Neurons in the monkey frontopolar cortex encode learning stage and goal during a fast learning task.

The frontopolar cortex (FPC) is, to date, one of the least understood regions of the prefrontal cortex. The current understanding of its function suggests that it plays a role in the control of exploratory behaviors by coordinating the activities of other prefrontal cortex areas involved in decision-making and exploiting actions based on their outcomes. Based on this hypothesis, FPC would drive fast-learning processes through a valuation of the different alternatives. In our study, we used a modified version of a well-known paradigm, the object-in-place (OIP) task, to test this hypothesis in electrophysiology. This paradigm is designed to maximize learning, enabling monkeys to learn in one trial, which is an ability specifically impaired after a lesion of the FPC. We showed that FPC neurons presented an extremely specific pattern of activity by representing the learning stage, exploration versus exploitation, and the goal of the action. However, our results do not support the hypothesis that neurons in the frontal pole compute an evaluation of different alternatives. Indeed, the position of the chosen target was strongly encoded at its acquisition, but the position of the unchosen target was not. Once learned, this representation was also found at the problem presentation, suggesting a monitoring activity of the synthetic goal preceding its acquisition. Our results highlight important features of FPC neurons in fast-learning processes without confirming their role in the disengagement of cognitive control from the current goals.

Connecting the dots in the zona incerta: A study of neural assemblies and motifs of inter-area coordination in mice.

The zona incerta (ZI), a subthalamic area connected to numerous brain regions, has raised clinical interest because its stimulation alleviates the motor symptoms of Parkinson's disease. To explore its coordinative nature, we studied the assembly formation in a dataset of neural recordings in mice and quantified the degree of functional coordination of ZI with other 24 brain areas. We found that the ZI is a highly integrative area. The analysis in terms of "loop-like" motifs, directional assemblies composed of three neurons spanning two areas, has revealed reciprocal functional interactions with reentrant signals that, in most cases, start and end with the activation of ZI units. In support of its proposed integrative role, we found that almost one-third of the ZI's neurons formed assemblies with more than half of the other recorded areas and that loop-like assemblies may stand out as hyper-integrative motifs compared to other types of activation patterns.

Disentangling the identity of the zona incerta: a review of the known connections and latest implications.

The zona incerta (ZI) is a subthalamic region composed by loosely packed neurochemically mixed neurons, juxtaposed to the main ascending and descending bundles. The extreme neurochemical diversity that characterizes this area, together with the diffuseness of its connections with the entire neuraxis and its hard-to-reach positioning in the brain caused the ZI to keep its halo of mystery for over a century. However, in the last decades, a rich albeit fragmentary body of knowledge regarding both the incertal anatomical connections and functional implications has been built mostly based on rodent studies and its lack of cohesion makes difficult to depict an integrated, exhaustive picture regarding the ZI and its roles. This review aims to provide a unified resource that summarizes the current knowledge regarding the anatomical profile of interactions of the ZI in rodents and non-human primates and the functional significance of its connections, highlighting the aspects still unbeknown to research.

Static and dynamic coding in distinct cell types during associative learning in the prefrontal cortex.

The prefrontal cortex maintains information in memory through static or dynamic population codes depending on task demands, but whether the population coding schemes used are learning-dependent and differ between cell types is currently unknown. We investigate the population coding properties and temporal stability of neurons recorded from male macaques in two mapping tasks during and after stimulus-response associative learning, and then we use a Strategy task with the same stimuli and responses as control. We identify a heterogeneous population coding for stimuli, responses, and novel associations: static for putative pyramidal cells and dynamic for putative interneurons that show the strongest selectivity for all the variables. The population coding of learned associations shows overall the highest stability driven by cell types, with interneurons changing from dynamic to static coding after successful learning. The results support that prefrontal microcircuitry expresses mixed population coding governed by cell types and changes its stability during associative learning.

The transitive inference task to study the neuronal correlates of memory-driven decision making: A monkey neurophysiology perspective.

A vast amount of literature agrees that rank-ordered information as A>B>C>D>E>F is mentally represented in spatially organized schemas after learning. This organization significantly influences the process of decision-making, using the acquired premises, i.e. deciding if B is higher than D is equivalent to comparing their position in this space. The implementation of non-verbal versions of the transitive inference task has provided the basis for ascertaining that different animal species explore a mental space when deciding among hierarchically organized memories. In the present work, we reviewed several studies of transitive inference that highlighted this ability in animals and, consequently, the animal models developed to study the underlying cognitive processes and the main neural structures supporting this ability. Further, we present the literature investigating which are the underlying neuronal mechanisms. Then we discuss how non-human primates represent an excellent model for future studies, providing ideal resources for better understanding the neuronal correlates of decision-making through transitive inference tasks.

Effects of contraction bias on the decision process in the macaque prefrontal cortex.

Our representation of magnitudes such as time, distance, and size is not always veridical because it is affected by multiple biases. From a Bayesian perspective, estimation errors are considered to be the result of an optimization mechanism for the behavior in a noisy environment by integrating previous experience with the incoming sensory information. One influence of the distribution of past stimuli on perceptual decisions is represented by the regression toward the mean, a type of contraction bias. Using a spatial discrimination task with 2 stimuli presented sequentially at different distances from the center, we show that this bias is also present in macaques when comparing the magnitude of 2 distances. We found that the contraction of the first stimulus magnitude toward the center of the distribution accounted for some of the changes in performance, even more so than the effect of difficulty related to the ratio between stimulus magnitudes. At the neural level in the dorsolateral prefrontal cortex, the coding of the decision after the presentation of the second stimulus reflected the effect of the contraction bias on the discriminability of the stimuli at the behavioral level.

Social monitoring of actions in the macaque frontopolar cortex.

The frontopolar cortex (FPC) of primates appeared as a main innovation in the evolution of anthropoid primates and it has been placed at the top of the prefrontal hierarchy. The only study to date that investigated the activity of FPC neurons in monkeys performing a cognitive task suggested that these cells were involved in the monitoring of self-generated actions. We recorded the activity of neurons in the FPCs of two rhesus monkeys while they performed a social variant of a nonmatch-to-goal task that required monitoring the actions of a human or computer agent. We discovered that the role of FPC neurons extends beyond self-generated actions to include monitoring others' actions. Their monitoring activity was very specific. First, neurons in the FPC encoded the spatial position of the target but not its object features. Second, a dedicated representation of the human agent actions was tied to the time of target acquisition, while it was reduced or absent in the successive epochs of the trial. Finally, this other-specific neural substrate did not emerge during the interaction with a virtual agent such as the computer. These results provide a new perspective on the functions of a uniquely primate brain area, suggesting that FPC might play an important role in social behaviors.

Dedicated Representation of Others in the Macaque Frontal Cortex: From Action Monitoring and Prediction to Outcome Evaluation.

Social neurophysiology has increasingly addressed how several aspects of self and other are distinctly represented in the brain. In social interactions, the self-other distinction is fundamental for discriminating one's own actions, intentions, and outcomes from those that originate in the external world. In this paper, we review neurophysiological experiments using nonhuman primates that shed light on the importance of the self-other distinction, focusing mainly on the frontal cortex. We start by examining how the findings are impacted by the experimental paradigms that are used, such as the type of social partner or whether a passive or active interaction is required. Next, we describe the 2 sociocognitive systems: mirror and mentalizing. Finally, we discuss how the self-other distinction can occur in different domains to process different aspects of social information: the observation and prediction of others' actions and the monitoring of others' rewards.

The importance of urgency in decision making based on dynamic information.

A standard view in the literature is that decisions are the result of a process that accumulates evidence in favor of each alternative until such accumulation reaches a threshold and a decision is made. However, this view has been recently questioned by an alternative proposal that suggests that, instead of accumulated, evidence is combined with an urgency signal. Both theories have been mathematically formalized and supported by a variety of decision-making tasks with constant information. However, recently, tasks with changing information have shown to be more effective to study the dynamics of decision making. Recent research using one of such tasks, the tokens task, has shown that decisions are better described by an urgency mechanism than by an accumulation one. However, the results of that study could depend on a task where all fundamental information was noiseless and always present, favoring a mechanism of non-integration, such as the urgency one. Here, we wanted to address whether the same conclusions were also supported by an experimental paradigm in which sensory evidence was removed shortly after it was provided, making working memory necessary to properly perform the task. Here, we show that, under such condition, participants' behavior could be explained by an urgency-gating mechanism that low-pass filters the mnemonic information and combines it with an urgency signal that grows with time but not by an accumulation process that integrates the same mnemonic information. Thus, our study supports the idea that, under certain situations with dynamic sensory information, decisions are better explained by an urgency-gating mechanism than by an accumulation one.

Macaque monkeys learn and perform a non-match-to-goal task using an automated home cage training procedure.

In neurophysiology, nonhuman primates represent an important model for studying the brain. Typically, monkeys are moved from their home cage to an experimental room daily, where they sit in a primate chair and interact with electronic devices. Refining this procedure would make the researchers' work easier and improve the animals' welfare. To address this issue, we used home-cage training to train two macaque monkeys in a non-match-to-goal task, where each trial required a switch from the choice made in the previous trial to obtain a reward. The monkeys were tested in two versions of the task, one in which they acted as the agent in every trial and one in which some trials were completed by a "ghost agent". We evaluated their involvement in terms of their performance and their interaction with the apparatus. Both monkeys were able to maintain a constant involvement in the task with good, stable performance within sessions in both versions of the task. Our study confirms the feasibility of home-cage training and demonstrates that even with challenging tasks, monkeys can complete a large number of trials at a high performance level, which is a prerequisite for electrophysiological studies of monkey behavior.

Neural Correlates of Strategy Switching in the Macaque Orbital Prefrontal Cortex.

We can adapt flexibly to environment changes and search for the most appropriate rule to a context. The orbital prefrontal cortex (PFo) has been associated with decision making, rule generation and maintenance, and more generally has been considered important for behavioral flexibility. To better understand the neural mechanisms underlying the flexible behavior, we studied the ability to generate a switching signal in monkey PFo when a strategy is changed. In the strategy task, we used a visual cue to instruct two male rhesus monkeys either to repeat their most recent choice (i.e., stay strategy) or to change it (i.e., shift strategy). To identify the strategy switching-related signal, we compared nonswitch and switch trials, which cued the same or a different strategy from the previous trial, respectively. We found that the switching-related signal emerged during the cue presentation and it was combined with the strategy signal in a subpopulation of cells. Moreover, the error analysis showed that the activity of the switch-related cells reflected whether the monkeys erroneously switched or not the strategy, rather than what was required for that trial. The function of the switching signal could be to prompt the use of different strategies when older strategies are no longer appropriate, conferring the ability to adapt flexibly to environmental changes. In our task, the switching signal might contribute to the implementation of the strategy cued, overcoming potential interference effects from the strategy previously cued. Our results support the idea that ascribes to PFo an important role for behavioral flexibility.SIGNIFICANCE STATEMENT We can flexibly adapt our behavior to a changing environment. One of the prefrontal areas traditionally associated with the ability to adapt to new contingencies is the orbital prefrontal cortex (PFo). We analyzed the switching related activity using a strategy task in which two rhesus monkeys were instructed by a visual cue either to repeat or change their most recent choice, respectively using a stay or a shift strategy. We found that PFo neurons were modulated by the strategy switching signal, pointing to the importance of PFo in behavioral flexibility by generating control over the switching of strategies.

Effects of reward size and context on learning in macaque monkeys.

The outcome of an action plays a crucial role in decision-making and reinforcement learning processes. Indeed, both human and animal behavioural studies have shown that different expected reward values, either quantitatively or qualitatively, modulate the motivation of subjects to perform an action and, as a consequence, affect their behavioural performance. Here, we investigated the effect of different amounts of reward on the learning of macaque monkeys using a modified version of the object-in-place task. This task offers the opportunity to shape rapid learning based on a set of external stimuli that enhance an animal's accuracy in terms of solving a problem. We compared the learning of three monkeys among three different reward conditions. Our results demonstrate that the larger the reward, the better the monkey's ability to learn the associations starting with the second presentation of the problem. Moreover, we compared the present results with those of our previous work using the same monkeys in the same task but with a unique reward condition, the intermediate one. Interestingly, the performance of our animals in our previous work matched with their performance in the largest and not intermediate reward condition of the present study These results suggest that learning is mostly influenced by the reward context and not by its absolute value.

Role of the social actor during social interaction and learning in human-monkey paradigms.

The social interactions between primates is drawn by their ability to predict others' behaviours, to learn from others' actions and to represent others' intentions. It allows them to extract information by observation to understand which action is leading to which outcome and to maximize the efficiency of their own future behaviours. These processes have mainly been investigated studying non-human primates observing conspecifics, but more recently an increasing body of work has adopted a human-monkey paradigm, and some have now convincingly shown that macaque monkeys understand human choices, consider them and can act accordingly. Two main hypotheses have been developed to explain macaque monkeys' ability to learn from humans: 1) the similarity between the behaviours of both species 2) the presence of a non-ambiguous link between the observed action and its outcome. Based on the literature examined the recent evidence appears to supports the second. The non-social observational learning, meaning the learning by observation of an inanimate agent, can be a powerful tool to understand the mechanisms underlying the social interactions.

Macaque monkeys learn by observation in the ghost display condition in the object-in-place task with differential reward to the observer.

Observational learning has been investigated in monkeys mainly using conspecifics or humans as models to observe. Some studies attempted to clarify the social agent's role and to test whether non-human primates could learn from observation of a non-social agent, usually mentioned as a 'ghost display' condition, but they reported conflicting results. To address this question, we trained three rhesus monkeys in an object-in-place task consisting of the presentation of five subsequent problems composed of two objects, one rewarded and one unrewarded, for six times, or runs. Three types of learning conditions were tested. In the individual learning condition, the monkeys performed the first run, learned from it and improved their performance in the following runs. In the social and non-social learning conditions, they observed respectively a human model and a computer performing the first run and learned by the observation of their successes or errors. In all three conditions, the monkeys themselves received the reward after correct choices only. One-trial learning occurred in all three conditions. The monkeys performed over chance in the second run in all conditions, providing evidence of non-social observational learning with differential reward in macaque monkeys using a "ghost display" condition in a cognitive task.

Neural Intrinsic Timescales in the Macaque Dorsal Premotor Cortex Predict the Strength of Spatial Response Coding.

Our brain continuously receives information over multiple timescales that are differently processed across areas. In this study, we investigated the intrinsic timescale of neurons in the dorsal premotor cortex (PMd) of two rhesus macaques while performing a non-match-to-goal task. The task rule was to reject the previously chosen target and select the alternative one. We defined the intrinsic timescale as the decay constant of the autocorrelation structure computed during a baseline period of the task. We found that neurons with longer intrinsic timescale tended to maintain a stronger spatial response coding during a delay period. This result suggests that longer intrinsic timescales predict the functional role of PMd neurons in a cognitive task. Our estimate of the intrinsic timescale integrates an existing hierarchical model (Murray et al., 2014), by assigning to PMd a lower position than prefrontal cortex in the hierarchical ordering of the brain areas based on neurons' timescales.

Coding of Self and Other's Future Choices in Dorsal Premotor Cortex during Social Interaction.

Representing others' intentions is central to primate social life. We explored the role of dorsal premotor cortex (PMd) in discriminating between self and others' behavior while two male rhesus monkeys performed a non-match-to-goal task in a monkey-human paradigm. During each trial, two of four potential targets were randomly presented on the right and left parts of a screen, and the monkey or the human was required to choose the one that did not match the previously chosen target. Each agent had to monitor the other's action in order to select the correct target in that agent's own turn. We report neurons that selectively encoded the future choice of the monkey, the human agent, or both. Our findings suggest that PMd activity shows a high degree of self-other differentiation during face-to-face interactions, leading to an independent representation of what others will do instead of entailing self-centered mental rehearsal or mirror-like activities.