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PubMed2004

Impairment of social perception associated with lesions of the prefrontal cortex.

OBJECTIVE: Behavioral and social impairments have been frequently reported after damage to the prefrontal cortex in humans. This study evaluated social perception in patients with prefrontal cortex lesions and compared their performance on a social perception task with that of healthy volunteers. METHOD: Thirty-three patients with prefrontal cortex lesions and 31 healthy volunteers were tested with the Interpersonal Perception Task. In this task, subjects viewed videotaped social interactions and relied primarily on nonverbal cues to make interpersonal judgments, such as determining the degree of intimacy between two persons depicted in the videotaped scene. Patients with prefrontal cortex lesions were classified according to lesion involvement of specific regions, including the orbitofrontal cortex, dorsolateral prefrontal cortex, and anterior cingulate cortex. RESULTS: Relative to the comparison subjects, patients whose lesions involved the orbitofrontal cortex demonstrated impaired social perception. Contrary to predictions, patients with lesions in the dorsolateral prefrontal cortex also showed deficits in using social cues to make interpersonal judgments. All patients, particularly those with lesions in the dorsolateral prefrontal cortex, showed poorer insight into their deficits, relative to healthy volunteers. CONCLUSIONS: These findings of deficits in social perception after damage to the orbitofrontal cortex extend previous clinical and experimental evidence of damage-related impairment in other aspects of social cognition, such as the ability to accurately evaluate emotional facial expressions. In addition, the results suggest that the dorsolateral prefrontal cortex is recruited when inferences about social interactions are made on the basis of nonverbal information.

Brain Injuries↗
PubMed1997

Collateral projections from the rat hippocampal formation to the lateral and medial prefrontal cortex.

Projections from the hippocampal formation to the medial prefrontal cortex are well known. In this report we used two retrogradely transported tracers to show that a small but significant subpopulation of pyramidal neurons in area CA1 and subiculum of the hippocampal formation projects to the lateral prefrontal cortex. About half of these neurons also possess collateral projections to the medial prefrontal cortex. The neurons projecting only to the lateral PFC are found in the intermediate hippocampal formation and in the most ventral part of the temporal subdivision. On the other hand, most of the neurons projecting to the medial prefrontal cortex only are present in the temporal and ventral intermediate hippocampal formation, and their number decreases in the dorsal intermediate subdivision. The distribution of neurons having collateral projections is comparable to that of neurons projecting to the medial prefrontal cortex only. In view of proposed functional differences between the septal one-third and the temporal two-third of the hippocampal formation, it is of interest that the neurons projecting to the prefrontal cortex are only present in the temporal two-thirds.

Amidines↗
PubMed2000

Fos expression following self-stimulation of the medial prefrontal cortex.

Self-stimulation of the medial prefrontal cortex and medial forebrain bundle appears to be mediated by different directly activated fibers. However, reward signals from the medial prefrontal cortex do summate with signals from the medial forebrain bundle, suggesting some overlap in the underlying neural circuitry. We have previously used Fos immunohistochemistry to visualize neurons activated by rewarding stimulation of the medial forebrain bundle. In this study, we assessed Fos immunolabeling after self-stimulation of the medial prefrontal cortex. Among the structures showing a greater density of labeled neurons in the stimulated hemisphere were the prelimbic and cingulate cortex, nucleus accumbens, lateral preoptic area, substantia innominata, lateral hypothalamus, anterior ventral tegmental area, and pontine nuclei. Surprisingly, little or no labeling was seen in the mediodorsal thalamic nucleus or the locus coeruleus. Double immunohistochemistry for tyrosine hydroxylase and Fos showed that within the ventral tegmental area, a substantial proportion of dopaminergic neurons did not express Fos. Despite previous suggestions to the contrary, comparison of the present findings with those of our previous Fos studies reveals a number of structures activated by rewarding stimulation of both the medial prefrontal cortex and the medial forebrain bundle. Some subset of activated cells in the common regions showing Fos-like immunoreactivity may contribute to the rewarding effect produced by stimulating either site.

Animals↗
PubMed1990

Cholecystokinin innervation of monkey prefrontal cortex: an immunohistochemical study.

Knowledge of the circuitry of chemically identified systems in primate prefrontal cortex is limited. Although cholecystokinin is very abundant in prefrontal cortex (Geola et al.: Journal of Clinical Endocrinology and Metabolism 53(2):270-275, 1981; Taquet et al.: Neuroscience 27(3):871-883, 1988), the organization of cholecystokinin-containing structures in primate prefrontal cortex has not been investigated. Using immunohistochemical and retrograde transport techniques, we characterized the cholecystokinin innervation of prefrontal cortex in macaque monkeys. The use of two antibodies directed against different portions of the cholecystokinin molecule revealed that distinct forms of the molecule were differentially localized in the same cortical neurons. These small, nonpyramidal cholecystokinin-positive neurons had a variety of somal morphologies and the density of labeled cells did not differ among cytoarchitectonic regions. Labeled neurons had a distinctive laminar distribution with the greatest density of cells present in layers II-superficial III. Labeled fibers also had a distinctive laminar pattern of distribution that differed from that of the immunoreactive neurons. In granular prefrontal cortex, terminal fields were evident in layers II, IV, and VI, with the greatest density in layer VI. Agranular area 24 exhibited a bilaminar pattern of immunoreactivity with a band in layer II and a very dense terminal field in layers V-VI. A high density of cholecystokinin-binding sites has been found in layers III-IV of prefrontal cortex and other association areas in the monkey; this finding has been attributed to possible cholecystokinin-containing afferents from the thalamus (Kritzer et al.: Journal of Comparative Neurology 263:418-435, 1987). The mediodorsal nucleus of the thalamus is known to be a source of afferents which terminate in layer IV of prefrontal cortex. However, combined retrograde transport and immunohistochemical techniques failed to reveal the presence of cholecystokinin-positive neurons in the mediodorsal nucleus of the thalamus that project to prefrontal cortex. These findings, and other observations, suggest that the terminal field in layer IV is formed by descending axons that arise from cholecystokinin-containing neurons in layers II and superficial III. This study demonstrates that the cholecystokinin innervation of prefrontal cortex has a laminar specific organization that is preserved across cytoarchitectonic regions. This distribution of immunoreactive structures suggests a distinctive role of cholecystokinin in cortical circuitry that is common to every region of prefrontal cortex.

Animals↗
PubMed2002

Memory trace in prefrontal cortex: theory for the cognitive switch.

The dorsolateral prefrontal cortex in human and non-human primates functions as the highest-order executor for the perception-action cycle. According to this view, when perceptual stimuli from the environment are novel or complex, the dorsolateral prefrontal cortex serves to set consciously a goal-directed scheme which broadly determines an action repertory to meet the particular demand from the environment. In this respect, the dorsolateral prefrontal cortex is a short-term activation device with the properties of a cognitive switch', because it couples a particular set of perceptual stimuli to a particular set of actions. Here, I suggest that, in order for the organism to react systematically to the environment, neural traces for the switch function must be stored in the brain. Thus, the highest-order, perception-action interface function of the dorsolateral prefrontal cortex per se depends on permanently stored neural traces in the dorsolateral prefrontal cortex and related structures. Such a memory system may be located functionally between two of the well-documented memory systems in the brain: the declarative memory system and the procedural memory system. Finally, based on available neurophysiological data, the possible mechanisms underlying the formation of cognitive switch traces are proposed.

Animals↗
PubMed1995

Local influence of endogenous norepinephrine on extracellular dopamine in rat medial prefrontal cortex.

Noradrenergic and dopaminergic projections converge in the medial prefrontal cortex and there is evidence of an interaction between dopamine (DA) and norepinephrine (NE) terminals in this region. We have examined the influence of drugs known to alter extracellular NE on extracellular NE and DA in medial prefrontal cortex using in vivo microdialysis. Local application of the NE uptake inhibitor desipramine (1.0 microM) delivered through a microdialysis probe increased extracellular DA (+149%) as well as NE (+201%) in medial prefrontal cortex. Furthermore, desipramine potentiated the tail shock-induced increase in both extracellular DA (stress alone, +64%; stress + desipramine, +584%) and NE (stress alone, +55%; stress + desipramine, +443%). In contrast, local application of desipramine did not affect extracellular DA in striatum, indicating that this drug does not influence DA efflux directly. Local application of the alpha 2-adrenoceptor antagonist idazoxan (0.1 or 5.0 mM) increased extracellular NE and DA in medial prefrontal cortex. Conversely, the alpha 2-adrenoceptor agonist clonidine (0.2 mg/kg; i.p.) decreased extracellular NE and DA in medial prefrontal cortex. These results support the hypothesis that NE terminals in medial prefrontal cortex regulate extracellular DA in this region. This regulation may be achieved by mechanisms involving an action of NE on receptors that regulate DA release (heteroreceptor regulation) and/or transport of DA into noradrenergic terminals (heterotransporter regulation).

Adrenergic Uptake Inhibitors↗
PubMed1995

The effects of dopamine on the subthreshold electrophysiological responses of rat prefrontal cortex neurons in vitro.

The rat prefrontal cortex is densely innervated by dopaminergic fibres originating in the mesencephalic ventral tegmental area, and dopamine application in vivo has an inhibitory effect. We have studied the effects of dopamine on the persistent sodium current that is present in prefrontal cortex neurons and on the subthreshold electrophysiological responses generated by that current: a slow depolarization and a fast oscillatory activity. Experiments were made in coronal slices of rat frontal cortex (300-400 microns thickness) and intracellular recordings from regularly spiking cells were obtained with 3 M potassium acetate-filled glass microelectrodes (80-150 M omega). Dopamine was applied dissolved in the extracellular medium and, in current-clamp recordings, reversibly inhibited the slow subthreshold depolarization. Dopamine was ineffective when applied after tetrodotoxin (1 microM) had blocked the action potentials. This inhibition was dose-dependent in the range of 0.1-10 microM). Dopamine, applied at 10 microM, decreased the steady-state firing frequency and also inhibited the subthreshold fast oscillatory activity. The currents activated in the subthreshold range were recorded with the single-electrode voltage-clamp technique and a clear persistent, tetrodotoxin-sensitive component was isolated. This component was inhibited by 50% in a reversible way by 20 microM dopamine. These results show that dopamine increases the threshold for spike firing and suggest a mechanism for the inhibitory action of this neurotransmitter in the prefrontal cortex.

Animals↗
PubMed1991

The prefrontal cortex and its relation to behavior.

The prefrontal cortex is critical for temporal organization of behavior. It mediates cross-temporal sensory-motor contingencies, integrating motor action (including speech) with recent sensory information. It performs this role through cooperation of two cognitive functions represented in its dorsolateral areas: short-term memory (STM) and preparatory set. Supporting data have been obtained from monkeys performing delay tasks, which epitomize the principle of cross-temporal contingency. In a given trial, the animal performs an act contingent on a sensory cue given a few seconds or minutes earlier. During the delay between cue and response, cells in dorsolateral prefrontal cortex show sustained activation. Two cell categories can be identified in tasks in which cue and response are spatially separate. Cells of the first participate in STM: Their activation tends to diminish as the delay progresses; in some, the activation level depends on the particular cue received. Similar cells are found elsewhere in cortex. Cells of the second category seem to take part in preparation of motor response: Their activation tends to increase in anticipation of it and may be attuned to the particular movement the cue calls for. This cell type is rare outside of frontal cortex. The temporally integrative function of the prefrontal cortex is probably based on local interactions between "memory" and "motor-set" cells, as well as on neural associations between prefrontal cortex and posterior cortical areas.

Animals↗
PubMed1991

Organization of amygdaloid projections to the prefrontal cortex and associated striatum in the rat.

The organization of connections between the amygdala, prefrontal cortex and striatum was studied using anterograde and retrograde tract tracing techniques in the rat. The anterograde transport of Phaseolus vulgaris leucoagglutinin and wheat germ agglutinin conjugated to horseradish peroxidase was used to examine the striatal projections of the prefrontal cortex. These studies revealed that the prelimbic area of the medial prefrontal cortex projects mainly to the medial part of the striatum, whereas the dorsal agranular insular area of the lateral prefrontal cortex projects mainly to the ventrolateral part of the striatum. The organization of amygdaloid projections to the prefrontal cortex and its associated portions of the striatum was investigated using the fluorescence retrograde tract tracing technique. Different color fluorescent dyes, True Blue and Diamidino Yellow, were injected into the prefrontal cortex and striatum. These studies demonstrated that medial portions of the basolateral nucleus, and adjacent portions of the lateral, basomedial and amygdalo-hippocampal nuclei, project to both the medial prefrontal cortex and its associated medial striatal region. The rostral pole and lateral portions of the basolateral nucleus project to both the lateral prefrontal cortex and its associated lateral striatal region. Many neurons in the basolateral amygdaloid nucleus, and to a lesser extent other amygdaloid nuclei, were double-labeled in these experiments, indicating that these cells send collaterals to both the prefrontal cortex and striatum. These findings indicate that discrete areas of the amygdala, and in some cases individual amygdaloid neurons, can modulate information processing in the first two links of distinct cortico-striato-pallidal systems arising in the medial and lateral prefrontal cortex.

Afferent Pathways↗
PubMed1986

[Visual information processing from the retina to the prefrontal cortex].

Studies on the neural bases of visual information processing were reviewed by tracing connections from the retina to the prefrontal cortex in the monkey; i.e., retina--lateral geniculate body (LGB)--striate cortex--prestriate cortex--inferotemporal (IT) cortex or posterior parietal (PP) cortex--prefrontal cortex. The retinotopy exists up to the level of prestriate cortex, but it is lost in the IT or PP cortex. A general tendency is observed that the later is the stage of information processing, the longer is the latency of cell activity changes, the larger is the size of receptive field, and more complex become trigger features. Small spot stimuli activate retinal ganglion cells or LGB cells while bars or edges with proper orientation are trigger stimuli for striate and some prestriate cells. In restricted prestriate areas, cells which are selective to color or movement are observed. IT cells are activated by complex pattern stimuli, while PP cells are selective to spatial aspects of the stimulus. Some prefrontal cells encode the meaning of the stimulus independent of its physical properties.

Animals↗
PubMed2006

Making working memory work: a computational model of learning in the prefrontal cortex and basal ganglia.

The prefrontal cortex has long been thought to subserve both working memory (the holding of information online for processing) and executive functions (deciding how to manipulate working memory and perform processing). Although many computational models of working memory have been developed, the mechanistic basis of executive function remains elusive, often amounting to a homunculus. This article presents an attempt to deconstruct this homunculus through powerful learning mechanisms that allow a computational model of the prefrontal cortex to control both itself and other brain areas in a strategic, task-appropriate manner. These learning mechanisms are based on subcortical structures in the midbrain, basal ganglia, and amygdala, which together form an actor-critic architecture. The critic system learns which prefrontal representations are task relevant and trains the actor, which in turn provides a dynamic gating mechanism for controlling working memory updating. Computationally, the learning mechanism is designed to simultaneously solve the temporal and structural credit assignment problems. The model's performance compares favorably with standard backpropagation-based temporal learning mechanisms on the challenging 1-2-AX working memory task and other benchmark working memory tasks.

Algorithms↗
PubMed1996

Response channel activation and the lateral prefrontal cortex.

The role of lateral prefrontal cortex in transducing perception into action was studied in 10 patients with chronic, unilateral lesions. They identified colors in the center of a visual display, while a flanking, distractor color was presented simultaneously in either the ipsilesional or contralesional field. The flanker could be either the same color as the target, or incompatible with the correct response. The effects of compatible and incompatible flankers on reaction time (RT) served as a measure of response channel activation by the flanker. Flankers in the contralesional field influenced RT less than did those in the ipsilesional field. These results suggest that the lateral prefrontal cortex is involved in maintaining stimulus-response channels.

Adult↗
PubMed1989

Comparison of human infants and rhesus monkeys on Piaget's AB task: evidence for dependence on dorsolateral prefrontal cortex.

This paper reports evidence linking dorsolateral prefrontal cortex with one of the cognitive abilities that emerge between 7.5-12 months in the human infant. The task used was Piaget's Stage IV Object Permanence Test, known as AB (pronounced "A not B"). The AB task was administered (a) to human infants who were followed longitudinally and (b) to intact and operated adult rhesus monkeys with bilateral prefrontal and parietal lesions. Human infants displayed a clear developmental progression in AB performance, i.e., the length of delay required to elicit the AB error pattern increased from 2-5 s at 7.5-9 months to over 10 s at 12 months of age. Monkeys with bilateral ablations of dorsolateral prefrontal cortex performed on the AB task as did human infants of 7.5-9 months; i.e., they showed the AB error pattern at delays of 2-5 s and chance performance at 10 s. Unoperated and parietally operated monkeys succeeded at delays of 2, 5, and 10 s; as did 12 month old human infants. AB bears a striking resemblance to Delayed Response, the classic test for dorsolateral prefrontal function in the rhesus monkey, and indeed performance on AB and Delayed Response in the same animals in the present study was fully comparable. These findings provide direct evidence that AB performance depends upon dorsolateral prefrontal cortex in rhesus monkeys and indicates that maturation of dorsolateral prefrontal cortex may underlie the developmental improvement in AB performance of human infants from 7.5-12 months of age. This improvement marks the development of the ability to hold a goal in mind in the absence of external cues, and to use that remembered goal to guide behavior despite the pull of previous reinforcement to act otherwise. This confers flexibility and freedom to choose and control what one does.

Aging↗
PubMed1999

5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex.

Monoamines, including both dopamine and serotonin, synapse onto prefrontal cortical interneurons. Dopamine has been shown to activate these GABAergic interneurons, but there are no direct data on the effects of serotonin on GABA release in the prefrontal cortex. We, therefore, examined the effects of the 5-HT2a/c agonist 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) on extracellular GABA levels in the prefrontal cortex of the rat. Local infusions of DOI dose-dependently increased cortical extracellular GABA levels. In addition, systemic DOI administration resulted in Fos protein expression in glutamic acid decarboxylase67-immunoreactive interneurons of the prefrontal cortex. These data indicate that serotonin, operating through a 5-HT2 receptor, acutely activates GABAergic interneurons in the prefrontal cortex. These data further suggest that there may be convergent regulation of interneurons by dopamine and serotonin in the prefrontal cortex.

Animals↗
PubMed2002

Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat.

Altered dopamine regulation in the medial prefrontal cortex has been linked to drug abuse and disorders such as schizophrenia. Heterogeneous expression of the dopamine transporter, as well as the ability of the norepinephrine transporter to clear dopamine in the prefrontal cortex, delineates two potential sites for the regulation of synaptic dopamine within the cortex. The present study used in vivo microdialysis to compare the effects of local infusions of dopamine and norepinephrine uptake blockers in the caudate putamen and two subregions of the prefrontal cortex, the anterior cingulate and prelimbic/infralimbic cortices. Results revealed that all dopamine uptake blockers produced greater increases in dopamine efflux in the caudate-putamen relative to the prefrontal cortex. In addition, amphetamine administration increased dopamine efflux to a greater degree in the prelimbic, relative to the anterior cingulate, cortex. In contrast, the increase in dopamine efflux was similar in both subregions in the presence of nomifensine and desmethylimipramine. Infusions of the selective dopamine uptake blocker GBR 12909 failed to alter dopamine efflux in any prefrontocortical subregion. These data indicate a more prominent role for the dopamine transporter in the clearance of extracellular dopamine in the caudate-putamen relative to the prefrontal cortex and an important role for NET in the clearance of dopamine in both the prelimbic and anterior cingulate subregions of the rat medial prefrontal cortex.

Adrenergic Uptake Inhibitors↗
PubMed2004

Influence of the hippocampus on interneurons of the rat prefrontal cortex.

The hippocampus and prefrontal cortex (PFC), two structures implicated in learning and memory processes, are linked by a direct hippocampo-prefrontal pathway. It has been shown that PFC pyramidal cells receive monosynaptic excitatory inputs from the hippocampus and, in this study, we sought to determine the influence of the hippocampus on PFC interneurons in anesthetized rats. Extracellular recordings were coupled to juxtacellular injections of neurobiotin or biotinylated dextran amine to morphologically differentiate interneurons from pyramidal cells. In all cases, the action potentials of labeled interneurons were of shorter duration (< 0.70 ms) than those of identified pyramidal cells (> 0.70 ms). Single pulse stimulation of the hippocampal CA1/subiculum region induced an excitatory response in 70% of recorded interneurons in the prelimbic and medial-orbital areas of the PFC. In contrast to the one to two action potentials generated by pyramidal cells, an important group of interneurons fired a burst of action potentials in response to hippocampal stimulation. A large proportion of these excitatory responses was probably monosynaptic as their latency is consistent with the conduction time of the hippocampo-prefrontal pathway. In addition, when both a pyramidal cell and an interneuron were simultaneously recorded and both responded to stimulation, the interneuron consistently fired before the pyramidal cell. In conclusion, the hippocampus exerts a direct excitatory influence on PFC interneurons and is thus capable of feedforward inhibition of pyramidal cells. Hippocampal output is spatially and temporally focalized via this inhibitory process and consequently could facilitate the synchronization of a specific subset of PFC neurons with hippocampal activity.

Action Potentials↗
PubMed2001

Behavioral planning in the prefrontal cortex.

Recent studies have presented evidence that the prefrontal cortex plays a crucial role in every aspect of the cognitive processes necessary for behavioral planning: processing and integration of perceived or memorized information, associative learning, reward-based behavioral control, behavioral selection/decision-making and behavioral guidance. We propose that the creation of novel information is the means by which the prefrontal cortex operates to achieve executive control over behavioral planning. The prefrontal cortex is the site of operation of nodal points, where neural circuits integrate currently available or memorized information to generate the information that is necessary to perform an action. The prefrontal cortex also regulates the flow of information through multiple nodes to meet behavioral demands.

Animals↗
PubMed1991

D1 dopamine receptors in prefrontal cortex: involvement in working memory.

The prefrontal cortex is involved in the cognitive process of working memory. Local injections of SCH23390 and SCH39166, selective antagonists of the D1 dopamine receptor, into the prefrontal cortex of rhesus monkeys induced errors and increased latency in performance on an oculomotor task that required memory-guided saccades. The deficit was dose-dependent and sensitive to the duration of the delay period. These D1 antagonists had no effect on performance in a control task requiring visually guided saccades, indicating that sensory and motor functions were unaltered. Thus, D1 dopamine receptors play a selective role in the mnemonic, predictive functions of the primate prefrontal cortex.

Animals↗