Neuronal categorization and discrimination of social behaviors in primate prefrontal cortex.

It has been implied that primates have an ability to categorize social behaviors between other individuals for the execution of adequate social-interactions. Since the lateral prefrontal cortex (LPFC) is involved in both the categorization and the processing of social information, the primate LPFC may be involved in the categorization of social behaviors. To test this hypothesis, we examined neuronal activity in the LPFC of monkeys during presentations of two types of movies of social behaviors (grooming, mounting) and movies of plural monkeys without any eye- or body-contacts between them (no-contacts movies). Although the monkeys were not required to categorize and discriminate the movies in this task, a subset of neurons sampled from the LPFC showed a significantly different activity during the presentation of a specific type of social behaviors in comparison with the others. These neurons categorized social behaviors at the population level and, at the individual neuron level, the majority of the neurons discriminated each movie within the same category of social behaviors. Our findings suggest that a fraction of LPFC neurons process categorical and discriminative information of social behaviors, thereby contributing to the adaptation to social environments.

Similar prefrontal cortical activities between general fluid intelligence and visuospatial working memory tasks in preschool children as revealed by optical topography.

General fluid intelligence (gF) is a major component of intellect in both adults and children. Whereas its neural substrates have been studied relatively thoroughly in adults, those are poorly understood in children, particularly preschoolers. Here, we hypothesized that gF and visuospatial working memory share a common neural system within the lateral prefrontal cortex (LPFC) during the preschool years (4-6 years). At the behavioral level, we found that gF positively and significantly correlated with abilities (especially accuracy) in visuospatial working memory. Optical topography revealed that the LPFC of preschoolers was activated and deactivated during the visuospatial working memory task and the gF task. We found that the spatio-temporal features of neural activity in the LPFC were similar for both the visuospatial working memory task and the gF task. Further, 2 months of training for the visuospatial working memory task significantly increased gF in the preschoolers. These findings suggest that a common neural system in the LPFC is recruited to improve the visuospatial working memory and gF in preschoolers. Efficient recruitment of this neural system may be important for good performance in these functions in preschoolers, and behavioral training using this system would help to increase gF at these ages.

Functional columns in the primate prefrontal cortex revealed by optical imaging in vitro.

Although the functional column has been implicated in the dorsolateral prefrontal cortex (DLPFC) of primates, its dynamics and even existence are still uncertain. We performed optical recording with a voltage-sensitive dye (RH482) in brain slices obtained from the principal sulcal region (area 46) of macaque monkeys. Columnar activity was evoked by electrical stimulation of the middle layer (lower layer III or layer IV); this activity consisted of two components: probably action potentials and excitatory postsynaptic potentials. The width of the columnar activity was saturated when the current intensity of stimulation exceeded a certain level, that is, approximately 900 microm at the peak with this intensity. The stimulation of different sites within the same slice activated different columnar activities with only slight overlaps. Furthermore, similar columnar activity appeared when a different site within the area with columnar activity was stimulated. These findings suggest that the primate DLPFC consists of functional columns formed by excitatory synaptic connections.

Involvement of the lateral prefrontal cortex in conditional suppression of gaze shift.

Conditional execution and suppression of gaze shift are important in everyday life. To examine the possible involvement of the lateral prefrontal cortex (LPFC) in this process, we induced a local and reversible inactivation by injecting muscimol into 66 sites within the LPFC of monkeys and examined muscimol's effect on their performance in an oculomotor Go/No-Go task. This task required a subject to execute (Go) or suppress (No-Go) its gaze toward a target location in response to an instructional visual cue. Local injection of muscimol into 22 regions of the LPFC resulted in significant increases in the number of error saccades toward a few specific target locations during No-Go trials, whereas there were no error saccades in the Go trials. The onset latency of error saccades in No-Go trials was significantly longer than that of correct saccades in Go trials, but their velocity and amplitude were similar to those of correct saccades in Go trials. Go correct saccades appeared intact after the injections. These findings provide evidence that different regions of the LPFC are involved in the conditional suppression of gaze shift toward a few specific target locations, which may occur through a top-down suppressive mechanism.

Plasticity of the primate prefrontal cortex.

Cortical plasticity refers to flexible and long-lasting changes in neuronal circuitry and information processing, which is caused by learning and experience. Although cortical plasticity can be observed in every cortex of the brain, the plasticity of the prefrontal cortex (PFC) is particularly important because the PFC is involved in various cognitive functions, and its plasticity could lead to adaptive changes in the use of other brain regions. Cortical plasticity occurs at several levels, from functional molecules to the organization of large areas of the brain. Here, the authors focus mainly on the development and remodeling of the functional and structural organization of the primate PFC. They discuss how the columnar modules of the PFC develop in the immature brain, how these modules form a "cognitive field" that is responsible for a specific cognitive function, how the cognitive field could be reorganized by training in the mature brain, and how monoaminergic systems contribute to these various levels of plasticity. They suggest that monoaminergic systems, especially the dopaminergic system, are involved in various levels of cortical plasticity, such as behavioral learning and learning-dependent cortical remodeling, thereby contributing to the reorganization of the cognitive field in the primate PFC.

Prediction of relative and absolute time of reward in monkey prefrontal neurons.

We studied single-neuron activity in the monkey dorsolateral prefrontal cortex during a saccade task, in which correct responses were rewarded after a delay of 0.5 or 1.5 s in one trial-block, and after 1.5 or 3-s delay in the other trial-block. Activity of some neurons depended on the relative length of the delays (longer or shorter) within each block, and activity for the 1.5-s trials was significantly different between the blocks. Activity of another group of neurons reflected the absolute length of delay: hence, the activity in the 1.5-s trials did not differ between the blocks. These results indicate that both relative and absolute time of future reward is represented in subsets of neurons in the dorsolateral prefrontal cortex.

Developmental fractionation of working memory and response inhibition during childhood.

The lateral prefrontal cortex (LPFC) plays a major role in both working memory (WM) and response inhibition (RI), which are fundamental for various cognitive abilities. We explored the relationship between these LPFC functions during childhood development by examining the performance of two groups of children in visuospatial and auditory WM tasks and a go/no-go RI task. In the younger children (59 5- and 6-year-olds), performance on the visuospatial WM task correlated significantly with that in the auditory WM task. Furthermore, accuracy in these tasks correlated significantly with performance on the RI task, particularly in the no-go trials. In contrast, there were no significant correlations among those tasks in older children (92 8- and 9-year-olds). These results suggest that functional neural systems for visuospatial WM, auditory WM, and RI, especially those in the LPFC, become fractionated during childhood, thereby enabling more efficient processing of these critical cognitive functions.

Rule-dependent shifting of sensorimotor representation in the primate prefrontal cortex.

When we react to the outer world, perceived sensory information is frequently memorized over a temporal interval then transformed into a motor command based on a behavioural rule. In this type of memory-based sensorimotor transformation, working memory is considered to play an important role. It has been suggested that the lateral prefrontal cortex is involved in the process of the working memory. However, the neuronal mechanism for guiding a motor command from the working memory has not been established. To examine how visuospatial working memory is linked with a forthcoming saccade direction, we used an antisaccade paradigm for monkeys in which a behavioural rule was presented in the middle of a delay period. In this task, the subjects were required to maintain cue location and to select a response based on a behavioural rule. We found that a subset of mnemonic neurons in the lateral prefrontal cortex changed their representation from cue to saccade direction. Furthermore, the discriminability for saccade direction of these neurons tended to appear soon after the behavioural rule presentation, indicating their significant dependency on the behavioural rule. These results suggest that a subset of mnemonic neurons in the lateral prefrontal cortex change their activity depending on a behavioural rule to guide a prospective motor command.

Contrasting effects of reward expectation on sensory and motor memories in primate prefrontal neurons.

The value of reward obtained with successful behavior is important for guiding purposeful behavior. The lateral prefrontal cortex (LPFC) has been implicated in working memory that guides goal-directed behavior. However, mechanism that integrates the reward value into the working memory for goal-directed behavior is not understood. To help clarify this issue, we examined the effect of reward expectation on the neuronal process in the LPFC associated with memory-based sensorimotor processing. By temporally dissociating visuospatial sensory and saccade-directional motor memories in the LPFC, we here show that reward expectation significantly enhanced the directional selectivity of sensory working memory but did not affect the directional selectivity of motor memory. The enhancement of sensory working memory in the neuronal population was sustained during the delay but extinguished soon after the motor memory appeared. These results suggest that the expectation of high reward value primarily affects the sensory working memory that may be used for behavioral guidance rather than preparation for forthcoming saccades. It thus appears that the LPFC is a neuronal substrate for working memory used to guide a reward-oriented behavior, rather than reflecting an efficient control of motor action in motivated states.

Neural representation of response category and motor parameters in monkey prefrontal cortex.

Conditional motor behavior, in which the relationship between stimuli and responses changes arbitrarily, is an important component of cognitive motor function in primates. It is still unclear how cognitive processing for conditional motor control determines movement parameters to directly specify motor output. To address this issue, we studied the neuronal representation of motor variables relating to conditional motor control and also directly to the metrics of motor output in prefrontal cortex (PFC). Monkeys were required to generate a force that fell within one of two categories ("small" and "large"). We found that most PFC neurons were activated as a function of force category, suggesting a role in conditional motor control. At the same time, we found that activity in many PFC neurons varied continuously with the force that was eventually produced, suggesting they participated in specifying the metrics of movements as they were executed. The results suggest that the PFC neural population encodes both "what" motor response should be performed and "how" the selected movement should be realized immediately after the visual instruction.

Neuronal activity representing temporal prediction of reward in the primate prefrontal cortex.

Temporal prediction of future events, especially regarding reward delivery, is critical for controlling/learning purposeful behavior. The dorsolateral prefrontal cortex (DLPFC) has been considered to be involved in behavioral control based on prospective coding for future events, including reward. Thus this area is likely to have a neuronal mechanism responsible for temporal prediction of forthcoming reward. To address this hypothesis, we recorded the neuronal activity from the DLPFC of macaque monkeys while they performed an oculomotor delayed-response task under two conditions regarding the time of reward delivery. In this task, when the subjects made a correct response, the reward was delivered after a reward-delay period of 0.5 or 2 s. At the behavioral level, the onset latency for saccades was significantly faster in the shorter reward-delay trials (0.5 s) than in longer reward-delay trials (2 s), indicating that our subjects actually predicted the time of reward delivery. At the neuronal level, we found that many DLPFC neurons showed differential activity depending on the predicted time of reward delivery during the cue and/or delay periods. These results suggest that a fraction of neurons in the DLPFC represent the temporal prediction of reward and probably a variety of other future events.

Context-dependent representation of response-outcome in monkey prefrontal neurons.

For behaviour to be purposeful, it is important to monitor the preceding behavioural context, particularly for factors regarding stimulus, response and outcome. The dorsolateral prefrontal cortex (DLPFC) appears to play a major role in such a context-dependent, flexible behavioural control system, and this area is likely to have a neuronal mechanism for such retrospective coding, which associates response-outcome with the information and/or neural systems that guided the response. To address this hypothesis, we recorded neuronal activity from the DLPFC of monkeys performing memory- and sensory-guided saccade tasks, each of which had two conditions with reward contingencies. We found that post-response activity of a subset of DLPFC neurons was modulated by three factors relating to earlier events: the direction of the immediately preceding response, its outcome (reward or non-reward) and the information type (memory or sensory) that guided the response. Such neuronal coding should play a role in associating response-outcome with information and/or neural systems used to guide behaviour - that is, 'retrospective monitoring' of behavioural context and/or neural systems used for guiding behaviour - thereby contributing to context-dependent, flexible control of behaviours.

Prefrontal cortical activation associated with working memory in adults and preschool children: an event-related optical topography study.

It is well known that lateral areas of the prefrontal cortex (LPFC) play a central role in working memory (a critical basis of various cognitive functions), but it remains unknown whether the LPFC of children of preschool age is responsible for working memory. To address this issue, we adopted a recently developed non-invasive imaging technique, optical topography (OT), which can potentially be applied to functional mapping in childhood. We firstly examined changes of activity in the LPFC using OT while adult subjects performed an item-recognition task, which requires working memory, under different memory-load conditions. We observed activation in the bilateral LPFC during performance of this task, the magnitude of which differed depending on memory-load. Then, we applied the same technique on 5- and 6-year-old children and observed the activation associated with working memory in the LPFC. Areas and properties of such activity were similar in adults and preschool children. Thus, for the first time, we demonstrate that the LPFC of preschoolers is active during working memory processes, indicating that in 5- and 6-year-old children, the LPFC has already developed processing of this important cognitive function.

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.

Neuronal representation of response-outcome in the primate prefrontal cortex.

For flexible control of behaviour, it is important to associate preceding behavioural response with its outcome. Since the dorsolateral prefrontal cortex (dlPFC) plays a major role in such control, it is likely that this area has a neuronal mechanism of coding response-outcome, such as reward/non-reward, based on the nature of the behavioural response made immediately before. To test this hypothesis, we examined neuronal activity in the dlPFC while monkeys performed a variant of the oculomotor delayed-response (ODR) task that had two reward conditions. In this task, the correct response was rewarded in half of the trials only and the subject could not expect the outcome (reward/non-reward). The response was followed by a fixation of 2 s (F2-period). We also employed a fixation (FIX) task that required monkeys to fixate on the peripheral target only, with two reward conditions that were similar to those in the ODR task. Post-response activity of a subset of dlPFC neurons was modulated by both the direction of the preceding response and its outcome. None of these neurons showed directional F2-period activity in the FIX task. These results suggest that a subset of dlPFC neurons represent response-outcome (i.e. reward/non-reward associated with directional saccade made immediately before).

Involvement of the dorsolateral prefrontal cortex of monkeys in visuospatial target selection.

To examine the involvement of the dorsolateral prefrontal cortex (PFC) in visuospatial target selection, we induced local, reversible inactivation with muscimol at various sites in the dorsolateral PFC of two rhesus monkeys while they performed oculomotor visual search (OVS) and oculomotor detection (OD) tasks. The OVS task required the subject to select a target stimulus from among distractors and to make a saccade to the target location (target selection was required for correct performance), whereas the OD task only required a saccade to the target (target selection was not required for correct performance). The local injection of muscimol (5 microg, 1 microl) into the dorsolateral PFC induced a specific deficit in the OVS task but not in the OD task. The deficit in the OVS task was characterized by the disordering of saccades for some (mostly a few) particular target locations as well as by prolongation of the time required for the visual search in most cases. The target locations affected by muscimol were biased to the contralateral visual field. Further, the OVS task with "pop-out" and "non-pop-out" conditions was similarly impaired by muscimol injection. These results suggest that the dorsolateral PFC plays a role in target selection in visual space to guide goal-directed motor acts and particular sites are involved in target selection for a particular visuospatial coordinate. Further, this function of the dorsolateral PFC appears to involve both top-down (active) and bottom-up (passive) target-selection/selective attention processes to control interfering information (distractors).

Working memory of action: a comparative study of ability to selecting response based on previous action in New World monkeys (Saimiri sciureus and Callithrix jacchus).

Working memory of the outcome of one's own action is important for organizing and learning appropriate behaviors in a given condition. To examine whether non-human primates with different neocortical sizes show different abilities regarding working memory for action, the performance of squirrel monkeys (Saimiri sciureus) and common marmosets (Callithrix jacchus) in a kind of delayed-response task was compared. In this task, subjects were required to select a response based on short-term memory of the outcome of their own prior action, which requires working memory of action. These monkeys have a similar phylogenetic status (i.e. Ceboidea), but the size of the neocortex relative to the rest of the brain (relative size of the neocortex) is quite different. We found that both two species could attend to and remember their own actions and could select a response based on that memory. However, the performance level was higher for squirrel monkeys than for marmosets. These results suggest that non-human primates with differentially developed neocortices have different abilities regarding working memory of action.

Neuronal activity representing visuospatial mnemonic processes associated with target selection in the monkey dorsolateral prefrontal cortex.

To investigate how visuospatial mnemonic and target selection processes are represented in the dorsolateral prefrontal cortex (PFC), we studied neuronal attributes of the dorsolateral PFC while monkeys were performing oculomotor delayed visual search (ODVS) and oculomotor delayed-response (ODR) tasks. In the ODVS task, the subject made a memory-guided saccade to a remembered target location that had been presented along with distractors before a delay period; in the ODR task, the target was presented without any distractors. A total of 252 neurons in the dorsolateral PFC showed directional delay-period activity and were divided into two groups; neurons that showed directional delay-period activity predominantly in the ODVS task (n=112), and those that showed such activity similarly in both the ODVS and ODR tasks (n=140). These neuronal groups shared similar temporal properties (i.e. onset latency, peak time of delay-period activity) and spatial tuning. Our findings suggest that the dorsolateral PFC contains a particular visuospatial memory system for information selected by target selection (selective attention), and this attention-memory system (or 'memory system for special use') appears to be represented in the dorsolateral PFC, in parallel with a more 'general' memory system that is not specifically associated with target selection.