Glutamatergic and dopaminergic afferents to the prefrontal cortex regulate spatial working memory in rats

The integrity of the prefrontal cortex is critical for the expression of working memory. The prefrontal cortex is innervated by dopaminergic afferents from the ventral tegmental area and glutamatergic afferents from the mediodorsal thalamus. To determine the role of dopaminergic and glutamatergic afferents in the regulation of working memory, rats were trained to perform a spatial delayed alternation task in a T-maze. The microinjection of the ionotropic glutamate antagonists 6-cyano-7-nitroquinoxaline-2,3-dione or 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid into the prefrontal cortex impaired working memory. Consistent with a role for glutamate receptor activation, microinjecting the GABA_B agonist baclofen into the mediodorsal thalamus produced a dose-dependent disruption of working memory. In contrast, inhibition of the mesocortical dopamine projection was without effect on working memory. The blockade of D₁ and/or D₂ dopamine receptors with SCH-23390 and sulpiride was without effect on working memory. Likewise, the microinjection of baclofen into the ventral tegmental area did not impair working memory. However, stimulating mu-opioid receptors in the ventral tegmental area with [d-Ala²,N-Me-Phe⁴,Gly-ol⁵]enkephalin produced a dose-dependent impairment of working memory that was reversed by blocking D₁ dopamine receptors with SCH-23390 in the prefrontal cortex.These data demonstrate that increased dopamine tone or reduced glutamate tone in the prefrontal cortex disrupts working memory in a spatial delayed alternation task.     

Prefrontal contributions to delayed spatial and object alternation: a positron emission tomography study

Delayed alternation tasks are frequently used as probes of frontal lobe functioning. To clarify the neural substrates of delayed alternation performance in humans, the authors measured regional cerebral blood flow with H2(15)O positron emission tomography in healthy subjects as they performed delayed spatial and object alternation. Consistent with the monkey lesion literature, increased dorsolateral prefrontal activity emerged during delayed spatial alternation but not delayed object alternation, whereas orbitofrontal activations emerged in both alternation tasks. The possible cognitive processes contributing to the orbitofrontal and dorsolateral prefrontal involvement in delayed alternation are discussed. Additional activations localized to several nonfrontal regions suggest caution in interpreting alternation deficits in patients as strictly reflecting frontal lobe impairment.     

Neonatal hippocampal lesions in rhesus macaques alter the monitoring, but not maintenance, of information in working memory

Neonatal hippocampal damage in rodents impairs medial prefrontal working memory functions. To examine whether similar impairment will follow the same damage in primates, adult monkeys with neonatal hippocampal lesions and sham-operated controls were trained on two working memory tasks. The session-unique delayed nonmatch-to-sample (SU-DNMS) task measures maintenance of information in working memory mediated by the ventral lateral prefrontal cortex. The object self-ordered (Obj-SO) task measures monitoring of information in working memory mediated by the dorsolateral prefrontal cortex. Adult monkeys with neonatal hippocampal lesions performed as well as sham-operated controls on the SU-DNMS task at either the 5- or 30-s delays but were severely impaired on the Obj-SO task. These results extend the earlier findings in rodents by demonstrating that early lesions of the hippocampus in monkeys impair working memory processes known to require the integrity of the dorsolateral prefrontal cortex while sparing lower order working memory processes such as recency. Although the present results suggest that the lack of functional hippocampal inputs may have altered the maturation of the dorsolateral prefrontal cortex, future studies will be needed to determine whether the nature of the observed working memory deficit is due to an absence of the hippocampus, a maldevelopment of the dorsolateral prefrontal cortex, or both.     

Effects of chewing in working memory processing

It has been generally suggested that chewing produces an enhancing effect on cognitive performance-related aspects of memory by the test battery. Furthermore, recent studies have shown that chewing is associated with activation of various brain regions, including the prefrontal cortex. However, little is known about the relation between cognitive performances affected by chewing and the neuronal activity in specified regions in the brain. We therefore examined the effects of chewing on neuronal activities in the brain during a working memory task using fMRI. The subjects chewed gum, without odor and taste components, between continuously performed two- or three-back (n-back) working memory tasks. Chewing increased the BOLD signals in the middle frontal gyrus (Brodmann's areas 9 and 46) in the dorsolateral prefrontal cortex during the n-back tasks. Furthermore, there were more prominent activations in the right premotor cortex, precuneus, thalamus, hippocampus and inferior parietal lobe during the n-back tasks after the chewing trial. These results suggest that chewing may accelerate or recover the process of working memory besides inducing improvement in the arousal level by the chewing motion.     

Dopaminergic control of working memory and its relevance to schizophrenia: a circuit dynamics perspective

This article argues how dopamine controls working memory and how the dysregulation of the dopaminergic system is related to schizophrenia. In the dorsolateral prefrontal cortex, which is the principal part of the working memory system, recurrent excitation is subtly balanced with intracortical inhibition. A potent controller of the dorsolateral prefrontal cortical circuit is the mesocortical dopaminergic system. To understand the characteristics of the dopaminergic control of working memory, the stability of the circuit dynamics under the influence of dopamine has been studied. Recent computational studies suggest that the hyperdopaminergic state is usually stable but the hypodopaminergic state tends to be unstable. The stability also depends on the efficacy of the glutamatergic transmission in the corticomesencephalic projections to dopamine neurons. When this cortical feedback is hypoglutamatergic, the circuit of the dorsolateral prefrontal cortex tends to be unstable, such that a slight increase in dopamine releasability causes a catastrophic jump of the dorsolateral prefrontal cortex activity from a low to a high level. This may account for the seemingly paradoxical overactivation of the dorsolateral prefrontal cortex observed in schizophrenic patients. Given that dopamine transmission is abnormal in the brains of patients with schizophrenia and working memory deficit is a core dysfunction in schizophrenia, the concept of circuit stability would be useful not only for understanding the mechanisms of working memory processing but for developing therapeutic strategies to enhance cognitive functions in schizophrenia.     

Primate rhinal cortex participates in both visual recognition and working memory tasks: functional mapping with 2-DG

The rhinal cortex in the medial temporal lobe has been implicated in object recognition memory tasks and indeed is considered to be the critical node in a visual memory network. Previous studies using the 2-deoxyglucose method have shown that thalamic and hippocampal structures thought to be involved in visual recognition memory are also engaged by spatial and object working memory tasks in the nonhuman primate. Networks engaged in memory processing can be recognized by analysis of patterns of activation accompanying performance of specifically designed tasks. In the present study, we compared metabolic activation of the entorhinal and perirhinal cortex during the performance of three working memory tasks [delayed response (DR), delayed alternation (DA), and delayed object alternation (DOA)] to that induced by a standard recognition memory task [delayed match-to-sample (DMS)] and a sensorimotor control task in rhesus monkeys. A region-of-interest analysis revealed elevated local cerebral glucose utilization in the perirhinal cortex in animals performing the DA, DOA, and DMS tasks, and animals performing the DMS task were distinct in showing a strong focus of activation in the lateral perirhinal cortex. No significant differences were evident between groups performing memory and control tasks in the entorhinal cortex. These findings suggest that the perirhinal cortex may play a much broader role in memory processing than has been previously thought, encompassing explicit working memory as well as recognition memory.     

Hippocampal-prefrontocortical circuits: PKA inhibition in the prefrontal cortex impairs delayed nonmatching in the radial maze in rats

Recent findings implicate the prefrontal cortex (PFC) and, in particular, frontocortical dopamine acting at D1-like receptors, in working memory. However, the mechanisms underlying this function of dopamine remain unknown. The present studies evaluated the hypothesis that dopamine contributes to working memory through its action on the 2nd messenger cyclic 3',5'-adenosine monophosphate (cAMP) and cAMP-dependent protein kinase (PKA). Thus, rats were trained to perform random foraging or delayed (30 min) nonmatching-to-position (delayed win-shift) tasks on the radial maze. With hippocampal output to the frontal cortex disconnected by injecting lidocaine (20 microg/0.5 microl) unilaterally into the ventral subiculum, contralateral frontocortical injections of lidocaine (20 microg/0.5 microl) or the D1-like dopamine receptor antagonist SCH 23390 (0.5 microg/0.5 microl) impaired delayed win-shift but not random foraging, replicating previous findings. In similarly disconnected rats, frontocortical injections of the PKA inhibitor Rp-cAMPS (5.0 and 10.0, but not 1.0, microg/0.5 microl) selectively impaired delayed nonmatching-to-position. Results suggest that activation of the cAMP-PKA pathway by dopamine acting at D1-like receptors in the frontal cortex is necessary for working memory.     

Executive functioning and speed of processing in phenylketonuria

Treated phenylketonuria (PKU) has been linked to dopaminergic depletion in the dorsolateral prefrontal cortex, potentially leading to selective executive impairment. White matter abnormalities may lead to generalized slowing of information processing. These 2 hypotheses were evaluated in adults with PKU on a lifelong diet. Those with PKU were significantly slower than the control group regardless of working memory load on an n-back task and marginally slower regardless of trial type (inhibitory or noninhibitory) on a flanker task. There were no significant differences in speed on object alternation learning or perceptual judgment tasks. There were no group differences in accuracy on any task. These findings do not appear consistent with the selective executive hypothesis. A cognitive slowing account may prove more informative in adults with PKU, but more evidence is needed. The findings suggest that continuous dietary management is a fairly successful strategy in terms of cognitive outcome for adults.     

The functional neuroanatomy of classic delayed response tasks in humans and the limitations of cross-method convergence in prefrontal function

Three classic delay tasks: spatial delayed response, delayed spatial alternation and delayed object-alternation are prototypical experimental paradigms for mapping the functional neuroanatomy of prefrontal cortex in animals. These tasks have been applied in human lesion studies, yet there have been very few studies investigating their functional neuroanatomy in healthy human subjects. We used functional magnetic resonance imaging to investigate the functional neuroanatomy of these classic paradigms (and a fourth: object delayed response) in a single sample of healthy human participants. Consistent with previous animal, human lesion, and functional neuroimaging studies, activity was observed in prefrontal and posterior parietal cortices across all three delay tasks. Task-specific activations, however, were not entirely consistent with predictions drawn from animal lesion studies. For example, delayed object-alternation activated dorsolateral prefrontal cortex, a region not generally implicated in animal lesion reports. Spatial delayed response, classically associated with the dorsolateral prefrontal cortex, did not activate this region; it rather activated posterior premotor cortices involved in response preparation, as did spatial alternation. All three tasks activated the frontopolar cortex, a region not considered crucial in animal research but associated with manipulation of internally generated information in recent human research. While cross-method convergence may be attained for lower level perceptual or motor tasks, the results of this study caution against the assumption that lesion-specific effects in animals generalize to human prefrontal cortex function.     

Differentiating among prefrontal substrates in psychopathy: neuropsychological test findings

Frontal lobe and consequent executive dysfunction have long been related to psychopathy. More recently, there have been suggestions that specific regions of frontal cortex, rather than all of frontal cortex, may be implicated in psychopathy. To examine this issue, the authors presented 25 individuals with psychopathy and 30 comparison individuals with measures preferentially indexing the orbitofrontal cortex (OFC; object alternation task), dorsolateral prefrontal cortex (DLPFC; spatial alternation task), and anterior cingulate cortex (ACC; number-Stroop reading and counting tasks). The individuals with psychopathy showed significant impairment on the measure preferentially sensitive to OFC functioning. In contrast, the 2 groups did not show impairment on the measures preferentially sensitive to the functioning of the DLPFC or ACC. These results are interpreted with reference to executive dysfunction accounts of the disorder.     

Under the curve: critical issues for elucidating D1 receptor function in working memory

It has been postulated that spatial working memory operates optimally within a limited range of dopamine transmission and D1 dopamine receptor signaling in prefrontal cortex. Insufficiency in prefrontal dopamine, as in aging, and excessive transmission, as in acute stress, lead to impairments in working memory that can be ameliorated by D1 receptor agonist and antagonist treatment, respectively. Iontophoretic investigations of dopamine's influence on the cellular mechanisms of working memory have revealed that moderate D1 blockade can enhance memory fields in primate prefrontal pyramidal neurons while strong blockade abolishes them. The combined behavioral and physiological evidence indicates that there is a normal range of dopamine function in prefrontal cortex that can be described as an "inverted-U" relationship between dopamine transmission and the integrity of working memory. Both in vivo and in vitro studies have demonstrated a role for dopamine in promoting the excitability of prefrontal pyramidal cells and facilitating their N-methyl-d-aspartate inputs, while simultaneously restraining recurrent excitation and facilitating feedforward inhibition. This evidence indicates that there is a fine balance between the synergistic mechanisms of D1 modulation in working memory. Given the critical role of prefrontal function for cognition, it is not surprising that this balancing act is perturbed by both subtle genetic influences and environmental events. Further, there is evidence for an imbalance in these dopaminergic mechanisms in multiple neuropsychiatric disorders, particularly schizophrenia, and in related nonhuman primate models. Elucidating the orchestration of dopamine signaling in key nodes within prefrontal microcircuitry is therefore pivotal for understanding the influence of dopamine transmission on the dynamics of working memory. Here, we explore the hypothesis that the window of optimal dopamine signaling changes on a behavioral time-scale, dependent upon current cognitive demands and local neuronal activity as well as long-term alterations in signaling pathways and gene expression. If we look under the bell-shaped curve of prefrontal dopamine function, it is the relationship between neuromodulation and cognitive function that promises to bridge our knowledge between molecule and mind.     

Age-related spatial working memory impairment is caused by prefrontal cortical dopaminergic dysfunction in rats

There is evidence of prefrontal cortex (PFC)–dependent cognitive deficits, such as working memory impairment, during the normal aging process in humans and animals. Although working memory function and the PFC dopaminergic system are thought to be closely related, the relationship between them in aged subjects remains unclear. The present study was aimed to clarify the involvement of PFC dopaminergic activity in age-related working memory impairment. For this purpose, we examined working memory in young (3-month-old) and aged (24-month-old) rats, using the T-maze delayed alternation task. As a result, delayed alternation performance was impaired in aged rats compared to young rats, indicating age-related working memory impairment. In addition, aged rats showed reduced dopaminergic transmission in the prelimbic cortical region of the PFC, concomitant with attenuated tyrosine hydroxylase activity in the PFC, but not in the ventral tegmental area and substantia nigra, which was evaluated immunohistochemically and enzymatically. Moreover, age-related working memory impairment was improved by direct stimulation of the prelimbic cortical region of the PFC with 10 or 30 ng, but not 100 ng, of a D1 receptor agonist, SKF 81297, indicating that the SKF 81297 response was an inverted “U” pattern. The maximum SKF 81297 response (30 ng) was abolished by a D1 receptor antagonist, SCH 23390. Thus, age-related working memory impairment was through reduced PFC dopaminergic transmission caused by decreased dopamine synthesis in the prefrontal termination region, but not at the site where the projections originate. This finding provides direct evidence showing the involvement of dopaminergic dysfunction in the development of PFC cognitive deficits during the normal aging process and would help to understand the aging physiology and pathology of the brain.     

Altered frontal cortical dopaminergic transmission in monkeys after subchronic phencyclidine exposure: involvement in frontostriatal cognitive deficits

Long-term exposure to the psychotomimetic drug phencyclidine produces prefrontal cortical cognitive and dopaminergic dysfunction in rats and monkeys, effects possibly relevant to the frontal cortical impairments of schizophrenia. In the present study, the effects of subchronic phencyclidine administration (0.3 mg/kg twice-daily for 14 days) on monoamine systems in the monkey brain were examined and related to cognitive performance on an object retrieval/detour task, which has been linked with frontostriatal function. Long-term (14 days) administration of phencyclidine resulted in a marked and persistent reduction in dopamine utilization in the frontal cortex. Moreover, the degree of cognitive impairment in phencyclidine-treated monkeys correlated significantly with the magnitude of dopaminergic inhibition within the dorsolateral prefrontal cortex and prelimbic cortex. No specific correlation was measured for dopamine utilization in other cortical regions or for indices of serotonin transmission in any brain region. These data show that repeated exposure to phencyclidine reduces prefrontal cortical dopamine transmission, and this inhibition of dopaminergic function is associated with performance impairments on a task sensitive to frontostriatal cognitive dysfunction. Thus, the cognitive deficits of phencyclidine-treated monkeys, as in schizophrenia, appear to be mediated, in part, by reduced dopaminergic function in specific subregions of the frontal cortex.     

Dopamine enhances the neuronal activity of spatial short-term memory task in the primate prefrontal cortex

The influence of dopamine and its antagonists on neuronal activity related to the delay period of a delayed response task was examined in the monkey prefrontal cortex. Iontophoretically applied dopamine enhanced the delay-related neuronal activity, while fluphenazine and haloperidol attenuated the activity. Sulpiride had no effect on the activity. The results suggest that dopamine promotes processing of spatial short-term memory by increasing memory-related activity in the primate prefrontal cortex, probably via D1-type dopamine receptor.     

Cholinergic modulation of working memory activity in primate prefrontal cortex

The prefrontal cortex, a cortical area essential for working memory and higher cognitive functions, is modulated by a number of neurotransmitter systems, including acetylcholine; however, the impact of cholinergic transmission on prefrontal activity is not well understood. We relied on systemic administration of a muscarinic receptor antagonist, scopolamine, to investigate the role of acetylcholine on primate prefrontal neuronal activity during execution of working memory tasks and recorded neuronal activity with chronic electrode arrays and single electrodes. Our results indicated a dose-dependent decrease in behavioral performance after scopolamine administration in all the working memory tasks we tested. The effect could not be accounted for by deficits in visual processing, eye movement responses, or attention, because the animals performed a visually guided saccade task virtually error free, and errors to distracting stimuli were not increased. Performance degradation under scopolamine was accompanied by decreased firing rate of the same cortical sites during the delay period of the task and decreased selectivity for the spatial location of the stimuli. These results demonstrate that muscarinic blockade impairs performance in working memory tasks and prefrontal activity mediating working memory.     

Neurons with inverted tuning during the delay periods of working memory tasks in the dorsal prefrontal and posterior parietal cortex

The dorsolateral prefrontal and posterior parietal cortices are two interconnected brain areas that are coactivated in tasks involving functions such as spatial attention and working memory. The response properties of neurons in the two areas are in many respects indistinguishable, yet only prefrontal neurons are able to resist interference by distracting stimuli when subjects are required to remember an initial stimulus. Several mechanisms have been proposed that could account for this functional difference, including the existence of specialized interneuron types, specific to the prefrontal cortex. Although such neurons with inverted tuning during the delay period of a working memory task have been described in the prefrontal cortex, no comparative data exist from other cortical areas that would establish a unique prefrontal role. To test this hypothesis, we analyzed a large database of recordings obtained in the dorsolateral prefrontal and posterior parietal cortex of the same monkeys as they performed working memory tasks. We found that in the prefrontal cortex, neurons with inverted tuning were more numerous and manifested unique properties. Our results give credence to the idea that a division of labor exists between separate neuron types in the prefrontal cortex and that this represents a functional specialization that is not present in its cortical afferents.     

The role of rat dorsomedial prefrontal cortex in spatial working memory

We used an operant delayed spatial alternation task to examine the role of rat dorsomedial prefrontal cortex (dmPFC) in spatial working memory. The task was designed to restrict movements during the delay period to minimize use of motor-mediating strategies. Inactivation of dmPFC (muscimol) resulted in increased errors and increased the temporal variability of responding. Animals did not show perseveration after errors (i.e., responding again at the erroneous location). Under control conditions, the time between spatial responses was greater and more variable before errors as compared to correct responses. These effects were eliminated when muscimol was infused into dmPFC. Trial outcome also affected movement and delay times in the next trial. This effect was diminished with muscimol in dmPFC. By contrast, when muscimol was infused in dorsal agranular insular cortex (AId)—a region that is strongly interconnected with dorsomedial prefrontal regions—there was no effect on delayed spatial alternation performance. These experiments confirm that dmPFC is necessary for successful delayed spatial alternation and establish that there is a relationship between response time variability and trial outcome that depends on dorsomedial prefrontal function.     

Errors of memory-guided saccades in humans with lesions of the frontal eye field and the dorsolateral prefrontal cortex.

Behavioral studies in monkeys and humans suggest that systematic and variable errors of memory-guided saccades reflect distinct neuronal computations in primate spatial memory. We recorded memory-guided saccades with a 2-s delay in three patients with unilateral ischemic lesions of the frontal eye field and in three patients with unilateral ischemic lesions of the frontal eye field and the dorsolateral prefrontal cortex. Results suggest that systematic errors of memory-guided saccades originate in the frontal eye field and variable errors in the dorsolateral prefrontal cortex. These data are the first human lesion data to support the hypothesis that these regions provide functionally distinct contributions to spatial short-term memory.     

Prefrontal cortex and working memory processes

Working memory is a mechanism for short-term active maintenance of information as well as for processing maintained information. The dorsolateral prefrontal cortex has been known to participate in working memory. The analysis of task-related dorsolateral prefrontal cortex activity while monkeys performed a variety of working memory tasks revealed that delay-period activity is a neural correlate of a mechanism for temporary active maintenance of information, because this activity persisted throughout the delay period, showed selectivity to a particular visual feature, and was related to correct behavioral performances. Information processing can be considered as a change of the information represented by a population of neural activities during the progress of the trial. Using population vectors calculated by a population of task-related dorsolateral prefrontal cortex activities, we demonstrated the temporal change of information represented by a population of dorsolateral prefrontal cortex activities during performances of spatial working memory tasks. Cross-correlation analysis using spike firings of simultaneously isolated pairs of neurons reveals widespread functional interactions among neighboring neurons, especially neurons having delay-period activity, and their dynamic modulation depending on the context of the trial. Functional interactions among neurons and their dynamic modulation could be a mechanism of information processing in the dorsolateral prefrontal cortex.     

Parallel visuospatial and audiospatial working memory processes in the monkey dorsolateral prefrontal cortex

The dorsolateral area of the prefrontal cortex (PFC) in primates is involved in visuospatial working memory, but the cellular basis of spatial working memory for auditory information is poorly understood. Here we examined dorsolateral PFC neurons using visual and auditory oculomotor delayed-response tasks. We found that the dorsolateral PFC contains two groups of neurons, each showing directional delay-period activity depending on the location of the visual or auditory cue, suggesting that parallel neuronal processes for visual and auditory spatial working memory occur in the dorsolateral PFC.