Neuronal activity in the monkey dorsolateral prefrontal cortex during a discrimination task with delay

Ninety-nine single neuron activities of the dorsolateral prefrontal cortex of 3 monkeys were recorded during performance of a Konorski task. Green or red lights were presented successively with a separation of fixed delay interval. The monkey responded as soon as the second stimulus was presented. If the two stimuli were color-matched, the ‘YES’ lever press was rewarded; if the two stimuli were not, the ‘NO’ lever press was rewarded. In the second task, after paired color stimuli, a tone pip was presented as the ‘GO’ signal for lever presses. During sample and matching periods 50 neurons increased their discharge rates and 10 decreased. In 86% of increasing type neurons rate increase occurred during both periods. During auditory GO periods, 27 neurons increased their rates and 11 decreased. Discharge peak was before or at the moment of hold key release. In 60% of these neurons were also observed the rate changes to sample and matching stimuli. Differential activations between left and right levers were found in 20%. It was suggested that the prefrontal cortex is related to a sensorial attention mechanism to the visual stimulus which enables correct choice of the behavior to be rewarded.     

Neuronal activity in primate dorsolateral and orbital prefrontal cortex during performance of a reward preference task

An important function of the prefrontal cortex (PFC) is the control of goal-directed behaviour. This requires information as to whether actions were successful in obtaining desired outcomes such as rewards. While lesion studies implicate a particular PFC region, the orbitofrontal cortex (OFC), in reward processing, neurons encoding reward have been reported in both the OFC and the dorsolateral prefrontal cortex (DLPFC). To compare and contrast their roles, we recorded simultaneously from both areas while two rhesus monkeys (Macaca mulatta) performed a reward preference task. The monkeys had to choose between pictures associated with different amounts of a juice reward. Neuronal activity in both areas reflected the reward amount. However, neurons in the DLPFC encoded both the reward amount and the monkeys' forthcoming response, while neurons in the OFC more often encoded the reward amount alone. Further, reward selectivity arose more rapidly in the OFC than the DLPFC. These results are consistent with reward information entering the PFC via the OFC, where it is passed to the DLPFC and used to control behaviour.     

Anticipatory activity in rat medial prefrontal cortex during a working memory task

Objective Working memory is a key cognitive function in which the prefrontal cortex plays a crucial role. This study aimed to show the firing patterns of a neuronal population in the prefrontal cortex of the rat in a working memory task and to explore how a neuronal ensemble encodes a working memory event.Methods Sprague-Dawley rats were trained in a Y-maze until they reached an 80%correct rate in a working memory task.Then a 16-channel microelectrode array was implanted in the prefrontal cortex.After recovery,neuronal population activity was recorded during the task, using the Cerebus data-acquisition system.Spatio-temporal trains of action potentials were obtained from the original neuronal population signals.Results During the Y-maze working memory task,some neurons showed significantly increased firing rates and evident neuronal ensemble activity.Moreover,the anticipatory activity was associated with the delayed alternate choice of the upcoming movement.In correct trials,the averaged pre-event firing rate(10.86±1.82 spikes/ bin) was higher than the post-event rate(8.17±1.15 spikes/bin)(P <0.05).However,in incorrect trials,the rates did not differ.Conclusion The results indicate that the anticipatory activity of a neuronal ensemble in the prefrontal cortex may play a role in encoding working memory events.     

Properties of delay-period neuronal activity in the primate prefrontal cortex during memory- and sensory-guided saccade tasks

The dorsolateral prefrontal cortex (DLPFC) is involved in visuospatial short-term (or working) memory. Its cellular basis has been widely examined using the delayed-response paradigm in nonhuman primates. Sustained delay-period activity in DLPFC neurons with directional difference (i.e. directional delay-period activity) has been thought to represent visuospatial short-term (or working) memory. However, little is known about the activity of these neurons during a delay period when the sensory input remains. To address this issue, we examined neuronal activity in the DLPFC while macaque monkeys performed a memory-guided saccade (MGS) task and a delayed visually guided saccade (VGS) task. The MGS task required a memory-guided saccade for a remembered target location. The VGS task had the same temporal sequence as the MGS task, but the sensory stimulus remained during the delay period. We found that most of the DLPFC neurons with directional delay-period activity showed sustained activation during the 'delay' period in the VGS task only ('V-neurons', 49%), or in both tasks ('MV-neurons', 46%). Neurons showing directional delay-period activity in the MGS task only ('M-neurons') were only 5% of the DLPFC neurons with directional delay-period activity. These findings indicate that most DLPFC neurons that are active during the delay period are also active when the sensory stimulus remains, suggesting that DLPFC neurons driven by mnemonic information are also driven by sensory input. Such sustained representation of information should have potential utility in flexible cognitive controls of behaviour.     

Correlated discharges in the primate prefrontal cortex before and after working memory training

The correlation of discharges between single neurons can provide information about the computations and network properties of neuronal populations during the performance of cognitive tasks. In recent years, dynamic modulation of neuronal correlations by attention has been revealed during the execution of behavioral tasks. Much less is known about the influence of learning and performing a task itself. We therefore sought to quantify the correlated firing of simultaneously recorded pairs of neurons in the prefrontal cortex of naïve monkeys that were only required to fixate, and to examine how this correlation was altered after they had learned to perform a working memory task. We found that the trial‐to‐trial correlation of discharge rates between pairs of neurons (noise correlation) differed across neurons depending on their responsiveness and selectivity for stimuli, even before training in a working memory task. After monkeys had learned to perform the task, correlated firing decreased overall, although the effects varied according to the functional properties of the neurons. The greatest decreases were observed on comparison of populations of neurons that exhibited elevated firing rates during the trial events and those that had more similar spatial and temporal tuning. Greater decreases in noise correlation were also observed for pairs comprising one fast spiking neuron (putative interneuron) and one regular spiking neuron (putative pyramidal neuron) than pairs comprising regular spiking neurons only. Our results demonstrate that learning and performance of a cognitive task alters the correlation structure of neuronal firing in the prefrontal cortex.     

Cholinergic enhancement eliminates modulation of neural activity by task difficulty in the prefrontal cortex during working memory

Previously, we demonstrated that enhancing cholinergic activity during a working memory (WM) task improves performance and reduces blood flow in the right anterior middle/superior frontal cortex, an area known to be important for WM. The purpose of this study was to evaluate the interaction between WM task demands and cholinergic enhancement on neural responses in the prefrontal cortex. Regional cerebral blood flow (rCBF) was measured using H(2)(15)O and positron emission tomography, as 10 young healthy volunteers performed a parametrically varied match-to-sample WM for faces task. For each item, a picture of a face was presented, followed by a delay (1, 6, 11, or 16 sec), then by the presentation of two faces. Subjects were instructed to identify which face they previously had seen. For control items, nonsense pictures were presented in the same spatial and temporal manner. All conditions were performed during an intravenous infusion of saline and physostigmine (1 mg/hr). Subjects were blind to the substance being infused. Reaction time increased significantly with WM delay, and physostigmine decreased reaction time across delay conditions. Significant task-related rCBF increases during saline infusion were seen in superior frontal, middle frontal, and inferior frontal regions, and the response magnitudes in the regions increased systematically with task difficulty. In all of these prefrontal regions, physostigmine administration significantly reduced rCBF during task, particularly at longer task delays, so that no correlation between task delay and rCBF was observed. In the ventral visual cortex, physostigmine increased rCBF at longer task delays in medial regions, and decreased rCBF over delay conditions in lateral cortical areas. These results indicate that, during cholinergic potentiation, brain activity in prefrontal regions is not modulated by increases in WM task demands, and lends further support to the hypothesis that cholinergic modulation enhances visual processing, making the task easier to perform, and thus, compensate for the need to recruit prefrontal cortical regions as task demands increase.     

Selective representation of task-relevant objects and locations in the monkey prefrontal cortex

In the monkey prefrontal cortex (PFC), task context exerts a strong influence on neural activity. We examined different aspects of task context in a temporal search task. On each trial, the monkey (Macaca mulatta) watched a stream of pictures presented to left or right of fixation. The task was to hold fixation until seeing a particular target, and then to make an immediate saccade to it. Sometimes (unilateral task), the attended pictures appeared alone, with a cue at trial onset indicating whether they would be presented to left or right. Sometimes (bilateral task), the attended picture stream (cued side) was accompanied by an irrelevant stream on the opposite side. In two macaques, we recorded responses from a total of 161 cells in the lateral PFC. Many cells (75/161) showed visual responses. Object-selective responses were strongly shaped by task relevance - with stronger responses to targets than to nontargets, failure to discriminate one nontarget from another, and filtering out of information from an irrelevant stimulus stream. Location selectivity occurred rather independently of object selectivity, and independently in visual responses and delay periods between one stimulus and the next. On error trials, PFC activity followed the correct rules of the task, rather than the incorrect overt behaviour. Together, these results suggest a highly programmable system, with responses strongly determined by the rules and requirements of the task performed.     

Encoding problem-solving strategies in prefrontal cortex: activity during strategic errors

The primate prefrontal cortex (PF) plays a central role in choosing goals and strategies. To better understand its mechanisms, we recorded from PF neurons as monkeys used abstract response strategies to select a spatial goal. A visual cue, selected randomly from a set of three cues, appeared on each trial. All three cues were novel when neuronal recording commenced. From trial to trial, the cue could have either been repeated or changed from the previous trial; these were called repeat trials and change trials, respectively. On repeat trials, the monkeys used a Repeat–stay strategy to gain a reward by choosing the same spatial goal as on the previous trial; on change trials, they used a Change–shift strategy to reject the previous goal in favour of an alternative. We reported previously that when monkeys performed the task correctly, many PF neurons had activity encoding one of these two strategies. The monkeys sometimes chose the incorrect strategy, however. Strategy coding was weak or absent during the cue period of error trials which was, for correct trials, the time when the monkeys used a strategy to choose a future goal. By contrast, later in the trial, after the chosen goal had been attained and the monkeys awaited feedback, strategy coding was present and it reflected the strategy used, whether correct or incorrect. The weak cue-period strategy signal could, whatever its cause, have contributed to the errors made, whereas the activity prior to feedback suggests a role in monitoring task performance.     

Dynamic reorganization of neural activity in motor cortex during new sequence production

Although previous studies have shown that primary motor cortex (M1) neurons are modulated during the performance of a sequence of movements, it is not known how this neural activity in the M1 reorganizes during new learning of sequence‐dependent motor skills. Here we trained monkeys to move to each of four spatial targets to produce multiple distinct sequences of movements in which the spatial organization of the targets determined uniquely the serial order of the movements. After the monkeys memorized the sequences, we changed one element of these over‐practised sequences and the subjects were required to learn the new sequence through trial and error. When one element in an over‐learned four‐element sequence was changed, the sequence‐specific neural activity was totally disrupted, but relatively minor changes in the direction‐specific activity were observed. The data suggest that sequential motor skills are represented within M1 in the context of the complete sequential behavior rather than as a series of single consecutive movements; and sequence‐specific neurons in the M1 are involved in new learning of sequence by using memorized knowledge to acquire complex motor skill efficiently.     

Single neuron activity in dorsolateral prefrontal cortex of monkey during operant behavior sustained by food reward

The activity of 190 neurons was recorded from the dorsolateral prefrontal cortex of monkeys during an operant task that consisted of 3 phases: visual discrimination of food and non-food, bar pressing to gain access to the food and ingestion. In area 8, a fairly large proportion of the 49 recorded neurons responded in both the visual discrimination (37%) and motor initiation (35%) phases. Some functional heterogeneity seems evident within area 8 since visual discrimination responses were rostral, visuokinesis was central and motor initiation was in the caudal bank of the arcuate sulcus. Neurons in area 9 responded primarily (37%) during the bar pressing phase and less during the visual discrimination phase. Neurons in area 10 responded variously during most phases of the task--food discrimination, bar pressing, and ingestion. Neurons in the periprincipal sulcal area usually responded in the visual discrimination phase, but some which did not respond to food presented in front of the subject responded to meaningful visual or auditory cues that were related to food reward. The data suggest that neurons in the dorsolateral prefrontal cortex have multiple functions related to all phases of complex, learned feeding behavior. Functional roles of the prefrontal cortex and the lateral hypothalamus in development of feeding behavior are discussed.     

Mirror trends of plasticity and stability indicators in primate prefrontal cortex

Research on plasticity markers in the cerebral cortex has largely focused on their timing of expression and role in shaping circuits during critical and normal periods. By contrast, little attention has been focused on the spatial dimension of plasticity–stability across cortical areas. The rationale for this analysis is based on the systematic variation in cortical structure that parallels functional specialization and raises the possibility of varying levels of plasticity. Here, we investigated in adult rhesus monkeys the expression of markers related to synaptic plasticity or stability in prefrontal limbic and eulaminate areas that vary in laminar structure. Our findings revealed that limbic areas are impoverished in three markers of stability: intracortical myelin, the lectin Wisteria floribunda agglutinin, which labels perineuronal nets, and parvalbumin, which is expressed in a class of strong inhibitory neurons. By contrast, prefrontal limbic areas were enriched in the enzyme calcium/calmodulin‐dependent protein kinase II (CaMKII), known to enhance plasticity. Eulaminate areas have more elaborate laminar architecture than limbic areas and showed the opposite trend: they were enriched in markers of stability and had lower expression of the plasticity‐related marker CaMKII. The expression of glial fibrillary acidic protein (GFAP), a marker of activated astrocytes, was also higher in limbic areas, suggesting that cellular stress correlates with the rate of circuit reshaping. Elevated markers of plasticity may endow limbic areas with flexibility necessary for learning and memory within an affective context, but may also render them vulnerable to abnormal structural changes, as seen in neurologic and psychiatric diseases.     

Influence of acetylcholine on neuronal activity in monkey orbitofrontal cortex during bar press feeding task

Cholinergic involvement in feeding-related neuronal activity was investigated in the orbitofrontal cortex (OBF) of the behaving monkey by means of a microiontophoretic application of acetylcholine (ACh) and atropine. The activity of ACh sensitive cells did not correlate with any particular event during the bar press feeding task. Atropine blocked the excitatory response to ACh and task events. The results suggest that the cholinergic system in the monkey OBF regulates excitatory neuronal responses in several phases of motivated behavior.     

Opposing influences of emotional and non-emotional distracters upon sustained prefrontal cortex activity during a delayed-response working memory task

Performance in delayed-response working memory (WM) tasks is typically associated with sustained activation in the dorsolateral prefrontal cortex (dlPFC) that spans the delay between the memoranda and the memory probe. Recent studies have demonstrated that novel distracters presented during the delay interval both affect sustained activation and impair WM performance. However, the effect of the performance-impairing distracters upon sustained dlPFC delay activity was related to the characteristics of the distracters: memoranda-confusable distracters increased delay activity, whereas memoranda-nonconfusable emotional distracters decreased delay activity. Because these different effects were observed in different studies, it is possible that different dlPFC regions were involved and the paradox is more apparent than real. To investigate this possibility, event-related fMRI data were recorded while subjects performed a WM task for faces with memoranda-confusable (novel faces) and memoranda-nonconfusable emotional (novel scenes) distracters presented during the delay interval. Consistent with previous findings, confusable face distracters increased dlPFC delay activity, while nonconfusable emotional distracters decreased dlPFC delay activity, and these opposing effects modulated activity in the same dlPFC regions. These results provide direct evidence that specific regions of the dlPFC are generally involved in mediating the effects of distraction, while showing sensitivity to the nature of distraction. These findings are relevant for understanding alterations in the neural mechanisms associated with both general impairment of cognitive control and with specific impairment in the ability to control emotional distraction, such as those observed in aging and affective disorders, respectively.     

Modifications of neuron activities of the dorsolateral prefrontal cortex during extrafoveal attention

In order to determine the involvement of the dorsolateral prefrontal cortex (PF) of monkeys in extrafoveal visual attention, PF neuron activities to the identical visual stimuli presented extrafoveally were compared during a simple visual fixation task and an extrafoveal attention task. Four out of 29 steady type neurons showed a clear change after the extrafoveal stimuli presented during the extrafoveal attention task. Ten out of 75 transient type neurons showed a subtle change during extrafoveal attention. It was concluded that a fraction of the prefrontal neurons of the steady type is involved in an attention mechanism to the extrafoveal vision.     

Distribution of mGluR1alpha and mGluR5 immunolabeling in primate prefrontal cortex

Metabotropic glutamate receptors (mGluRs) mediate important modulatory glutamatergic influences throughout the brain. However, the specific localization and functions of group I mGluR subtypes (mGluR1alpha and mGluR5) in cortical neurotransmission are not well known, particularly in primates. To address this issue, we used immunoelectron microscopy to compare the subcellular localizations of mGluR1alpha and mGluR5 in the prefrontal cortex of macaque monkeys. Both receptor subtypes were found in a variety of subcellular compartments, including spines, dendrites, preterminal axons, axon terminals, and glia; however, quantitative differences were found in the relative abundance of labeled elements for each receptor. The mGluR1alpha-immunoreactive (-IR) elements were overwhelmingly the spines and dendrites, with labeled terminals, axons, and glia seen more rarely. The mGluR5-IR elements were also mostly spines and dendrites, but the proportion of labeled unmyelinated axons, terminals, and glia was higher than for mGluR1alpha-IR elements. Double labeling with SMI-32 and parvalbumin confirmed that both receptors were found in pyramidal cell and interneuron dendrites. The localization of mGluR1alpha to pyramidal cells in primate cortex contrasts with reports that mGluR1alpha is found almost exclusively in interneurons in rodent cortex. By using double labeling, we found no evidence for mGluR1alpha or mGluR5 in dopaminergic afferents to prefrontal cortex. The data presented here provide an anatomical substrate for a differential role of mGluR1alpha and mGluR5 in post-and presynaptic actions of glutamate in primate prefrontal cortex. They further suggest differences in the cortical distribution of group I mGluRs between primates and rodents.     

Caudate unit activity during operant feeding behavior in monkeys and modulation by cooling prefrontal cortex

Activity was recorded from 351 neurons in the head of the caudate nucleus (CD) of monkeys during an operant feeding task consisting of: (1) food or non-food presentation (P); (2) bar pressing (B); and (3) food acquisition and ingestion (I). Of 45 neurons which responded in the P phase and were tested systematically, 27 responded to visual presentation of both food and non-food (non-specific response), and 18 responded to food presentation only (food specific response). The magnitude of food specific responses depended on the nature of the food and was inversely related to the latency of the onset of bar pressing. Thirty-five neurons responded in the B phase: 28 changed firing rate continuously with no correlation to individual bar presses, while the activity of the other 7 was related to each bar press. In the I phase, 62 neurons responded to separate events: the activity of more than half (39 neurons) was often related to chewing movement or gustatory stimuli, and that of one third (23 neurons) changed during individual arm movements. The neurons which responded in the P phase were found to be distributed widely in the head of the CD except for its central zone, while the neurons which responded in the I phase were in the medial part. Cooling of the dorsolateral prefrontal cortex abolished the continuous responses seen in the B phase, but did not abolish the feeding behavior. The data suggest that in the head of the CD there are several groups of neurons that have different functions and different distributions: food specific, sensory integration responses, non-motor responses driven by the frontal cortex, motor responses coupled to various movements, and sensory responses which apparently originate in the intra-oral cavity. These functions may arise sequentially, or in correspondence with integration of the sensory and motor systems to produce coordinated behavior.     

Functional heterogeneity of single neuronal activity in the monkey dorsolateral prefrontal cortex

Extracellular single unit recording during high fixed ratio bar press behavior, guided by multimodal cue stimuli for food intake, revealed functional heterogeneity in the monkey dorsolateral prefrontal cortex. Cells were found significantly more often in the ventral arcuate concavity, the dorsal arcuate concavity, the principal sulcal area and the inferior convexity which responded, respectively, to visual events, auditory events, visual plus auditory events and bar press.     

Neurotoxic lesions of ventrolateral prefrontal cortex impair object-in-place scene memory

Disconnection of the frontal lobe from the inferotemporal cortex produces deficits in a number of cognitive tasks that require the application of memory-dependent rules to visual stimuli. The specific regions of frontal cortex that interact with the temporal lobe in performance of these tasks remain undefined. One capacity that is impaired by frontal-temporal disconnection is rapid learning of new object-in-place scene problems, in which visual discriminations between two small typographic characters are learned in the context of different visually complex scenes. In the present study, we examined whether neurotoxic lesions of ventrolateral prefrontal cortex in one hemisphere, combined with ablation of inferior temporal cortex in the contralateral hemisphere, would impair learning of new object-in-place scene problems. Male macaque monkeys learned 10 or 20 new object-in-place problems in each daily test session. Unilateral neurotoxic lesions of ventrolateral prefrontal cortex produced by multiple injections of a mixture of ibotenate and N-methyl-D-aspartate did not affect performance. However, when disconnection from inferotemporal cortex was completed by ablating this region contralateral to the neurotoxic prefrontal lesion, new learning was substantially impaired. Sham disconnection (injecting saline instead of neurotoxin contralateral to the inferotemporal lesion) did not affect performance. These findings support two conclusions: first, that the ventrolateral prefrontal cortex is a critical area within the frontal lobe for scene memory; and second, the effects of ablations of prefrontal cortex can be confidently attributed to the loss of cell bodies within the prefrontal cortex rather than to interruption of fibres of passage through the lesioned area.     

Comparison of primate prefrontal and premotor cortex neuronal activity during visual categorization

Previous work has shown that neurons in the PFC show selectivity for learned categorical groupings. In contrast, brain regions lower in the visual hierarchy, such as inferior temporal cortex, do not seem to favor category information over information about physical appearance. However, the role of premotor cortex (PMC) in categorization has not been studied, despite evidence that PMC is strongly engaged by well-learned tasks and reflects learned rules. Here, we directly compare PFC neurons with PMC neurons during visual categorization. Unlike PFC neurons, relatively few PMC neurons distinguished between categories of visual images during a delayed match-to-category task. However, despite the lack of category information in the PMC, more than half of the neurons in both PFC and PMC reflected whether the category of a test image did or did not match the category of a sample image (i.e., had match information). Thus, PFC neurons represented all variables required to solve the cognitive problem, whereas PMC neurons instead represented only the final decision variable that drove the appropriate motor action required to obtain a reward. This dichotomy fits well with PFC's hypothesized role in learning arbitrary information and directing behavior as well as the PMC's role in motor planning.     

Modulation of neuronal responses in macaque primary visual cortex in a memory task

The primary visual cortex, a relatively early station in the visual pathway, has long been considered mainly as a site of basic feature detection but evidence is emerging that is consistent with the existence of feedback influences from higher cortical areas. We show that in a delayed match-to-sample memory task, where the monkey needs to remember both the visual pattern and its location, there is significant modulation of neuronal activity in the primary visual cortex suggestive of a feedback signal. Responses to identical patterns are remarkably different depending upon their place in the memory task. These modulatory influences are significantly less when the same visual patterns are shown during a simple fixation task, where these stimuli can be ignored and not attended to. The results indicate that neural processing specific to attentional and mnemonic functions can involve even primary sensory areas.