidal neurons projecting to DR after electrical stimulation of this nucleus. We also examined whether the effects of DOI in mPFC involve thalamic excitatory inputs. The disinhibition of the mediodorsal and centromedial nuclei of the thalamus by local bicuculline resembled the effects of DOI as it increased pyramidal cell firing and 5-HT release in mPFC. However, the selective activation of prefrontal micro -opioid and mGlu II receptors counteracted the effects of the thalamic disinhibition but not those of DOI. Moreover, extensive thalamic lesions did not alter the effect of DOI on pyramidal cell firing and 5-HT release. We conclude that DOI increases the activity of the mPFC-DR circuit by an action on postsynaptic 5-HT(2A) receptors unrelated to thalamocortical afferents.

Action Potentials↗

PubMed2006

Specific configuration of dendritic degeneration in pyramidal neurons of the medial prefrontal cortex induced by differing corticosteroid regimens.

We previously demonstrated that hypercorticalism induces pronounced volumetric reductions in the rat medial prefrontal cortex (mPFC) and that these structural changes correlate with deficits in executive function. By applying 3-dimensional analysis of Golgi-Cox-stained material, we now demonstrate that corticosteroids can exert differential effects on dendritic arborizations of pyramidal neurons in lamina II/III of the mPFC. Treatment with the glucocorticoid receptor-selective agonist dexamethasone and with the natural adrenosteroid, corticosterone (CORT), results in significant reductions in the total length of apical dendrites in the pyramidal neurons in lamina II/III of the anterior cingulate/prelimbic and infralimbic cortices. Interestingly, although these treatments do not affect the number of dendritic branches, they are associated with impoverished arborizations in their distal portions and, in CORT-treated animals, with increased branching in the middle portions of the apical dendritic tree. Deprivation of corticosteroids by adrenalectomy leads to decreases in total apical dendritic length and spine number, but in this case, dendritic impoverishment was restricted to the middle/proximal segments of the dendritic trees. None of the treatments influenced the architecture of the basal dendrites. These results add to our knowledge of the morphological substrates through which corticosteroids may disrupt mPFC-dependent behaviors.

Adrenal Cortex Hormones↗

PubMed2005

Expression of c-fos and BDNF mRNA in subregions of the prefrontal cortex of male and female rats after acute uncontrollable stress.

Women exhibit higher lifetime prevalences of stress-related disorders than men. These disorders have been associated with changes in prefrontal cortex structure and function. Here, we examine the effects of acute inescapable stress, an animal model of behavioral depression and post-traumatic stress disorder, on plasma corticosterone (CORT) and on c-fos mRNA and brain-derived neurotrophic factor (BDNF) mRNA in regions of the prefrontal and frontal cortex in male and cycling female rats. Inescapable stress consisted of 100 1 mA tailshocks, and no-stress controls remained in their home cages. Rats were sacrificed immediately (0 min) or 60 min after termination of the stressor. CORT levels were increased at both 0 and 60 min post-stress termination relative to controls, and the increase was greater in females at both time points. c-fos mRNA expression increased at 0 min in prefrontal cortical regions, but this increase was greater in males than estrus and proestrus females. At 60 min, c-fos mRNA levels were lower than at 0 min in males but not females. No correlations between CORT and c-fos mRNA levels in prefrontal regions were observed in females in the stress groups, but significant correlations were observed in males in several prefrontal regions. BDNF mRNA expression was greater in control females than control males. Inescapable stress increased BDNF mRNA expression at 0 but not 60 min in males, but there was no effect of inescapable stress on BDNF mRNA in females. These results reveal sex differences in inescapable stress-induced gene expression that may have implications for differences in vulnerability to stress-related disorders.

Animals↗

PubMed1988

Convergence of skin and hypothalamic temperature signals on the sulcal prefrontal cortex in the rat.

Single unit activities in the sulcal prefrontal cortex (S-PEC) were recorded during thermal stimulation of scrotal skin and the hypothalamus in urethane-anesthetized rats. (1) Of all the 146 S-PFC units tested, 126 (86%) units changed the firing rate in response to changes in scrotal skin temperature (Tsc), and 98 (67%) units to alterations in hypothalamic temperature (Thyp). Sixty-five percent of the S-PFC units responded to both Tsc and Thyp changes. (2) Response characteristics of Tsc-responding S-PFC units were modified when the hypothalamus was warmed or cooled. (3) Microinjection of procaine into the dorsomedial nucleus of the thalamus reversibly blocked the response of S-PFC units to changes in Tsc and/or Thyp. (4) The high degree of convergence of thermal signals from scrotal skin and the hypothalamus on the S-PFC suggests that the S-PFC neurons play a role in processing and integrating thermal signals arising from different parts of the body, probably in connection with the emotional and/or motivational aspect of neural sensation and thermoregulatory behavior.

Animals↗

PubMed1990

Persistent elevations in dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex.

This study assessed the possible influence of the medial prefrontal cortex (MPFC) on the response of subcortical dopamine (DA) systems to subchronic, mild stress. DA and its metabolites as well as noradrenaline were assayed in the nucleus accumbens and corpus striatum, 1 and 7 days after one week of daily intraperitoneal saline injections (Stress) or no handling (No stress), in rats with sham (Sham) or ibotenic acid (IA) lesions of the MPFC. One day after the last saline injection the level of dihydroxyphenylacetic acid (DOPAC) was elevated in the nucleus accumbens of IA/Stress rats in comparison to the Sham/No stress, Sham/Stress, and IA/No Stress groups. Levels of mesolimbic DA, DOPAC and homovanillic acid were still elevated 7 days after the last injection in IA/Stress animals in comparison to all other groups. There were no other significant differences between the groups. The data suggest that in rats with MPFC impairment, mild subchronic stress can induce alterations in mesolimbic DA activity that persist beyond the duration of the stress.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

[3H]clonidine binds at multiple high affinity states in human prefrontal cortex.

[3H]Clonidine binds at particulate membrane fractions of human prefrontal cortex in a process that demonstrates high affinity, saturability, reversibility, alpha 2-adrenergic selectivity and the existence of multiple affinity states. At 37 degrees C maximal specific [3H]clonidine binding was briefly attained at 10 and lasted only until 15 min, while at 21 degrees C maximal binding was maintained from 20 to 90 min. At 21 degrees C, rate dissociation studies and saturation analyses were at least biphasic, and adrenergic competitors decreased [3H]clonidine binding with Hill coefficients less than 0.70. Analysis of these data showed at least two affinity states with apparent KDs of 0.34 and 6.0 nM, and the order in which ligands decreased [3H]clonidine binding was clonidine greater than (-)-epinephrine greater than (-)-norepinephrine greater than yohimbine greater than (+)-norepinephrine greater than (+/-)-isoproterenol greater than prazosin greater than serotonin.

Adult↗

PubMed1977

Brain self-stimulation: direct evidence for the involvement of dopamine in the prefrontal cortex.

Rats were trained to self-stimulate the medial prefrontal cortex, a region rich in dopaminergic terminals. After the region adjacent to the electrode site was labeled with [14C]dopamine, it was perfused repeatedly by means of push-pull cannulas. Electrical stimulation of this cortical area in six animals enhanced the release of dopamine and its associated metabolites in nine of 16 experiments. Thus in vivo evidence is provided that dopamine is involved in the brain self-stimulation mechanism within the frontal cortex.

Animals↗

PubMed1980

[Self-stimulation of supracallosal bundle (SCB) and associated behavior comparing to those of prefrontal cortex (PFC) (author's transl)].

The supracallosal bundle (SCB) and prefrontal cortex (PFC) receive projection from medial forbrain bundle (MFB) of the lateral hypothalamus (LH) in relation to reward system. The major purpose of the present study was to compare the intracranial self-stimulation (ICSS) rate of both the SCB and PFC with special emphasis on its associated behavior. The results obtained were as follows: 1) self-stimulation was obtained with electrodes historogically varified as being in the SCB (16 of 23 electrodes positive for ICSS) and the medial PFC (3 of 16 electrodes positive for ICSS). Electrodes dorsal and far lateral to the SCB and PFC were mainly negative (see Fig. 1). 2) Rats with SCB or PFC electrodes, chiefly showed a rearing associated with its ICSS. When stimulation electrodes were more posterior or lateral sites in the SCB and PFC, clonic movements of forelimb and head were occasionally observed (Fig. 1). 3) For neuron in the LH, stimulation of the SCB via chronic electrodes positive for ICSS produced two characteristic types, i.e. postinhibitory rebound type (Fig. 2A) and driven inhibitory type (Fig. 2B-1). It was suggested that fibers of MFB were activated by stimulating SCB-ICSS sites.

Animals↗

PubMed1992

Partial dopamine depletion of the prefrontal cortex leads to enhanced mesolimbic dopamine release elicited by repeated exposure to naturally reinforcing stimuli.

High-speed chronoamperometry was used to monitor the extracellular concentration of dopamine within the nucleus accumbens, a terminal field of the mesolimbic dopamine system, in freely behaving rats exposed daily, on 6 consecutive days, to one of two naturally reinforcing stimuli; a highly palatable food or sex-related olfactory cues. The animals either were intact or had previously received microinjections of 6-hydroxydopamine into prefrontal cortex to lesion dopamine terminals. Food reliably elicited increases in dopamine levels within the nucleus accumbens, and if prefrontal cortical dopamine had been depleted, the response to food increased with repeated testing. Animals exposed to the sexually relevant olfactory stimulus showed progressively enhanced dopamine release with repeated testing, and this enhancement was potentiated by prefrontal cortical dopamine depletion. These results indicate that repeated exposure to naturally reinforcing events can lead to a hyperresponsiveness of the mesolimbic dopamine system upon future activation, and suggest that the dopamine projection to prefrontal cortex exerts an indirect, inhibitory influence on mesolimbic dopamine neurotransmission.

Animals↗

PubMed2004

Prefrontal cortex asymmetry for memory encoding of words and abstract shapes.

Previous work suggested a differential contribution of prefrontal cortex (PFC) to successful encoding depending on the stimulus material. Here, we tested the hypothesis that encoding of words preferentially involves the left PFC, while encoding of nonverbal items (abstract shapes) relies on the right PFC. We used an experimental design that evaluated encoding of both words and abstract shapes in the same healthy volunteers. A transient virtual lesion of the left or the right PFC was elicited with transcranial magnetic stimulation (TMS) while subjects memorized verbal and nonverbal items. We found that encoding of verbal material was disrupted by left PFC stimulation, whereas encoding of nonverbal material was disrupted by right PFC stimulation. These results demonstrate a functionally relevant lateralization of prefrontal contribution for verbal and nonverbal memory encoding.

Adult↗

PubMed1997

Vasoactive intestinal polypeptide containing neurones in monkey medial prefrontal cortex (mPFC): colocalisation with calretinin.

Neurones immunoreactive for vasoactive intestinal polypeptide (VIP) were studied in monkey medial prefrontal cortex. The majority (78.0%) of VIP+ neurones were bipolar cells located mainly in layers 2/3. Calretinin (CR) immunoreactivity was colocalised in 80.5% of VIP+ neurones. Furthermore, VIP+ puncta formed pericellular baskets around GABA immunonegative somata in layers 2/3. These results indicate that VIP/CR are colocalised in some bipolar cells and superficial pyramidal somata are likely targets of VIP+ neurones.

Animals↗

PubMed2006

Go-no-go task performance improvement after anodal transcranial DC stimulation of the left dorsolateral prefrontal cortex in major depression.

BACKGROUND: We recently showed that repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) can affect the performance in an affective go-no-go (AGN) task. We aimed to extend this previous investigation testing whether one session of anodal transcranial direct current stimulation (tDCS) of the left DLPFC, as compared with anodal occipital and sham tDCS, affects this AGN task performance. METHODS: Twenty-six patients with major depression were randomized to receive anodal tDCS of the left DLPFC, occipital cortex or sham tDCS (the cathode electrode was placed over the frontopolar area for the three conditions). An AGN task was performed immediately before and after treatment. Performance changes (pre and post-treatment) were compared across groups of treatment and correlated with Hamilton Depression Rating Scale (HDRS) score changes. RESULTS: The results show that anodal stimulation of the left DLPFC was the only condition that induced a significant improvement in task performance as shown by the increase in the number of correct responses. In addition, this effect was specific for figures with positive emotional content. This performance enhancement was not correlated with mood changes after 10 days of tDCS treatment. LIMITATIONS: Although the effects of tDCS are less focal than rTMS, it can induce a longer and stronger modulation of cortical excitability. CONCLUSIONS: Our findings suggest that left DLPFC activity is associated with positive emotional processing, confirming and extending results of previous studies that associated right DLPFC and orbito-frontal cortex activity with emotional processing. Furthermore the effects of tDCS on mood and cognition seem to be independent in major depression. These lines of evidence together shed light on the neural circuitry involved with emotional processing in major depression.

Adult↗

PubMed2005

Differential effects of distraction during working memory on delay-period activity in the prefrontal cortex and the visual association cortex.

Maintaining relevant information for later use is a critical aspect of working memory (WM). The lateral prefrontal cortex (PFC) and posterior sensory cortical areas appear to be important in supporting maintenance. However, the relative and unique contributions of these areas remain unclear. We have designed a WM paradigm with distraction to probe the contents of maintenance representations in these regions. During delayed recognition trials of faces, selective interference was evident behaviorally with face distraction leading to significantly worse performance than with scene distraction. Event-related fMRI of the human brain showed that maintenance activity in the lateral PFC, but not in visual association cortex (VAC), was selectively disrupted by face distraction. Additionally, the functional connectivity between the lateral PFC and the VAC was perturbed during these trials. We propose a hierarchical and distributed model of active maintenance in which the lateral PFC codes for abstracted mnemonic information, while sensory areas represent specific features of the memoranda. Furthermore, persistent coactivation between the PFC and sensory areas may be a mechanism by which information is actively maintained.

Adult↗