Proselfs depend more on model-based than model-free learning in a non-social probabilistic state-transition task.

Humans form complex societies in which we routinely engage in social decision-making regarding the allocation of resources among ourselves and others. One dimension that characterizes social decision-making in particular is whether to prioritize self-interest or respect for others-proself or prosocial. What causes this individual difference in social value orientation? Recent developments in the social dual-process theory argue that social decision-making is characterized by its underlying domain-general learning systems: the model-free and model-based systems. In line with this "learning" approach, we propose and experimentally test the hypothesis that differences in social preferences stem from which learning system is dominant in an individual. Here, we used a non-social state transition task that allowed us to assess the balance between model-free/model-based learning and investigate its relation to the social value orientations. The results showed that proselfs depended more on model-based learning, whereas prosocials depended more on model-free learning. Reward amount and reaction time analyses showed that proselfs learned the task structure earlier in the session than prosocials, reflecting their difference in model-based/model-free learning dependence. These findings support the learning hypothesis on what makes differences in social preferences and have implications for understanding the mechanisms of prosocial behavior.

Dissecting the Prefrontal Network With Pathway-Selective Manipulation in the Macaque Brain-A Review.

Macaque monkeys are prime animal models for studying the neural mechanisms of decision-making because of their close kinship with humans. Manipulation of neural activity during decision-making tasks is essential for approaching the causal relationship between the brain and its functions. Conventional manipulation methods used in macaque studies are coarse-grained, and have worked indiscriminately on mutually intertwined neural pathways. To systematically dissect neural circuits responsible for a variety of functions, it is essential to analyze changes in behavior and neural activity through interventions in specific neural pathways. In recent years, an increasing number of studies have applied optogenetics and chemogenetics to achieve fine-grained pathway-selective manipulation in the macaque brain. Here, we review the developments in macaque studies involving pathway-selective operations, with a particular focus on applications to the prefrontal network. Pathway selectivity can be achieved using single viral vector transduction combined with local light stimulation or ligand administration directly into the brain or double-viral vector transduction combined with systemic drug administration. We discuss the advantages and disadvantages of these methods. We also highlight recent technological developments in viral vectors that can effectively infect the macaque brain, as well as the development of methods to deliver photostimulation or ligand drugs to a wide area to effectively manipulate behavior. The development and dissemination of such pathway-selective manipulations of macaque prefrontal networks will enable us to efficiently dissect the neural mechanisms of decision-making and innovate novel treatments for decision-related psychiatric disorders.

Chemogenetic inactivation reveals the inhibitory control function of the prefronto-striatal pathway in the macaque brain.

The lateral prefrontal cortex (LPFC) has a strong monosynaptic connection with the caudate nucleus (CdN) of the striatum. Previous human MRI studies have suggested that this LPFC-CdN pathway plays an important role in inhibitory control and working memory. We aimed to validate the function of this pathway at a causal level by pathway-selective manipulation of neural activity in non-human primates. To this end, we trained macaque monkeys on a delayed oculomotor response task with reward asymmetry and expressed an inhibitory type of chemogenetic receptors selectively to LPFC neurons that project to the CdN. Ligand administration reduced the inhibitory control of impulsive behavior, as well as the task-related neuronal responses observed in the local field potentials from the LPFC and CdN. These results show that we successfully suppressed pathway-selective neural activity in the macaque brain, and the resulting behavioral changes suggest that the LPFC-CdN pathway is involved in inhibitory control.

Microendoscopic calcium imaging of the primary visual cortex of behaving macaques.

In vivo calcium imaging with genetically encoded indicators has recently been applied to macaque brains to monitor neural activities from a large population of cells simultaneously. Microendoscopic calcium imaging combined with implantable gradient index lenses captures neural activities from deep brain areas with a compact and convenient setup; however, this has been limited to rodents and marmosets. Here, we developed miniature fluorescent microscopy to image neural activities from the primary visual cortex of behaving macaques. We found tens of clear fluorescent signals from three of the six brain hemispheres. A subset of these neurons showed clear retinotopy and orientation tuning. Moreover, we successfully decoded the stimulus orientation and tracked the cells across days. These results indicate that microendoscopic calcium imaging is feasible and reasonable for investigating neural circuits in the macaque brain by monitoring fluorescent signals from a large number of neurons.

[Cognitive Functions in the Prefrontal Association Cortex; Transitive Inference and the Lateral Prefrontal Cortex].

To behave appropriately in a complex and uncertain world, the brain makes use of several distinct learning systems. One such system is called the "model-free process", via which conditioning allows the association between a stimulus or response and a given reward to be learned. Another system is called the "model-based process". Via this process, the state transition between a stimulus and a response is learned so that the brain is able to plan actions prior to their execution. Several studies have tried to relate the difference between model-based and model-free processes to the difference in functions of the lateral prefrontal cortex (LPFC) and the striatum. Here, we describe a series of studies that demonstrate the ability of LPFC neurons to categorize visual stimuli by their associated behavioral responses and to generate abstract information. If LPFC neurons utilize abstract code to associate a stimulus with a reward, they should be able to infer similar relationships between other stimuli of the same category and their rewards without direct experience of these stimulus-reward contingencies. We propose that this ability of LPFC neurons to utilize abstract information can contribute to the model-based learning process.

Dissociable functions of reward inference in the lateral prefrontal cortex and the striatum.

In a complex and uncertain world, how do we select appropriate behavior? One possibility is that we choose actions that are highly reinforced by their probabilistic consequences (model-free processing). However, we may instead plan actions prior to their actual execution by predicting their consequences (model-based processing). It has been suggested that the brain contains multiple yet distinct systems involved in reward prediction. Several studies have tried to allocate model-free and model-based systems to the striatum and the lateral prefrontal cortex (LPFC), respectively. Although there is much support for this hypothesis, recent research has revealed discrepancies. To understand the nature of the reward prediction systems in the LPFC and the striatum, a series of single-unit recording experiments were conducted. LPFC neurons were found to infer the reward associated with the stimuli even when the monkeys had not yet learned the stimulus-reward (SR) associations directly. Striatal neurons seemed to predict the reward for each stimulus only after directly experiencing the SR contingency. However, the one exception was "Exclusive Or" situations in which striatal neurons could predict the reward without direct experience. Previous single-unit studies in monkeys have reported that neurons in the LPFC encode category information, and represent reward information specific to a group of stimuli. Here, as an extension of these, we review recent evidence that a group of LPFC neurons can predict reward specific to a category of visual stimuli defined by relevant behavioral responses. We suggest that the functional difference in reward prediction between the LPFC and the striatum is that while LPFC neurons can utilize abstract code, striatal neurons can code individual associations between stimuli and reward but cannot utilize abstract code.

Double Virus Vector Infection to the Prefrontal Network of the Macaque Brain.

To precisely understand how higher cognitive functions are implemented in the prefrontal network of the brain, optogenetic and pharmacogenetic methods to manipulate the signal transmission of a specific neural pathway are required. The application of these methods, however, has been mostly restricted to animals other than the primate, which is the best animal model to investigate higher cognitive functions. In this study, we used a double viral vector infection method in the prefrontal network of the macaque brain. This enabled us to express specific constructs into specific neurons that constitute a target pathway without use of germline genetic manipulation. The double-infection technique utilizes two different virus vectors in two monosynaptically connected areas. One is a vector which can locally infect cell bodies of projection neurons (local vector) and the other can retrogradely infect from axon terminals of the same projection neurons (retrograde vector). The retrograde vector incorporates the sequence which encodes Cre recombinase and the local vector incorporates the "Cre-On" FLEX double-floxed sequence in which a reporter protein (mCherry) was encoded. mCherry thus came to be expressed only in doubly infected projection neurons with these vectors. We applied this method to two macaque monkeys and targeted two different pathways in the prefrontal network: The pathway from the lateral prefrontal cortex to the caudate nucleus and the pathway from the lateral prefrontal cortex to the frontal eye field. As a result, mCherry-positive cells were observed in the lateral prefrontal cortex in all of the four injected hemispheres, indicating that the double virus vector transfection is workable in the prefrontal network of the macaque brain.