A place with a view: A first-person perspective in the hippocampal memory space.

How do rodents' and primates' differences in visual perception impact the way the brain constructs egocentric and allocentric reference frames to represent stimuli in space? Strikingly, there are important similarities in the egocentric spatial reference frames through which cortical regions represent objects with respect to an animal's head or body in rodents and primates. These egocentric representations are suitable for navigation across species. However, while the rodent hippocampus represents allocentric place, I draw on several pieces of evidence suggesting that an egocentric reference frame is paramount in the primate hippocampus, and relates to the first-person perspective characteristic of a primate's field of view. I further discuss the link between an allocentric reference frame and a conceptual frame to suggest that an allocentric reference frame is a semantic construct in primates. Finally, I discuss how views probe memory recall and support prospective coding, and as they are based on a first-person perspective, are a powerful tool for probing episodic memory across species.

The human posterior cingulate, retrosplenial, and medial parietal cortex effective connectome, and implications for memory and navigation.

The human posterior cingulate, retrosplenial, and medial parietal cortex are involved in memory and navigation. The functional anatomy underlying these cognitive functions was investigated by measuring the effective connectivity of these Posterior Cingulate Division (PCD) regions in the Human Connectome Project-MMP1 atlas in 171 HCP participants, and complemented with functional connectivity and diffusion tractography. First, the postero-ventral parts of the PCD (31pd, 31pv, 7m, d23ab, and v23ab) have effective connectivity with the temporal pole, inferior temporal visual cortex, cortex in the superior temporal sulcus implicated in auditory and semantic processing, with the reward-related vmPFC and pregenual anterior cingulate cortex, with the inferior parietal cortex, and with the hippocampal system. This connectivity implicates it in hippocampal episodic memory, providing routes for "what," reward and semantic schema-related information to access the hippocampus. Second, the antero-dorsal parts of the PCD (especially 31a and 23d, PCV, and also RSC) have connectivity with early visual cortical areas including those that represent spatial scenes, with the superior parietal cortex, with the pregenual anterior cingulate cortex, and with the hippocampal system. This connectivity implicates it in the "where" component for hippocampal episodic memory and for spatial navigation. The dorsal-transitional-visual (DVT) and ProStriate regions where the retrosplenial scene area is located have connectivity from early visual cortical areas to the parahippocampal scene area, providing a ventromedial route for spatial scene information to reach the hippocampus. These connectivities provide important routes for "what," reward, and "where" scene-related information for human hippocampal episodic memory and navigation. The midcingulate cortex provides a route from the anterior dorsal parts of the PCD and the supracallosal part of the anterior cingulate cortex to premotor regions.

Face cells in orbitofrontal cortex represent social categories.

Perceiving social and emotional information from faces is a critical primate skill. For this purpose, primates evolved dedicated cortical architecture, especially in occipitotemporal areas, utilizing face-selective cells. Less understood face-selective neurons are present in the orbitofrontal cortex (OFC) and are our object of study. We examined 179 face-selective cells in the lateral sulcus of the OFC by characterizing their responses to a rich set of photographs of conspecific faces varying in age, gender, and facial expression. Principal component analysis and unsupervised cluster analysis of stimulus space both revealed that face cells encode face dimensions for social categories and emotions. Categories represented strongly were facial expressions (grin and threat versus lip smack), juvenile, and female monkeys. Cluster analyses of a control population of nearby cells lacking face selectivity did not categorize face stimuli in a meaningful way, suggesting that only face-selective cells directly support face categorization in OFC. Time course analyses of face cell activity from stimulus onset showed that faces were discriminated from nonfaces early, followed by within-face categorization for social and emotion content (i.e., young and facial expression). Face cells revealed no response to acoustic stimuli such as vocalizations and were poorly modulated by vocalizations added to faces. Neuronal responses remained stable when paired with positive or negative reinforcement, implying that face cells encode social information but not learned reward value associated to faces. Overall, our results shed light on a substantial role of the OFC in the characterizations of facial information bearing on social and emotional behavior.

Gaze-informed, task-situated representation of space in primate hippocampus during virtual navigation.

To elucidate how gaze informs the construction of mental space during wayfinding in visual species like primates, we jointly examined navigation behavior, visual exploration, and hippocampal activity as macaque monkeys searched a virtual reality maze for a reward. Cells sensitive to place also responded to one or more variables like head direction, point of gaze, or task context. Many cells fired at the sight (and in anticipation) of a single landmark in a viewpoint- or task-dependent manner, simultaneously encoding the animal's logical situation within a set of actions leading to the goal. Overall, hippocampal activity was best fit by a fine-grained state space comprising current position, view, and action contexts. Our findings indicate that counterparts of rodent place cells in primates embody multidimensional, task-situated knowledge pertaining to the target of gaze, therein supporting self-awareness in the construction of space.

Independent Neuronal Representation of Facial and Vocal Identity in the Monkey Hippocampus and Inferotemporal Cortex.

Social interactions make up to a large extent the prime material of episodic memories. We therefore asked how social signals are coded by neurons in the hippocampus. Human hippocampus is home to neurons representing familiar individuals in an abstract and invariant manner ( Quian Quiroga et al. 2009). In contradistinction, activity of rat hippocampal cells is only weakly altered by the presence of other rats ( von Heimendahl et al. 2012; Zynyuk et al. 2012). We probed the activity of monkey hippocampal neurons to faces and voices of familiar and unfamiliar individuals (monkeys and humans). Thirty-one percent of neurons recorded without prescreening responded to faces or to voices. Yet responses to faces were more informative about individuals than responses to voices and neuronal responses to facial and vocal identities were not correlated, indicating that in our sample identity information was not conveyed in an invariant manner like in human neurons. Overall, responses displayed by monkey hippocampal neurons were similar to the ones of neurons recorded simultaneously in inferotemporal cortex, whose role in face perception is established. These results demonstrate that the monkey hippocampus participates in the read-out of social information contrary to the rat hippocampus, but possibly lack an explicit conceptual coding of as found in humans.

Context-dependent incremental timing cells in the primate hippocampus.

We examined timing-related signals in primate hippocampal cells as animals performed an object-place (OP) associative learning task. We found hippocampal cells with firing rates that incrementally increased or decreased across the memory delay interval of the task, which we refer to as incremental timing cells (ITCs). Three distinct categories of ITCs were identified. Agnostic ITCs did not distinguish between different trial types. The remaining two categories of cells signaled time and trial context together: One category of cells tracked time depending on the behavioral action required for a correct response (i.e., early vs. late release), whereas the other category of cells tracked time only for those trials cued with a specific OP combination. The context-sensitive ITCs were observed more often during sessions where behavioral learning was observed and exhibited reduced incremental firing on incorrect trials. Thus, single primate hippocampal cells signal information about trial timing, which can be linked with trial type/context in a learning-dependent manner.

Spontaneous voice-face identity matching by rhesus monkeys for familiar conspecifics and humans.

Recognition of a particular individual occurs when we reactivate links between current perceptual inputs and the previously formed representation of that person. This recognition can be achieved by identifying, separately or simultaneously, distinct elements such as the face, silhouette, or voice as belonging to one individual. In humans, those different cues are linked into one complex conceptual representation of individual identity. Here we tested whether rhesus macaques (Macaca mulatta) also have a cognitive representation of identity by evaluating whether they exhibit cross-modal individual recognition. Further, we assessed individual recognition of familiar conspecifics and familiar humans. In a free preferential looking time paradigm, we found that, for both species, monkeys spontaneously matched the faces of known individuals to their voices. This finding demonstrates that rhesus macaques possess a cross-modal cognitive representation of individuals that extends from conspecifics to humans, revealing the adaptive potential of identity recognition for individuals of socioecological relevance.

Distinct neural adaptations to time demand in the striatum and the hippocampus.

How do neural codes adjust to track time across a range of resolutions, from milliseconds to multi-seconds, as a function of the temporal frequency at which events occur? To address this question, we studied time-modulated cells in the striatum and the hippocampus, while macaques categorized three nested intervals within the sub-second or the supra-second range (up to 1, 2, 4, or 8 s), thereby modifying the temporal resolution needed to solve the task. Time-modulated cells carried more information for intervals with explicit timing demand, than for any other interval. The striatum, particularly the caudate, supported the most accurate temporal prediction throughout all time ranges. Strikingly, its temporal readout adjusted non-linearly to the time range, suggesting that the striatal resolution shifted from a precise millisecond to a coarse multi-second range as a function of demand. This is in line with monkey's behavioral latencies, which indicated that they tracked time until 2 s but employed a coarse categorization strategy for durations beyond. By contrast, the hippocampus discriminated only the beginning from the end of intervals, regardless of the range. We propose that the hippocampus may provide an overall poor signal marking an event's beginning, whereas the striatum optimizes neural resources to process time throughout an interval adapting to the ongoing timing necessity.

Encoding identity in the marmoset.

Hippocampal cells integrate multisensory input to represent the identity of others.

Gap in the conditioned stimulus: Differential impacts on temporal expectancy in appetitive and aversive conditions in rats.

We analyzed, through a Pavlovian conditioning procedure in rats, the temporal pattern of behavior in appetitive and aversive conditions within subjects, and the difference in inferred temporal working memory functioning with the Gap paradigm. For both conditions, we paired a 60-s conditioned stimulus (CS: tone1 or tone2) with an unconditioned stimulus (US: shock or chocolate pellet) delivered 20s after CS onset. The analyses of mean response rate and individual-trial data were performed during Probe trials, consisting of CS alone, and trials in which gaps of different position or duration were inserted, to assess the effect of the temporal manipulation on behavior. The results showed: (1) An anticipatory peak time in the aversive condition but better accuracy in the appetitive condition, (2) constancy in the Weber fraction suggesting that the difference in peak time was under clock control, (3) a graded effect of gap parameters only in the aversive condition and (4) different gap effects between conditions when a gap was inserted early in the CS. These results highlight behavioral differences between aversive and appetitive conditions and suggest that the temporal working memory mechanism was not engaged in the same manner in each condition.

Computing confidence intervals for point process models.

Characterizing neural spiking activity as a function of intrinsic and extrinsic factors is important in neuroscience. Point process models are valuable for capturing such information; however, the process of fully applying these models is not always obvious. A complete model application has four broad steps: specification of the model, estimation of model parameters given observed data, verification of the model using goodness of fit, and characterization of the model using confidence bounds. Of these steps, only the first three have been applied widely in the literature, suggesting the need to dedicate a discussion to how the time-rescaling theorem, in combination with parametric bootstrap sampling, can be generally used to compute confidence bounds of point process models. In our first example, we use a generalized linear model of spiking propensity to demonstrate that confidence bounds derived from bootstrap simulations are consistent with those computed from closed-form analytic solutions. In our second example, we consider an adaptive point process model of hippocampal place field plasticity for which no analytical confidence bounds can be derived. We demonstrate how to simulate bootstrap samples from adaptive point process models, how to use these samples to generate confidence bounds, and how to statistically test the hypothesis that neural representations at two time points are significantly different. These examples have been designed as useful guides for performing scientific inference based on point process models.

Primate memory, from simple associations to abstract concepts.

The hippocampus is a neural structure central to the formation of memories and wayfinding. To understand the neural mechanisms at work during memory formation over multiple episodes, Electrophysiological recordings show that neurons in the macaque hippocampus encode complex conjunctions of traits relevant to the navigational task during virtual navigation. While a majority encode environment-specific cues, about one third exhibit correlated firing across different environments sharing the same spatial structure. The similarity of firing appeared to encode the logic of the task in a way akin to a schema. The existence of the schema cells offers a foundation for abstraction in the monkey and suggests that memory storage in the primate could proceed in a similar way from simple cue associations up to conceptual thinking.

L'hippocampe est une structure neuronale essentielle à la formation des souvenirs et à l'orientation spatiale. Afin de comprendre les mécanismes neuronaux qui sous-tendent la mémorisation au cours d'expériences multiples, nous avons réalisé des enregistrements électrophysiologiques dans l'hippocampe du macaque, alors que les animaux se prêtaient à une série de tâches de navigation virtuelle. Nos résultats montrent que les neurones encodent des conjonctions complexes d'éléments pertinents pour la navigation, liées aux repères visuels, la position du singe et aux actions à venir. Si la majorité des neurones encodent une information spécifique à chaque environnement, environ un tiers d'entre eux présentent une activité corrélée dans des environnements différents qui partagent la même structure spatiale : ces cellules semblent coder la logique d'organisation de l'environnement et plus généralement, de la tâche, indépendamment des détails propres à chaque environnement, d'une manière proche d'un schéma mental. Ces cellules de schéma pourraient être un fondement de l'abstraction chez le singe et leur existence suggère un mécanisme relationnel général pour le stockage de la mémoire chez le primate, depuis de simples associations de repères spatiaux jusqu'à une pensée conceptuelle.

The contributions of entorhinal cortex and hippocampus to error driven learning.

Computational models proposed that the medial temporal lobe (MTL) contributes importantly to error-driven learning, though little direct in-vivo evidence for this hypothesis exists. To test this, we recorded in the entorhinal cortex (EC) and hippocampus (HPC) as macaques performed an associative learning task using an error-driven learning strategy, defined as better performance after error relative to correct trials. Error-detection signals were more prominent in the EC relative to HPC. Early in learning hippocampal but not EC neurons signaled error-driven learning by increasing their population stimulus-selectivity following error trials. This same pattern was not seen in another task where error-driven learning was not used. After learning, different populations of cells in both the EC and HPC signaled long-term memory of newly learned associations with enhanced stimulus-selective responses. These results suggest prominent but differential contributions of EC and HPC to learning from errors and a particularly important role of the EC in error-detection.

Two functions of the primate amygdala in social gaze.

Appropriate gaze interaction is essential for primate social life. Prior studies have suggested the involvement of the amygdala in processing eye cues but its role in gaze behavior during live social exchanges remains unknown. We recorded the activity of neurons in the amygdala of two monkeys as they engaged in spontaneous visual interactions. We showed that monkeys adjust their oculomotor behavior and actively seek to interact with each other through mutual gaze. During fixations on the eye region, some amygdala neurons responded with short latency and more strongly to mutual than non-reciprocal gaze (averted gaze). Other neurons responded with long latency and were more strongly modulated by active, self-terminated mutual gaze fixations than by passively terminated ones. These results suggest that the amygdala not only participates to the evaluation of eye contact, but also plays a role in the timing of fixations which is crucial for adaptive social interactions through gaze.

Territorial blueprint in the hippocampal system.

As we skillfully navigate through familiar places, neural computations of distances and coordinates escape our attention. However, we perceive clearly the division of space into socially meaningful territories. 'My space' versus 'your space' is a distinction familiar to all of us. Spatial frontiers are social in nature since they regulate individuals' access to utilities in space depending on hierarchy and affiliation. How does the brain integrate spatial geometry with social territory? We propose that the action of oxytocin (OT) in the entorhinal-hippocampal regions supports this process. Grounded on the functional role of the hypothalamic neuropeptide in the hippocampal system, we show how OT-induced plasticity may bias the geometrical coding of place and grid cells to represent social territories.

Comparison of associative learning-related signals in the macaque perirhinal cortex and hippocampus.

Strong evidence suggests that the macaque monkey perirhinal cortex is involved in both the initial formation as well as the long-term storage of associative memory. To examine the neurophysiological basis of associative memory formation in this area, we recorded neural activity in this region as monkeys learned new conditional-motor associations. We report that a population of perirhinal neurons signal newly learned associations by changing their firing rate correlated with the animal's behavioral learning curve. Individual perirhinal neurons signal learning of one or more associations concurrently and these neural changes could occur before, at the same time, or after behavioral learning was expressed. We also compared the associative learning signals in the perirhinal cortex to our previous findings in the hippocampus. We report global similarities in both the learning-related and task-related activity seen across these areas as well as clear differences in the within and across trial timing and relative proportion of different subtypes of learning-related signals. Taken together, these findings emphasize the important role of the perirhinal cortex in new associative learning and suggest that the perirhinal cortex together with the hippocampus contribute importantly to conditional-motor associative memory formation.

Representation of well-learned information in the monkey hippocampus.

In the neocortex, extensive training results in enhanced neuronal selectivity for learned stimuli relative to novel stimuli. This enhanced selectivity has been taken as evidence for learning-related plasticity. Much less is known, in contrast, about the representation of well-learned information in the hippocampus. In this study, we examined the responses of individual hippocampal neurons to well-learned and novel stimuli presented in the context of an associative learning task. There was no difference in the response magnitude or visual response latency of hippocampal neurons to the well-learned and novel stimuli. In contrast, hippocampal neurons responded significantly more selectively to the well-learned stimuli relative to the novel stimuli. These findings show that hippocampal cells, like neocortical cells, show greater selectivity to well-learned stimuli compared to novel stimuli.

Spatial representations in the primate hippocampus, and their functions in memory and navigation.

Hippocampal spatial view neurons in primates respond to the place where a monkey is looking, with some modulation by place. In contrast, hippocampal neurons in rodents respond mainly to the place where the animal is located. We relate this difference to the development of a fovea in primates, and the highly developed primate visual system which enables identification of what is at the fovea, and a system for moving the eyes to view different parts of the environment. We show that the spatial view representation in primates is allocentric, and provide new animations using recorded neuronal activity to illustrate this. We also show that this spatial representation becomes engaged in tasks in which the location 'out there' in a scene of objects and rewards must be remembered. We show that this representation of space being viewed provides a framework for the encoding of episodic memory and the recall of these memories in primates including humans, with hippocampal neurons responding for example in a one-trial object / place recall task. These functions of the primate hippocampus in scene-related memory, provide a way for the primate hippocampus to contribute to actions in space and navigation. We consider in a formal model the mechanisms by which these different spatial representations may be formed given the presence of the primate fovea, and how these mechanisms may contribute to the representations found during navigation in a virtual environment.

Functional magnetic resonance imaging activity during the gradual acquisition and expression of paired-associate memory.

Recent neurophysiological findings from the monkey hippocampus showed dramatic changes in the firing rate of individual hippocampal cells as a function of learning new associations. To extend these findings to humans, we used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine the patterns of brain activity during learning of an analogous associative task. We observed bilateral, monotonic increases in activity during learning not only in the hippocampus but also in the parahippocampal and right perirhinal cortices. In addition, activity related to simple novelty signals was observed throughout the medial temporal lobe (MTL) memory system and in several frontal regions. A contrasting pattern was observed in a frontoparietal network in which a high level of activity was sustained until the association was well learned, at which point the activity decreased to baseline. Thus, we found that associative learning in humans is accompanied by striking increases in BOLD fMRI activity throughout the MTL as well as in the cingulate cortex and frontal lobe, consistent with neurophysiological findings in the monkey hippocampus. The finding that both the hippocampus and surrounding MTL cortex exhibited similar associative learning and novelty signals argues strongly against the view that there is a clear division of labor in the MTL in which the hippocampus is essential for forming associations and the cortex is involved in novelty detection. A second experiment addressed a striking aspect of the data from the first experiment by demonstrating a substantial effect of baseline task difficulty on MTL activity capable of rendering mnemonic activity as either "positive" or "negative."