RESUMEN
Certain memories resist extinction to continue invigorating maladaptive actions. The robustness of these memories could depend on their widely distributed implementation across populations of neurons in multiple brain regions. However, how dispersed neuronal activities are collectively organized to underpin a persistent memory-guided behavior remains unknown. To investigate this, we simultaneously monitored the prefrontal cortex, nucleus accumbens, amygdala, hippocampus, and ventral tegmental area (VTA) of the mouse brain from initial recall to post-extinction renewal of a memory involving cocaine experience. We uncover a higher-order pattern of short-lived beta-frequency (15-25 Hz) activities that are transiently coordinated across these networks during memory retrieval. The output of a divergent pathway from upstream VTA glutamatergic neurons, paced by a slower (4-Hz) oscillation, actuates this multi-network beta-band coactivation; its closed-loop phase-informed suppression prevents renewal of cocaine-biased behavior. Binding brain-distributed neural activities in this temporally structured manner may constitute an organizational principle of robust memory expression.
Asunto(s)
Encéfalo , Memoria , Animales , Ratones , Amígdala del Cerebelo/fisiología , Encéfalo/fisiología , Cocaína/farmacología , Cocaína/metabolismo , Memoria/fisiología , Corteza Prefrontal/fisiologíaRESUMEN
Attention filters sensory inputs to enhance task-relevant information. It is guided by an "attentional template" that represents the stimulus features that are currently relevant. To understand how the brain learns and uses templates, we trained monkeys to perform a visual search task that required them to repeatedly learn new attentional templates. Neural recordings found that templates were represented across the prefrontal and parietal cortex in a structured manner, such that perceptually neighboring templates had similar neural representations. When the task changed, a new attentional template was learned by incrementally shifting the template toward rewarded features. Finally, we found that attentional templates transformed stimulus features into a common value representation that allowed the same decision-making mechanisms to deploy attention, regardless of the identity of the template. Altogether, our results provide insight into the neural mechanisms by which the brain learns to control attention and how attention can be flexibly deployed across tasks.
Asunto(s)
Atención , Toma de Decisiones , Aprendizaje , Lóbulo Parietal , Recompensa , Animales , HaplorrinosRESUMEN
Social preference, the decision to interact with one member of the same species over another, is critical to optimize social interactions. Thus, adult rodents favor interacting with novel conspecifics over familiar ones, but whether this social preference stems from neural circuits facilitating interactions with novel individuals or suppressing interactions with familiar ones remains unknown. Here, we identify neurons in the infra-limbic area (ILA) of the mouse prefrontal cortex that express the neuropeptide corticotropin-releasing hormone (CRH) and project to the dorsal region of the rostral lateral septum (rLS). We show how release of CRH during familiar encounters disinhibits rLS neurons, thereby suppressing social interactions with familiar mice and contributing to social novelty preference. We further demonstrate how the maturation of CRH expression in ILA during the first 2 post-natal weeks enables the developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults.
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Hormona Liberadora de Corticotropina , Corteza Prefrontal , Animales , Ratones , Neuronas , Transducción de Señal , PercepciónRESUMEN
Prefrontal cortex (PFC) is postulated to exert "top-down control" on information processing throughout the brain to promote specific behaviors. However, pathways mediating top-down control remain poorly understood. In particular, knowledge about direct prefrontal connections that might facilitate top-down control of hippocampal information processing remains sparse. Here we describe monosynaptic long-range GABAergic projections from PFC to hippocampus. These preferentially inhibit vasoactive intestinal polypeptide-expressing interneurons, which are known to disinhibit hippocampal microcircuits. Indeed, stimulating prefrontal-hippocampal GABAergic projections increases hippocampal feedforward inhibition and reduces hippocampal activity in vivo. The net effect of these actions is to specifically enhance the signal-to-noise ratio for hippocampal encoding of object locations and augment object-induced increases in spatial information. Correspondingly, activating or inhibiting these projections promotes or suppresses object exploration, respectively. Together, these results elucidate a top-down prefrontal pathway in which long-range GABAergic projections target disinhibitory microcircuits, thereby enhancing signals and network dynamics underlying exploratory behavior.
Asunto(s)
Hipocampo , Corteza Prefrontal , Conducta Exploratoria , Hipocampo/fisiología , Interneuronas/metabolismo , Corteza Prefrontal/fisiología , Péptido Intestinal VasoactivoRESUMEN
Single-cell transcriptomics has been widely applied to classify neurons in the mammalian brain, while systems neuroscience has historically analyzed the encoding properties of cortical neurons without considering cell types. Here we examine how specific transcriptomic types of mouse prefrontal cortex (PFC) projection neurons relate to axonal projections and encoding properties across multiple cognitive tasks. We found that most types projected to multiple targets, and most targets received projections from multiple types, except PFCâPAG (periaqueductal gray). By comparing Ca2+ activity of the molecularly homogeneous PFCâPAG type against two heterogeneous classes in several two-alternative choice tasks in freely moving mice, we found that all task-related signals assayed were qualitatively present in all examined classes. However, PAG-projecting neurons most potently encoded choice in cued tasks, whereas contralateral PFC-projecting neurons most potently encoded reward context in an uncued task. Thus, task signals are organized redundantly, but with clear quantitative biases across cells of specific molecular-anatomical characteristics.
Asunto(s)
Cognición/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Análisis y Desempeño de Tareas , Animales , Calcio/metabolismo , Conducta de Elección , Señales (Psicología) , Imagenología Tridimensional , Integrasas/metabolismo , Ratones Endogámicos C57BL , Odorantes , Optogenética , Sustancia Gris Periacueductal/fisiología , Recompensa , Análisis de la Célula Individual , Transcriptoma/genéticaRESUMEN
The curse of dimensionality plagues models of reinforcement learning and decision making. The process of abstraction solves this by constructing variables describing features shared by different instances, reducing dimensionality and enabling generalization in novel situations. Here, we characterized neural representations in monkeys performing a task described by different hidden and explicit variables. Abstraction was defined operationally using the generalization performance of neural decoders across task conditions not used for training, which requires a particular geometry of neural representations. Neural ensembles in prefrontal cortex, hippocampus, and simulated neural networks simultaneously represented multiple variables in a geometry reflecting abstraction but that still allowed a linear classifier to decode a large number of other variables (high shattering dimensionality). Furthermore, this geometry changed in relation to task events and performance. These findings elucidate how the brain and artificial systems represent variables in an abstract format while preserving the advantages conferred by high shattering dimensionality.
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Hipocampo/anatomía & histología , Corteza Prefrontal/anatomía & histología , Animales , Conducta Animal , Mapeo Encefálico , Simulación por Computador , Hipocampo/fisiología , Aprendizaje , Macaca mulatta , Masculino , Modelos Neurológicos , Redes Neurales de la Computación , Neuronas/fisiología , Corteza Prefrontal/fisiología , Refuerzo en Psicología , Análisis y Desempeño de TareasRESUMEN
Working memory is a form of short-term memory that involves maintaining and updating task-relevant information toward goal-directed pursuits. Classical models posit persistent activity in prefrontal cortex (PFC) as a primary neural correlate, but emerging views suggest additional mechanisms may exist. We screened â¼200 genetically diverse mice on a working memory task and identified a genetic locus on chromosome 5 that contributes to a substantial proportion (17%) of the phenotypic variance. Within the locus, we identified a gene encoding an orphan G-protein-coupled receptor, Gpr12, which is sufficient to drive substantial and bidirectional changes in working memory. Molecular, cellular, and imaging studies revealed that Gpr12 enables high thalamus-PFC synchrony to support memory maintenance and choice accuracy. These findings identify an orphan receptor as a potent modifier of short-term memory and supplement classical PFC-based models with an emerging thalamus-centric framework for the mechanistic understanding of working memory.
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Memoria a Corto Plazo/fisiología , Receptores Acoplados a Proteínas G/genética , Tálamo/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Corteza Prefrontal/fisiología , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Social interactions involve complex decision-making tasks that are shaped by dynamic, mutual feedback between participants. An open question is whether and how emergent properties may arise across brains of socially interacting individuals to influence social decisions. By simultaneously performing microendoscopic calcium imaging in pairs of socially interacting mice, we find that animals exhibit interbrain correlations of neural activity in the prefrontal cortex that are dependent on ongoing social interaction. Activity synchrony arises from two neuronal populations that separately encode one's own behaviors and those of the social partner. Strikingly, interbrain correlations predict future social interactions as well as dominance relationships in a competitive context. Together, our study provides conclusive evidence for interbrain synchrony in rodents, uncovers how synchronization arises from activity at the single-cell level, and presents a role for interbrain neural activity coupling as a property of multi-animal systems in coordinating and sustaining social interactions between individuals.
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Encéfalo/metabolismo , Neuronas/metabolismo , Animales , Señalización del Calcio , Conducta Competitiva/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/metabolismo , Análisis de Componente Principal , Predominio SocialRESUMEN
Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN's pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning.
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Afecto/efectos de la radiación , Aprendizaje/efectos de la radiación , Luz , Afecto/fisiología , Animales , Encéfalo/fisiología , Ritmo Circadiano , Aprendizaje/fisiología , Ratones , Ratones Endogámicos C57BL , Fototerapia/métodos , Retina/metabolismo , Retina/fisiología , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/fisiología , Células Ganglionares de la Retina/efectos de la radiación , Transducción de Señal/fisiología , Núcleo Supraquiasmático/metabolismo , Visión Ocular/fisiología , Vías Visuales/metabolismo , Percepción Visual/fisiologíaRESUMEN
Social behaviors are crucial to all mammals. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant or how they contribute. We found that PL contains anatomically and molecularly distinct subpopulations that target three downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), amygdala, and ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased the preference for a social target. To determine what information PL-NAc neurons convey, we selectively recorded from them and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially specific manipulation of these neurons bidirectionally regulated the formation of a social-spatial association. Thus, the unexpected combination of social and spatial information within the PL-NAc may contribute to social behavior by supporting social-spatial learning.
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Sistema Límbico , Neuronas/citología , Núcleo Accumbens/citología , Corteza Prefrontal/citología , Conducta Social , Conducta Espacial , Amígdala del Cerebelo/fisiología , Animales , Aprendizaje , Ratones , Vías Nerviosas , Neuronas/fisiología , Núcleo Accumbens/fisiología , Corteza Prefrontal/fisiología , Área Tegmental Ventral/fisiologíaRESUMEN
Reward-seeking behavior is fundamental to survival, but suppression of this behavior can be essential as well, even for rewards of high value. In humans and rodents, the medial prefrontal cortex (mPFC) has been implicated in suppressing reward seeking; however, despite vital significance in health and disease, the neural circuitry through which mPFC regulates reward seeking remains incompletely understood. Here, we show that a specific subset of superficial mPFC projections to a subfield of nucleus accumbens (NAc) neurons naturally encodes the decision to initiate or suppress reward seeking when faced with risk of punishment. A highly resolved subpopulation of these top-down projecting neurons, identified by 2-photon Ca2+ imaging and activity-dependent labeling to recruit the relevant neurons, was found capable of suppressing reward seeking. This natural activity-resolved mPFC-to-NAc projection displayed unique molecular-genetic and microcircuit-level features concordant with a conserved role in the regulation of reward-seeking behavior, providing cellular and anatomical identifiers of behavioral and possible therapeutic significance.
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Recompensa , Animales , Conducta Animal , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Vías Nerviosas , Neuroimagen , Corteza Prefrontal/citología , Corteza Prefrontal/metabolismo , CastigoRESUMEN
Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, "rational" decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict. VIDEO ABSTRACT.
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Toma de Decisiones , Corteza Prefrontal/fisiopatología , Estrés Fisiológico , Animales , Ganglios Basales/metabolismo , Interneuronas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas , Optogenética , Ratas , Ratas Long-EvansRESUMEN
Flexible behavior requires the creation, updating, and expression of memories to depend on context. While the neural underpinnings of each of these processes have been intensively studied, recent advances in computational modeling revealed a key challenge in context-dependent learning that had been largely ignored previously: Under naturalistic conditions, context is typically uncertain, necessitating contextual inference. We review a theoretical approach to formalizing context-dependent learning in the face of contextual uncertainty and the core computations it requires. We show how this approach begins to organize a large body of disparate experimental observations, from multiple levels of brain organization (including circuits, systems, and behavior) and multiple brain regions (most prominently the prefrontal cortex, the hippocampus, and motor cortices), into a coherent framework. We argue that contextual inference may also be key to understanding continual learning in the brain. This theory-driven perspective places contextual inference as a core component of learning.
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Encéfalo , Aprendizaje , Hipocampo , Corteza Prefrontal , Simulación por ComputadorRESUMEN
As a frontal node in the primate social brain, the medial prefrontal cortex (MPFC) plays a critical role in coordinating one's own behavior with respect to that of others. Current literature demonstrates that single neurons in the MPFC encode behavior-related variables such as intentions, actions, and rewards, specifically for self and other, and that the MPFC comes into play when reflecting upon oneself and others. The social moderator account of MPFC function can explain maladaptive social cognition in people with autism spectrum disorder, which tips the balance in favor of self-centered perspectives rather than taking into consideration the perspective of others. Several strands of evidence suggest a hypothesis that the MPFC represents different other mental models, depending on the context at hand, to better predict others' emotions and behaviors. This hypothesis also accounts for aberrant MPFC activity in autistic individuals while they are mentalizing others.
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Trastorno del Espectro Autista , Imagen por Resonancia Magnética , Animales , Mapeo Encefálico , Corteza Prefrontal , PrimatesRESUMEN
This article reviews the behavioral neuroscience of extinction, the phenomenon in which a behavior that has been acquired through Pavlovian or instrumental (operant) learning decreases in strength when the outcome that reinforced it is removed. Behavioral research indicates that neither Pavlovian nor operant extinction depends substantially on erasure of the original learning but instead depends on new inhibitory learning that is primarily expressed in the context in which it is learned, as exemplified by the renewal effect. Although the nature of the inhibition may differ in Pavlovian and operant extinction, in either case the decline in responding may depend on both generalization decrement and the correction of prediction error. At the neural level, Pavlovian extinction requires a tripartite neural circuit involving the amygdala, prefrontal cortex, and hippocampus. Synaptic plasticity in the amygdala is essential for extinction learning, and prefrontal cortical inhibition of amygdala neurons encoding fear memories is involved in extinction retrieval. Hippocampal-prefrontal circuits mediate fear relapse phenomena, including renewal. Instrumental extinction involves distinct ensembles in corticostriatal, striatopallidal, and striatohypothalamic circuits as well as their thalamic returns for inhibitory (extinction) and excitatory (renewal and other relapse phenomena) control over operant responding. The field has made significant progress in recent decades, although a fully integrated biobehavioral understanding still awaits.
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Conducta Animal/fisiología , Conducta/fisiología , Encéfalo/fisiología , Condicionamiento Clásico/fisiología , Extinción Psicológica/fisiología , Animales , Condicionamiento Operante , HumanosRESUMEN
The claustrum is one of the most widely connected regions of the forebrain, yet its function has remained obscure, largely due to the experimentally challenging nature of targeting this small, thin, and elongated brain area. However, recent advances in molecular techniques have enabled the anatomy and physiology of the claustrum to be studied with the spatiotemporal and cell type-specific precision required to eventually converge on what this area does. Here we review early anatomical and electrophysiological results from cats and primates, as well as recent work in the rodent, identifying the connectivity, cell types, and physiological circuit mechanisms underlying the communication between the claustrum and the cortex. The emerging picture is one in which the rodent claustrum is closely tied to frontal/limbic regions and plays a role in processes, such as attention, that are associated with these areas.
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Ganglios Basales/fisiología , Corteza Cerebral/anatomía & histología , Corteza Cerebral/fisiología , Claustro/anatomía & histología , Vías Nerviosas/fisiología , Animales , Ganglios Basales/anatomía & histología , Claustro/fisiopatología , Lóbulo Frontal/anatomía & histología , Lóbulo Frontal/fisiología , Corteza Prefrontal/anatomía & histología , Corteza Prefrontal/fisiologíaRESUMEN
Social behavior is essential for health, survival, and reproduction of animals; however, the role of astrocytes in social behavior remains largely unknown. The transmembrane protein CD38, which acts both as a receptor and ADP-ribosyl cyclase to produce cyclic ADP-ribose (cADPR) regulates social behaviors by promoting oxytocin release from hypothalamic neurons. CD38 is also abundantly expressed in astrocytes in the postnatal brain and is important for astroglial development. Here, we demonstrate that the astroglial-expressed CD38 plays an important role in social behavior during development. Selective deletion of CD38 in postnatal astrocytes, but not in adult astrocytes, impairs social memory without any other behavioral abnormalities. Morphological analysis shows that depletion of astroglial CD38 in the postnatal brain interferes with synapse formation in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, astroglial CD38 expression promotes synaptogenesis of excitatory neurons by increasing the level of extracellular SPARCL1 (also known as Hevin), a synaptogenic protein. The release of SPARCL1 from astrocytes is regulated by CD38/cADPR/calcium signaling. These data demonstrate a novel developmental role of astrocytes in neural circuit formation and regulation of social behavior in adults.
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Antígenos CD , ADP-Ribosa Cíclica , Animales , ADP-Ribosil Ciclasa 1/genética , Antígenos CD/metabolismo , ADP-Ribosa Cíclica/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Astrocitos/metabolismo , Sinapsis/metabolismoRESUMEN
Modulation of neuronal firing rates by the spatial locations of physical objects is a widespread phenomenon in the brain. However, little is known about how neuronal responses to the actions of biological entities are spatially tuned and whether such spatially tuned responses are affected by social contexts. These issues are of key importance for understanding the neural basis of embodied social cognition, such as imitation and perspective-taking. Here, we show that spatial representation of actions can be dynamically changed depending on others' social relevance and agents of action. Monkeys performed a turn-taking choice task with a real monkey partner sitting face-to-face or a filmed partner in prerecorded videos. Three rectangular buttons (left, center, and right) were positioned in front of the subject and partner as their choice targets. We recorded from single neurons in two frontal nodes in the social brain, the ventral premotor cortex (PMv) and the medial prefrontal cortex (MPFC). When the partner was filmed rather than real, spatial preference for partner-actions was markedly diminished in MPFC, but not PMv, neurons. This social context-dependent modulation in the MPFC was also evident for self-actions. Strikingly, a subset of neurons in both areas switched their spatial preference between self-actions and partner-actions in a diametrically opposite manner. This observation suggests that these cortical areas are associated with coordinate transformation in ways consistent with an actor-centered perspective-taking coding scheme. The PMv may subserve such functions in context-independent manners, whereas the MPFC may do so primarily in social contexts.
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Lóbulo Frontal , Animales , Masculino , Lóbulo Frontal/fisiología , Macaca mulatta , Neuronas/fisiología , Corteza Prefrontal/fisiología , Percepción Espacial/fisiología , MacacaRESUMEN
The medial prefrontal cortex (mPFC) is a key brain structure for higher cognitive functions such as decision-making and goal-directed behavior, many of which require awareness of spatial variables including one's current position within the surrounding environment. Although previous studies have reported spatially tuned activities in mPFC during memory-related trajectory, the spatial tuning of mPFC network during freely foraging behavior remains elusive. Here, we reveal geometric border or border-proximal representations from the neural activity of mPFC ensembles during naturally exploring behavior, with both allocentric and egocentric boundary responses. Unlike most of classical border cells in the medial entorhinal cortex (MEC) discharging along a single wall, a large majority of border cells in mPFC fire particularly along four walls. mPFC border cells generate new firing fields to external insert, and remain stable under darkness, across distinct shapes, and in novel environments. In contrast to hippocampal theta entrainment during spatial working memory tasks, mPFC border cells rarely exhibited theta rhythmicity during spontaneous locomotion behavior. These findings reveal spatially modulated activity in mPFC, supporting local computation for cognitive functions involving spatial context and contributing to a broad spatial tuning property of cortical circuits.
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Corteza Prefrontal , Ritmo Teta , Corteza Prefrontal/fisiología , Corteza Prefrontal/citología , Animales , Ritmo Teta/fisiología , Masculino , Ratones , Corteza Entorrinal/fisiología , Neuronas/fisiología , Hipocampo/fisiología , Memoria Espacial/fisiología , Ratones Endogámicos C57BL , Memoria a Corto Plazo/fisiologíaRESUMEN
Activity in a network of areas spanning the superior temporal sulcus, dorsomedial frontal cortex, and anterior cingulate cortex is concerned with how nonhuman primates negotiate the social worlds in which they live. Central aspects of these circuits are retained in humans. Activity in these areas codes for primates' interactions with one another, their attempts to find out about one another, and their attempts to prevent others from finding out too much about themselves. Moreover, important features of the social world, such as dominance status, cooperation, and competition, modulate activity in these areas. We consider the degree to which activity in these regions is simply encoding an individual's own actions and choices or whether this activity is especially and specifically concerned with social cognition. Recent advances in comparative anatomy and computational modeling may help us to gain deeper insights into the nature and boundaries of primate social cognition.