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Place learning and object recognition by rats subjected to transection of the fimbria-fornix and/or ablation of the prefrontal cortex.

The acquisition of a water maze-based allocentric place learning task and an exploration based object recognition task were studied in four groups of rats: animals in which the fimbria-fornix had been transected, rats who had received bilateral ablations of the anteromedial prefrontal cortex, animals in which both of these structures had been lesioned, and a sham operated control group. None of the groups showed impairments of object recognition. Ablations of the prefrontal cortex caused a mild impairment in the acquisition of the place learning task. The two fimbria-fornix transected groups exhibited a severe impairment during the acquisition of this task. All groups reached criterion level task performance eventually. All groups were subjected to a number of behavioural and pharmacological challenges in order to elucidate the neural and cognitive mechanisms of this behavioural recovery. During a no-platform session both the fimbria-fornix transected group and the prefrontally ablated group demonstrated a normal preference for the former platform position. The combined lesion group, however, failed to show a similar preference for this position. The outcome of the pharmacological challenges demonstrated that while the task performance of all four groups relied equally on catecholaminergic mediation, only the task solution of the fimbria-fornix transected group was significantly impaired by disturbance of the catecholaminergic systems. The data indicated a high likelihood that prefrontal cortical mechanisms contribute to the recovery of allocentric place learning after fimbria-fornix transections.

Animals↗

Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats.

Serotonin (5-HT) receptors are increasingly recognized as major targets for cognitive enhancement in schizophrenia. Several lines of evidence suggest a pathophysiological role for glutamate NMDA receptors in the prefrontal cortex in schizophrenia and associated disorders in attention and executive functioning. We investigated how the interactions between 5-HT1A and 5-HT2A and glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC) contribute to the control of different aspects of attentional performance. Rats were trained on a five-choice serial reaction time (5-CSRT) task, which provides indices of attentional functioning (percentage of correct responses), executive control (measured by anticipatory and perseverative responses), and speed. The competitive NMDA receptor antagonist CPP (50 ng/side) was infused directly into the mPFC 5 min after infusion of either 8-OH-DPAT (30 and 100 ng/side) or M100907 (100 and 300 ng/side) into the same brain area. Impairments in attentional functioning induced by CPP were completely abolished by both doses of 8-OH-DPAT or M100907. In addition, M100907 abolished the CPP-induced anticipatory responding but had no effects on perseverative over-responding, while 8-OH-DPAT reduced the perseverative over-responding but had no effects on anticipatory responding induced by CPP. The selective 5-HT(1A) receptor antagonist WAY100635 (30 ng/side) antagonized the effects of 8-OH-DPAT (100 ng/side). 8-OH-DPAT at 30 ng/side reduced the latency of correct responses in controls and CPP-injected rats and lowered the percentage of omissions in CPP-injected rats. The data show that 5-HT1A and 5-HT2A receptors in the mPFC exert opposing actions on attentional functioning and demonstrate a dissociable contribution of 5-HT1A and 5-HT2A receptors in the mPFC to different aspects of executive control such as impulsivity and compulsive perseveration.

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

Hypoactivation of the prefrontal cortex during verbal fluency test in PTSD: a near-infrared spectroscopy study.

Several studies have suggested that there is frontal dysfunction in subjects with posttraumatic stress disorder (PTSD). We investigated the relationship between alterations of the hemodynamic response of the prefrontal cortex during a cognitive task (verbal fluency task; VFT) and memory function measured using the Wechsler Memory Scale-Revised (WMS-R). The subjects were victims of the Tokyo Subway Sarin attack with (n = 8) or without (n = 26) PTSD. Hemodynamic response in the prefrontal cortex was measured using a 24-channel near-infrared spectroscopy (NIRS) system. Subjects with PTSD had a significantly smaller response of oxygenated hemoglobin and total hemoglobin during the VFT compared with those without PTSD, although there was no significant difference in performance on the VFT. Subjects with PTSD had significantly lower scores on attention and concentration in the WMS-R, which was positively correlated with the increase of total hemoglobin during the VFT. The 'frontal dysfunction' observed in subjects with PTSD may be a secondary phenomenon to reduced attentional capacity.

Adult↗

The prefrontal cortex and cognitive control.

One of the enduring mysteries of brain function concerns the process of cognitive control. How does complex and seemingly willful behaviour emerge from interactions between millions of neurons? This has long been suspected to depend on the prefrontal cortex--the neocortex at the anterior end of the brain--but now we are beginning to uncover its neural basis. Nearly all intended behaviour is learned and so depends on a cognitive system that can acquire and implement the 'rules of the game' needed to achieve a given goal in a given situation. Studies indicate that the prefrontal cortex is central in this process. It provides an infrastructure for synthesizing a diverse range of information that lays the foundation for the complex forms of behaviour observed in primates.

Animals↗

[Alterations in the decision making processes linked to the ventromedial prefrontal cortex in drug-abusing patients].

INTRODUCTION: The somatic marker hypothesis proposes that somatic signals guide the decision making processes in an adaptive sense for the organism. The processing of these somatic signals is linked to the ventromedial prefrontal cortex activity. The influence of somatic markers on decision making processes has been studied by means of the 'gambling task' (GT). Several studies using the GT in substance abusers have showed the existence of decision making impairments in these patients. AIMS: To examine the performance in the GT of a Spanish sample of substance abusers; and to study the influence of clinically relevant variables: type of substance, years of abuse and abstinence period on GT performance. PATIENTS AND METHODS: 106 substance abusers patients during the dishabituation phase participated in the study. We administered a computerized version of the GT in a single individual session. We used descriptive analyses to study the patients' performance in the GT. Next we carried out multiple regression analyses to study the influence of the clinical variables on the GT performance. RESULTS: A 76.4% of the sample patients showed impairments in the decision making processes measured by the GT. None of the clinical variables significantly predicted performance in the task. CONCLUSIONS: These results suggest the existence of decision making impairments in substance abusers that may be related to pre morbid alterations, or to a neurotoxic effect of drugs of abuse on the activity of the ventromedial prefrontal cortex.

Adaptation, Psychological↗

Topographic studies on visual neurons in the dorsolateral prefrontal cortex of the monkey.

The topographic distribution and organization of visual neurons in the prefrontal cortex was examined in alert monkeys. The animal was trained to fixate straight ahead onto a tinty, dim light spot. While he was fixating, we presented a stationary second light spot (RF spot) at various locations in the visual field and examined unit responses of the prefrontal neurons to the RF-spot stimulus. Many prefrontal neurons, especially those located in the relatively superficial layers of the cortex, responded with a phasic and/or tonic activation to the RF spot illuminating a limited extent of the visual field, a receptive field (RF) being so determined. The visual neurons were found to be widely distributed in the prearcuate and inferior dorsolateral areas. One hemisphere mainly represented the contralateral visual field. According to the location of the neurons in these areas, their visual properties varied with respect to RF eccentricity from the fovea and in size. The neurons located in the lateral part of the areas and close to the inferior arcuate sulcus had relatively small RFs representing the foveal and parafoveal regions. When the recording site was moved medially, the RFs became eccentric from the fovea and were larger. Then, the neurons located between the caudal end of the principal sulcus and the arcuate sulcus had RFs with a considerable eccentricity. The size of the RF became progressively larger for anteriorly located neurons and this occurred generally without a change in RF eccentricity. The visual neurons were not organized on a regular pattern in the cortex with regard to their RF direction (vector angle) from the foveal region. From these observations, we conclude, first, that the prearcuate and inferior dorsolateral areas of the prefrontal cortex are functionally differentiated so that the lateral area's function is related to central vision, while that of the medial area to ambient vision. Second, the RF representation on the cortex with loss of the vector relation may generate an interaction between separate objects in visual space and may subserve the control of attention performance.

Animals↗

Expanding the response space in chronic schizophrenia: the relevance of left prefrontal cortex.

OBJECTIVE: This study probed the ability of people with chronic schizophrenia to control their behavior in time by requiring them to deliberately vary responses within the temporal domain (i.e., to avoid regular inter-response intervals). METHODS: Thirteen schizophrenia patients performed single finger movements (at moments of their own choosing) in an event-related functional magnetic resonance imaging paradigm. Their performance was computed using the coefficient of variation of inter-response interval duration. RESULTS: Task performance was positively correlated with activation of left lateral prefrontal cortex. Post hoc analyses revealed an inverse correlation between activation in this region and severity of attentional impairment. CONCLUSION: These findings implicate left lateral prefrontal cortex in the modulation of the temporal response space in schizophrenia and imply greater attentional (executive) impairment among those who fail to modulate their behavior in time.

Adult↗

Cyclic AMP-mediated signaling components are upregulated in the prefrontal cortex of depressed suicide victims.

The components of cyclic AMP signaling cascade (catalytic (Calpha) subunit of cyclic AMP-dependent protein kinase (PKA) and cyclic AMP response element binding protein (CREB)) were quantitated by Western blotting in the prefrontal cortex of depressed suicide victims (n=23) and their matched controls (n=14). There was a significant increase in the levels of CREB, both in total (tCREB; 121+/-8% (mean+/-S.E.M.), P<0.02) and phosphorylated (pCREB; 128+/-9%, P<0.01) forms, but not in PKA Calpha levels (109+/-9%, ns), in brains of depressed suicides compared to those in control subjects. The increases in CREB were specifically observed in antidepressant drug-free subjects (tCREB: 137+/-11%, P<0.01; pCREB: 136+/-12%, P<0.02; n=9), but not in the antidepressant-treated subjects (tCREB: 108+/-18%, ns; pCREB: 111+/-17%, ns; n=8). There were significant correlations between the levels of PKA and those of tCREB and pCREB in the prefrontal cortex of depressed suicides. These results indicate that the components of cyclic AMP signaling are upregulated in a coordinated manner in brains of depressed suicides and that this alteration is not related to antidepressant treatment.

Adult↗

Interactions of the hippocampal system and the prefrontal cortex in learning language-like rules.

One of the most influential views on the hippocampal function suggests that this brain region is critically involved in relational memory processing, that is, binding converging inputs to mediate the representation of relationships among the constituents of episodes. It has been proposed that this binding is automatic and obligatory during learning and remembering In addition, neuroimaging studies have highlighted the importance of the prefrontal cortex, in learning, memory, and language processing. However, the posited importance of hippocampal-prefrontal interaction remains to be empirically tested. In the present study we used functional magnetic resonance imaging to examine in detail this interaction by assessing learning-related changes in hemodynamic activity during artificial language acquisition. It has been shown previously that artificial grammar systems might be learned by evaluating pattern-based relations in word sequences and generalizing beyond specific word order, that is, rule abstraction. During scanning, participants learned an artificial language whose miniature grammar meets the universal principles of a natural language. Increased proficiency level of the artificial language is associated with decreased left hippocampal activity. In contrast, we observed an increased recruitment of the left inferior frontal gyrus (Broca's area), a region that contributes to syntax processing in natural language. The present results, therefore, indicate a learning-related change in brain circuitry underlying relational processes of language learning, with a transition from a similarity-based learning system in the medial temporal lobes to a language-related processing system in the left prefrontal cortex.

Adult↗

Cerebellar, prefrontal cortex, and thalamic volumes over two time points in adolescent-onset schizophrenia.

OBJECTIVE: Structural and functional studies implicate multiple brain lesions as a basis for a functional dysconnectivity underlying the cognitive and symptom profiles in schizophrenia. The aim of this study was to examine the hypothesis that early-onset schizophrenia is associated with structural abnormalities in the prefrontal cortex, thalamus, and cerebellum, compatible with a dysconnectivity syndrome. METHOD: Two magnetic resonance imaging scans of 16 patients and 16 normal comparison subjects were undertaken on average 2 to 3 years apart. The participants were all from a defined geographic area in the United Kingdom with a population of 2.5 million. RESULTS: In comparison to the normal adolescents, the schizophrenic subjects demonstrated low prefrontal cortex and thalamic volumes. The relatively large difference in prefrontal and thalamic volumes in these adolescents with schizophrenia implies a more severe disease process than in adult subjects. CONCLUSIONS: The thalamic and frontal lobe findings provide preliminary, supportive structural evidence for a neurodevelopmental basis for a dysconnectivity syndrome, although the cerebellar findings were inconclusive.

Adolescent↗

Cytochemical correlates of the sleep-wake interface: concerted expression of brain-derived nitric oxide synthase (bNOS) and the nicotinic acetylcholine receptor (nAChR) in a columnoid organization of the primate prefrontal cortex.

Nitric oxide (NO) was recently proposed to be involved in the sleep-wake cycle and cortical spreading depression. As a structural correlate of these functions, we found that bNOS IR was expressed by three cell types in the prefrontal cortex, viz. bipolar, multipolar, and stellate cells. Dendrites of bipolar cells established bundles resulting in a columnoid organization; in addition, the monoclonal antibody mAb 35 which labels subunits alpha1, alpha3 and alpha5 of nAChR, also visualized apical axons proceeding alongside the columnoids. In contrast, alpha-bungarotoxin which labels the alpha7-subunit of nAChR, visualized only perikarya of interneurons from where the apical axons arose. In the prefrontal cortex of monkeys which were anesthetized for 6-24 hours, only traces of the columnoid organization were found, while perikaryal bNOS and nAChR were invariably expressed. It is suggested that interactions between NO and presynaptically released ACh might be involved in cortical functions such as the sleep/wake cycle.

Animals↗

The selective 5-HT2A receptor antagonist, MDL 100,907, increases dopamine efflux in the prefrontal cortex of the rat.

Diminished function within the mesocortical dopamine system has been to hypothesized to contribute directly to the negative and indirectly to the positive symptoms of schizophrenia. Based on the proposed role of 5-HT2 receptor blockade in the antipsychotic profile of clozapine and its preferential augmentation of prefrontal dopamine release, we have examined the effects of the selective 5-HT2A receptor antagonist, R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidi ne- methanol (MDL 100,907), on dopamine release in the rat medial prefrontal cortex using in vivo microdialysis. The results indicate that local 5-HT2A receptors exert a tonic inhibitory influence on dopamine efflux in the medial prefrontal cortex. These observations are consistent with the hypothesis that 5-HT2A receptor blockade contributes to the unique antipsychotic profile of clozapine and that MDL 100,907 may have antipsychotic activity.

3,4-Dihydroxyphenylacetic Acid↗

Laminar origin of striatal and thalamic projections of the prefrontal cortex in rhesus monkeys.

Prefrontostriatal and prefrontothalamic connections in rhesus monkeys have been shown to be organized in a topographic manner. These projections originate largely from infragranular layers V and VI. To examine whether the striatal and thalamic connections from the prefrontal cortex arise from separate neuronal populations or are collateralized, two different fluorescent retrograde tracers (diamidino yellow and fast blue) were injected into topographically similar regions of the head of the caudate nucleus and the mediodorsal nucleus in the same animal. The results show that although prefrontostriatal and prefrontothalamic projections arise from similar topographic regions, their laminar origins are distinctive. The connections to the head of the caudate nucleus originate mainly from layer Va, to a lesser extent from layer Vb, with a minor contribution from layers III and VI. In contrast, the projections to the mediodorsal nucleus emanate largely from layer VI, and also from layer Vb. Only occasional double-labeled neurons were observed, indicating that prefrontostriatal and prefrontothalamic connections originate from separate neuronal populations. The differential laminar distributions of neurons projecting to the head of the caudate nucleus and the mediodorsal nucleus suggest that these structures may receive independent types of information from the prefrontal cortex.

Amidines↗

Stimulus duration in working memory is represented by neuronal activity in the monkey prefrontal cortex.

Humans are capable of memorizing several attributes of a presented stimulus as well as its duration of presentation. However, the neuronal representation of stimulus duration in memory remains unknown. This study investigated activities of single neurons in the prefrontal cortex of monkeys while they were performing a behavioral task in which working memory for stimulus duration was needed. Here we describe specific neurons whose discharge rates reflect encoding or retention of the duration of the presentation of stimuli to be remembered. We also describe other specific neurons whose activities reflect encoding or retention of fixed duration, similar but unrelated to the stimulus duration presented in each trial. Some of these specific neurons showed the same duration-related discharges even while the monkeys were performing a different task, in which working memory for stimulus duration was no longer needed. From these results, we suggest that neurons in the prefrontal cortex play roles in encoding and retention of temporal information in working memory and that some of those neurons are dedicated to representation of temporal information attributed to stimuli even when the temporal information is unnecessary for correct performance.

Action Potentials↗

Antidepressant efficacy of two different rTMS procedures. High frequency over left versus low frequency over right prefrontal cortex compared with sham stimulation.

BACKGROUND: This placebo-controlled study was designed to investigate the influence of two different stimulation procedures of repetitive transcranial magnetic stimulation (rTMS) on depressive symptoms in patients with depressive disorders. Furthermore, effects on cognitive functions and psychomotor functioning were tested. METHODS: Thirty patients with depression (22 females and 8 males; mean age of 56.4 years) were included. They were treated with a stable dosage of antidepressant medication. They received either high frequency rTMS (20 Hz) over the left dorsolateral prefrontal cortex (LDLPFC), low frequency rTMS (1 Hz) over the right dorsolateral prefrontal cortex (RDLPFC) or sham stimulations (10 patients in each group) as add on treatment at 10 days within 2 weeks. Depressive symptoms were registered by means of observer ratings (Hamilton Depression Rating Scale - HDRS) and self reports (Beck Depression Inventory - BDI). Psychomotor retardation was investigated by the Motor Agitation and Retardation Scale and cognitive function by d2 test. RESULTS AND CONCLUSIONS: Differences between the rTMS procedures regarding depressive symptoms could not be found. Motor abnormalities, however, significantly improved exclusively after real stimulation procedures. Patients with less severe deficits in psychomotor speed and concentration responded more intensively than patients with severe deficits.

Aged↗

R(+)-8-OH-DPAT, a 5-HT1A receptor agonist, inhibits amphetamine-induced serotonin and dopamine release in rat medial prefrontal cortex.

Pretreatment with R(+)-8-OH-DPAT, a selective serotonin (5-HT)1A receptor agonist (50 micrograms/kg, s.c.), inhibited D-amphetamine sulfate (1.0 mg/kg, s.c.)-induced increases in extracellular levels of both 5-HT and dopamine (DA) in rat medial prefrontal cortex, as determined by in vivo microdialysis. The inhibitory effect of R(+)-8-OH-DPAT was completely reversed by the selective 5-HT1A receptor antagonist WAY 100,635 (100 micrograms/kg s.c.) administered 5 min prior to R(+)-8-OH-DPAT. These results suggest that stimulation of 5-HT1A receptors may inhibit amphetamine-induced release of 5-HT and DA in the medial prefrontal cortex.

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

Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on neurotransmitter systems in subcortical sites in the rat.

The effect of lesions of the catecholamine nerve terminals in the medial prefrontal cortex of the rat on neurotransmitter mechanisms within the basal ganglia has been investigated. Bilateral 6-hydroxydopamine lesions were stereotaxically placed in the dopamine-rich (DA) area of th frontal cortex. Animals were pretreated with desmethylimipramine to block the uptake of neurotoxin into noradrenergic (NA) terminals and to make it more selective for DA terminals. The lesion produced a selective reduction of both NA and DA from the medial prefrontal cortex, a result related to falls in tyrosine hydroxylase activity at this site. Lesioned animals showed enhanced DA turnover and utilisation in striatal and limbic regions. There was no change in subcortical tyrosine hydroxylase activity. In addition there were significant falls in other putative neurotransmitters within basal sites, including 5-hydroxytryptamine and GABA. Decreased activity of the neurotransmitter-synthesizing enzyme glutamate decarboxylase and choline acetyltransferase was also recorded in certain regions of the basal ganglia. The results suggest that frontal cortical catecholamine systems may serve to regulate various neurotransmitter mechanisms in the basal ganglia.

Animals↗

The role of ventral and orbital prefrontal cortex in conditional visuomotor learning and strategy use in rhesus monkeys (Macaca mulatta).

Four rhesus monkeys (Macaca mulatta) were trained to learn novel sets of visuomotor associations in 50 trials or less, within single test sessions. After bilateral ablation of the orbital and ventral prefrontal cortex, the monkeys lost the ability to learn these associations within a session, although they could learn them when given several daily sessions. Thus, relatively slow, across-session visuomotor learning depends on neither the ventral nor orbital prefrontal cortex, but rapid, within-session learning does. The ablations also eliminated at least 2 response strategies, repeat-stay and lose-shift, which might account, in part, for the deficit in rapid learning. The deficit is unlikely to result from a failure of visual discriminative ability or working memory: The monkeys could discriminate similar stimulus material within a session, and reducing the working memory load did not improve within-session learning.

Animals↗