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PubMed2003

Ventral medial prefrontal cortex and emotional perseveration: the memory for prior extinction training.

Several years ago, we found that lesions of ventral medial prefrontal cortex (mPFCv) disrupted performance during the extinction component of a classical fear conditioning task without affecting acquisition performance. We called this emotional perseveration, hypothesizing that mPFCv may normally act to inhibit fear responses to a conditioned stimulus (CS) when the CS no longer signals danger. Subsequent studies have supported this hypothesis, showing that mPFCv is crucial for the memory of prior extinction training. The present study examined the effects of mPFCv lesions made after training. Such lesions resulted in reduced freezing to contextual stimuli and normal responding to the CS presented alone during a retention test. Rats were then subjected to extinction trials (CS without US) over multiple days. In contrast to pre-training lesions, post-training lesions had little effect on extinction rate. All rats were given additional training. Lesioned rats expressed greater fear reactions than controls, indicating that prior extinction was less effective in them. Lesioned rats also showed resistance to extinction during reextinction trials, confirming our earlier finding that lesions made before training weaken the effectiveness of extinction trials. These results suggest three conclusions. First, an intact mPFCv during acquisition may protect the animal from prolonged responding during extinction trials following brain insult. Second, changes in mPFCv may predispose subjects toward enhanced fear reactions that are difficult to extinguish when reexposed to fearful stimuli, due to a diminished capacity to benefit from the fear-reducing impact of prior extinction experience. Third, contextual cues processed by mPFCv may influence extinction performance.

Acoustic Stimulation↗

PubMed2004

Anticipatory cues differentially provoke in vivo peptidergic and monoaminergic release at the medial prefrontal cortex.

Like primary reinforcers, the anticipation of reward ought to affect neurochemical release in brain regions, such as the medial prefrontal cortex (mPFC), which are associated with appraisal processes. To assess the neurochemical changes associated with anticipation, rats were exposed to the pairing of auditory (60-dB white noise), visual, and olfactory cues with the daily presentation of a palatable snack (Cue Relevant group). Rats of a second group were similarly trained, but for a 2-week period, the snack was no longer provided following cue presentation (Extinction group). In the third condition, the presentation of the snack and cues was uncorrelated (Cue Irrelevant group). Analyses of dialysates collected in vivo from the mPFC revealed that release of corticotropin-releasing hormone (CRH), gastrin-releasing peptide (GRP), and the 5-HT catabolite, 5-hydroxyindole acetic acid (5-HIAA), had increased bilaterally in response to the anticipatory cues, whereas DA release increased only within the right mPFC. In the case of CRH and GRP, these increases were also apparent in the extinction condition, despite the fact that behavioral arousal to the anticipatory cues (increased exploration, rearing, grooming, and vigilance) was only evident in the Cue Relevant condition. In contrast, the elevated DA and 5-HIAA were apparent exclusively in the Cue Relevant condition. Thus, CRH and GRP systems may serve to allocate salience and/or incentive reward value to biologically significant stimuli or reflect the emotional response to the anticipatory stimulus. The activity of DA and 5-HT neurons, in contrast, is more closely aligned with the cognitive appraisal of predictor stimuli.

Animals↗

PubMed2005

Synaptic targets of calretinin-containing axon terminals in macaque monkey prefrontal cortex.

The coordinated activity of specific populations of pyramidal cells and GABA-containing, local circuit neurons in the primate prefrontal cortex (PFC) appears to be critical for working memory. Different subclasses of GABA-containing neurons can be distinguished by their content of the calcium-binding proteins parvalbumin (PV) and calretinin (CR). The postsynaptic targets of PV-containing cells have been well characterized in the primate PFC, but the postsynaptic targets of CR-containing neurons in this cortical region remain unknown. In the present study, we used immuno-electron microscopy to examine the synaptic type and postsynaptic targets of CR-immunoreactive (IR) axon terminals in the superficial and deep layers of macaque monkey PFC. Labeled axon terminals formed both symmetric and asymmetric synapses. Within the superficial layers, 93% of the synapses formed by CR-IR were symmetric, whereas in the deep layers the labeled axon terminals forming synapses were more evenly divided between symmetric (57%) and asymmetric (43%). The primary postsynaptic target of these two populations of CR-IR axon terminals also differed; unlabeled dendritic shafts were the predominant target of the symmetric synapses, whereas dendritic spines were the most common target of the asymmetric synapses. In addition, the mean cross-sectional area of the terminals forming asymmetric synapses was significantly larger than that of the terminals forming symmetric synapses. The presence of CR-IR asymmetric synapses suggested that they might arise from neurons that do not utilize GABA; indeed, dual-label fluorescent immunocytochemistry revealed that a subpopulation (23%) of CR-containing neurons in monkey PFC were not GABA-IR. These findings indicate that the synaptology of CR-containing neurons is more heterogeneous than that of PV-containing cells and suggests that the contributions of CR-containing neurons to cognitive processes mediated by the PFC may be more diverse.

Animals↗

PubMed2005

Hallucinogen-induced UP states in the brain slice of rat prefrontal cortex: role of glutamate spillover and NR2B-NMDA receptors.

Psychedelic hallucinogens (eg LSD or DOI) induce disturbances of mood, perception, and cognition through stimulation of serotonin 5-HT2A receptors. While these drugs are not proconvulsant, they have been shown by microdialysis to increase extracellular glutamate in the prefrontal cortex. Electrophysiological studies in the rat prefrontal slice have shown that both LSD and DOI enhance a prolonged, late wave of glutamate release onto layer V pyramidal neurons after an electrical stimulus. Here, we hypothesize that the network activity underlying this UP state involves glutamate spillover from excitatory synapses. To test this hypothesis, we raised the viscosity of the extracellular solution by adding the inert macromolecule dextran (approximately 1 mM) that is known to retard glutamate overflow into the extrasynaptic space. Dextran suppressed the UP state or late excitatory postsynaptic current (EPSC), but neither the fast EPSC, the traditional polysynaptic EPSC, nor a synaptic form of 5-HT2A-mediated transmission (serotonin-induced spontaneous EPSCs). Consistent with the previous work showing that extrasynaptic glutamate transmission in adult depends on NR2B-containing NMDA receptors, we found that NR2B-selective antagonists, ifenprodil and Ro25-6981, also suppressed the late EPSCs. The effect of psychedelic hallucinogens on UP states could be partially mimicked by inhibiting glutamate uptake but only after blocking inhibitory group II metabotropic glutamate receptors. This difference suggests that hallucinogens increase glutamate spillover in a phasic manner unlike glutamate uptake inhibitors. Increases in glutamate spillover have been suggested to recruit synapses not directly in the pathway activated by the electrical stimulus. Such recruitment could account for certain cognitive, affective, and sensory perturbations generated by psychedelic hallucinogens.

Animals↗

PubMedDate not supplied

Synaptogenesis in the prefrontal cortex of rhesus monkeys.

Since the turn of the century, the prefrontal association areas of the cerebral cortex have been thought to be among the last regions of the cortical mantle to develop. We have examined the course of synaptogenesis in the macaque prefrontal cortex by quantitative electron microscopic analysis in 25 rhesus monkeys ranging in age from embryonic day 47 (E47) to 20 years of age. A series of overlapping electron micrographs spanning the whole cortical thickness in each animal provided data on the number, the proportion, and the density of synapses per unit area (NA) and per unit volume (NV) of neuropil. The tempo and kinetics of synapse formation in prefrontal cortex closely resemble those described for sensory and motor areas, particularly during the stages of synapse acquisition and overproduction (Rakic et al., 1986). In young embryos, we describe a precortical phase (E47-E78), when synapses are found only above and below, but not within, the cortical plate. Following that, there is an early cortical phase, from E78 to E104, during which synapses accumulate within the cortical plate, initially exclusively on dendritic shafts. The next rapid phase of synaptogenesis begins at 2 months before birth and ends approximately at 2 months after birth, culminating with a mean density of 750 million synapses per cubic micrometer. This accumulation is largely accounted for by a selective increase in axospine synapses in the supragranular layers. The period of explosive synaptic density is followed by a protracted plateau stage that lasts from 2 months to 3 years of age when synaptic density remains relatively constant. The final period of decline, from 3 years through over 20 years of age, is marked by a slight but statistically significant decline in synaptic density. Concurrent recruitment of synapses with that of sensory and motor areas supports the concept that the initial establishment of cortical circuitry is governed by general mechanisms common to all areas, independent of their specific functional domain. The finding that synaptic density is relatively stable from early adolescence through puberty (the plateau period) is indicative of the importance, in primates, of a consistent and high synaptic density during the formative years when learning experiences are most intense.

Aging↗

PubMed2005

Transient disruption of ventrolateral prefrontal cortex during verbal encoding affects subsequent memory performance.

Episodic memory supports conscious remembrance of everyday experience. Prior functional neuroimaging data indicate that episodic encoding during phonological task performance is correlated with activation in bilateral posterior ventrolateral prefrontal cortex (pVLPFC), although uncertainty remains regarding whether these prefrontal regions make necessary contributions to episodic memory formation. Using functional MRI data to guide application of single-pulse transcranial magnetic stimulation (spTMS), this study examined the necessity of left and right pVLPFC for episodic encoding (as expressed through subsequent memory performance). To assess the timing of critical computations, pVLPFC function was transiently disrupted at different poststimulus onset times while subjects made syllable decisions about visually presented familiar and unfamiliar words; subsequent memory for these stimuli was measured. Results revealed that left pVLPFC disruption during encoding of familiar words impaired subsequent memory, expressed as a decline in recognition confidence, with disruption being maximal at 380 ms after stimulus onset. In contrast, right pVLPFC disruption facilitated subsequent memory for familiar words, expressed as an increase in medium confidence recognition, with this facilitation being maximal at 380 ms. Finally, phonological (syllable) decision accuracy was facilitated by right pVLPFC disruption, with this effect being maximal at 340 ms, but was unaffected by left pVLPFC disruption. These findings suggest that left pVLPFC mechanisms onset between 300 and 400 ms during phonological processing of words, with these mechanisms appearing necessary for effective episodic encoding. In contrast, disruption of correlated mechanisms in right pVLPFC facilitates encoding, perhaps by inducing a functional shift in the mechanisms engaged during learning.

Adolescent↗

PubMed1993

Nicotinic and muscarinic modulations of excitatory synaptic transmission in the rat prefrontal cortex in vitro.

The importance of the cholinergic innervation of the neocortex in cognitive functions has been shown in a number of clinical and animal studies. Until recently, attempts to study the mode of action of acetylcholine in the neocortex have concentrated on muscarinic effects, whereas cholinergic actions mediated by nicotinic receptors have been difficult to demonstrate. The present work was undertaken to study the mechanism of action of nicotinic agents on cortical neurons and compare it to muscarinic effects by means of intracellular recordings in a slice preparation. The study was performed in the prelimbic area of the rat prefrontal cortex, a cortical region particularly involved in cognitive processes. Recordings were made from pyramidal cells located in layers II/III and synaptic potentials were evoked by stimulation of superficial cortical layers. Iontophoretic applications of nicotinic agonists (nicotine, dimethylphenylpiperazinium, cytisine) increased the amplitude of the monosynaptic excitatory postsynaptic potential mediated by non-N-methyl-D-aspartate glutamate receptors in 14% (22/159) of cells. This effect was abolished by the selective nicotinic blocker, neuronal bungarotoxin (IC50 = 0.6-0.7 microM) and by dihydro-beta-erythroidine (IC50 = 20-30 microM), whereas hexamethonium, mecamylamine, curare and alpha-bungarotoxin were ineffective. The nicotinic agonists did not change resting membrane potential, input resistance or current-voltage relationship. They also did not affect the depolarizations produced by glutamate applied by iontophoresis in the somatic or dendritic area. In contrast, the muscarinic agonists (muscarine, acetyl-beta-methylcholine) decreased the amplitude of the excitatory postsynaptic potential in 100% of the neurons tested. Atropine was more effective (IC50 = 0.08 microM) than pirenzepine (IC50 = 2 microM) to antagonize the muscarinic action. These effects were observed in the absence of any direct postsynaptic change in membrane potential or input resistance, provided that the site of the iontophoretic application was more than 100 microM distant from the soma. The muscarinic agonists did not influence the actions of iontophoretically applied glutamate. These results suggest that nicotinic and muscarinic agonists modulate excitatory synaptic transmission mediated at dendritic sites by non-N-methyl-D-aspartate glutamate receptors, possibly through a presynaptic action. Thus ascending cholinergic systems may take part in information processing in the prefrontal cortex through the control of ongoing excitation to pyramidal cells.

2-Amino-5-phosphonovalerate↗

PubMed2000

Self-recognition and the right prefrontal cortex.

Although the anatomical and functional substrates subserving face recognition have been subject to extensive investigation, the underpinnings of self-face recognition are not well understood. Given the evidence that own-face recognition has been demonstrated by a select number of species, it is intriguing to speculate whether self-face recognition is accomplished via a 'self-network' or simply a 'face-network' within the brain. Furthermore, the relationship of self-recognition to other self-processes, such as self-evaluation and autobiographical retrieval, are not clearly defined. However, data from fMRI, ERPs and repetitive transcranial magnetic stimulation as well as from split-brain studies and patients with focal lesions, indicate that the prefrontal cortex, with possible right hemisphere lateralization, may be a preferential component in self-recognition. Studies using these methods, as well as PET, have indicated that the self-processes of self-evaluation and autobiographical memory preferentially engage networks within the right fronto-temporal region. Although it is highly improbable that there is a 'self-recognition' or 'self' center, it appears that there may be a bias for the processing of 'self' within the right prefrontal cortex.

Journal Article↗

PubMed2001

Enhancing analogic reasoning with rTMS over the left prefrontal cortex.

The authors utilized repetitive transcranial magnetic stimulation (rTMS) in 16 normal volunteers to investigate the role of the left dorsolateral prefrontal cortex (PFC) in analogic reasoning. rTMS over the left and right PFC, over the left motor cortex, and sham stimulation over the left PFC were administered during memory and analogic reasoning conditions. rTMS over the left PFC led to a significant reduction in response times only in the analogy condition without affecting accuracy. These results indicate that the left PFC is relevant for analogic reasoning and that rTMS applied to the PFC can speed up solution time.

Adult↗

PubMed2005

Hemodynamic changes in the prefrontal cortex during mental works as measured by multi channel near-infrared spectroscopy (NIRS).

To investigate the brain activation in the prefrontal cortex (PFC) during mental works, we examined blood oxygenation changes of healthy subjects by using multi channel near infrared spectropcopy (NIRS). It was directly confirmed that the PFC was activated during mental tasks in vivo and it was suggested that distribution of the activation in the PFC is different among healthy individuals.

Functional Laterality↗

PubMed2003

Role of the prelimbic subregion of the medial prefrontal cortex in acquisition, extinction, and reinstatement of cocaine-conditioned place preference.

Previous research suggests that the prelimbic subregion of the medial prefrontal cortex (mPFC) is necessary for acquisition of cocaine-conditioned place preference (CPP). Recently, it has been shown that extinguished cocaine-CPP can be reinstated by cocaine priming injections, and that this effect reflects the incentive motivational effects of the cocaine prime. To determine whether the prelimbic cortex is necessary for cocaine-reinstated CPP, rats received bilateral infusions of quinolinic acid (lesion group) or vehicle (sham group) into the prelimbic cortex and were later tested for acquisition, extinction, and reinstatement of cocaine-CPP. Both sham and lesion rats exhibited robust CPP established by systemic injections of cocaine (15 mg/kg, i.p.) following either one or three drug-environment pairings. Following repeated exposure to the cocaine- and saline-paired environments, sham and lesion rats showed similar rates of extinction of cocaine-CPP. In contrast, reinstatement of cocaine-CPP by cocaine priming injections (5 and 10 mg/kg, i.p.) was attenuated in rats with prelimbic cortex lesions relative to sham controls. This finding suggests that the prelimbic cortex is involved in the incentive motivational effects of cocaine priming.

Animals↗

PubMed1995

Novelty-induced increase in dopamine release in the rat prefrontal cortex in vivo: inhibition by diazepam.

The effects of graded stressful conditions on extracellular concentrations of dopamine (DA) in the medial prefrontal cortex of rats were measured in vivo using microdialysis. Picking up the rat twice with a 20-min interval increased extracellular DA to 120%, exposure to a novel environment by placement in a clean cage for 20 min to 150% and holding the rat in the hands for 20 min to over 200%. Diazepam (5 mg/kg) decreased DA to about 75% and attenuated the novelty- and handling-induced increases. Exposure to novelty or handling are easy and simple methods to obtain graded increases of in vivo cortical DA release.

Animals↗

PubMed2002

Aging and the myelinated fibers in prefrontal cortex and corpus callosum of the monkey.

In the rhesus monkey, the myelin sheaths of nerve fibers in area 46 of prefrontal cortex and in splenium of the corpus callosum show age-related alterations in their structure. The alterations are of four basic types. Most common is splitting of the dense line of myelin sheaths to accommodate electron dense cytoplasm derived from the oligodendroglia. Less common are splits of the intraperiod line to form balloons or blisters that appear to contain fluid, the occurrence of sheaths with redundant myelin, and thick sheaths that are almost completely split so that one set of compact lamellae is surrounded by another set. But despite these alterations in the sheaths, few nerve fibers show axonal degeneration. To quantify the frequency of the age-related alterations in myelin, transversely sectioned nerve fibers from the splenium of the corpus callosum and from the vertical bundles of nerve fibers within area 46 were examined in electron photomicrographs. The material was taken from 19 monkeys, ranging between 5 and 35 years of age. It was found that the frequency of alterations in myelin sheaths from both locations correlates significantly with age. In area 46, the age-related alterations also significantly correlate (P < 0.001) with an overall assessment of impairment in cognition, i.e., the cognitive impairment index, displayed by individual monkeys. The correlation is also significant when only the old monkeys are considered as a group. A similar result was obtained previously in our examination of the effects of age on the myelin sheaths of nerve fibers in primary visual cortex (Peters et al. [2000] J Comp Neurol. 419:364-376). However, in the corpus callosum the myelin alterations correlate significantly with only one component of the cognitive impairment index, namely the delayed nonmatching to sample task with a 2-minute delay. It is proposed that age-related myelin alterations are ubiquitous and that the correlations between their frequency and impairments in cognition occur because the conduction velocity along the affected nerve fibers is reduced, so that the normal timing sequences within neuronal circuits break down.

Aging↗

PubMed2005

Prefrontal cortex and flexible cognitive control: rules without symbols.

Human cognitive control is uniquely flexible and has been shown to depend on prefrontal cortex (PFC). But exactly how the biological mechanisms of the PFC support flexible cognitive control remains a profound mystery. Existing theoretical models have posited powerful task-specific PFC representations, but not how these develop. We show how this can occur when a set of PFC-specific neural mechanisms interact with breadth of experience to self organize abstract rule-like PFC representations that support flexible generalization in novel tasks. The same model is shown to apply to benchmark PFC tasks (Stroop and Wisconsin card sorting), accurately simulating the behavior of neurologically intact and frontally damaged people.

Cognition↗

PubMed1999

Presumed 'prefrontal cortex' lesions in pigeons: effects on visual discrimination performance.

The posterodorsolateral neostriatum (PDLNS) in pigeons may be an equivalent of the prefrontal cortex (PFC) in mammals. Here we report that lesions of this brain region in pigeons have a detrimental effect on various learned visual discriminations. Pigeons with lesions of the overlying area corticoidea dorsolateralis (CDL) served as controls. Both the postoperative re-learning to criterion of a preoperatively learned simultaneous double visual mirror pattern discrimination and the learning of a simple successive go, no-go discrimination were impaired by the PDLNS lesions. The PDLNS and CDL groups did not differ significantly in the postoperative learning of a reversal of the simultaneous discrimination. The results are discussed in relation to the presumed equivalence between the avian PDNLS and the mammalian PFC.

Animals↗

PubMed1997

Catecholamine regulation of the prefrontal cortex.

The catecholamines dopamine (DA) and norepinephrine provide an essential modulatory influence on the working memory and attentional functions of the prefrontal cortex (PFC). The following critique reviews evidence that (1) either insufficient or excessive DA D1 receptor stimulation is detrimental to PFC function, while DA stimulation of the D2 family of receptors may contribute to detrimental actions in PFC and (2) that norepinephrine has an important beneficial influence on PFC function through its actions at post-synaptic, alpha 2A adrenergic receptors, but impairs PFC function through actions at alpha 1 adrenergic receptors. Critical levels of catecholamine stimulation may be needed to optimize PFC cognitive function; high levels of catecholamine release during stress may serve to take the PFC 'off-line' to allow faster, more habitual responses mediated by the posterior and/or subcortical structures to regulate behavior. These studies have relevance to our understanding and treatment of disorders with prominent symptoms of PFC dysfunction.

Age Factors↗

PubMed1999

Medial prefrontal cortex lesions cause deficits in a variable-goal location task but not in object exploration.

The role of the medial prefrontal cortex (PFC) in goal-directed behavior was examined in rats with aspiration lesions. In Experiment 1, PFC lesions resulted in an impaired ability to relearn the location of a behaviorally defined goal arm of a plus-maze after it was moved from an initially fixed position. Lesioned rats also exhibited a significantly greater degree of perseveration compared with control animals. Experiment 2 was an object exploration task in which rats had to respond to a change in the layout of the environment. PFC-lesioned rats performed identically to controls, therefore demonstrating that the deficits observed in Experiment 1 did not result from a deficit in the ability to explore the environment. The results are discussed in terms of several competing, but not mutually exclusive explanations of the role of the PFC in navigation and spatial representation.

Animals↗

PubMed2002

Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar subjects.

This study attempted to replicate previous findings of decreased gray matter content in the subgenual prefrontal cortex (SGPFC) in mood disorder patients. Eighteen DSM-IV unipolar patients, 27 DSM-IV bipolar patients, and 38 healthy controls were studied. A 1.5T GE Signa Imaging System with Signa 5.4.3 software was used. The semi-automated software MedX (Sensor Systems, Sterling, VA) was utilized for the anatomical measures of SGPFC volumes. There were no significant differences in SGPFC volumes in familial and non-familial unipolar and bipolar patients compared with healthy controls, nor between drug-free and lithium-treated bipolar patients (ANOVA, p >.05). In vivo abnormalities in the volumes of SGPFC were not identified in mildly depressed or euthymic unipolar or bipolar mood disorder outpatients, either familial or non-familial.

Adult↗