Sharp-wave ripple features in macaques depend on behavioral state and cell-type specific firing.

Sharp-wave ripples (SWRs) are spontaneous, synchronized neural population events in the hippocampus widely thought to play a role in memory consolidation and retrieval. They occur predominantly in sleep and quiet immobility, and in primates, they also appear during active visual exploration. Typical measures of SWRs in behaving rats include changes in the rate of occurrence, or in the incidence of specific neural ensemble activity contained within the categorical SWR event. Much less is known about the relevance of spatiotemporal SWR features, though they may index underlying activity of specific cell types including ensemble-specific internally generated sequences. Furthermore, changes in SWR features during active exploratory states are unknown. In this study, we recorded hippocampal local-field potentials and single-units during periods of quiescence and as macaques performed a memory-guided visual search task. We observed that (a) ripples during quiescence have greater amplitudes and larger postripple waves (PRW) compared to those in task epochs, and (b) during "remembered" trials, ripples have larger amplitudes than during "forgotten" trials, with no change in duration or PRWs. We further found that spiking activity influences SWR features as a function of cell type and ripple timing. As expected, larger ripple amplitudes were associated with putative pyramidal or putative basket interneuron (IN) activity, even when the spikes in question exceed the duration of the ripple. In contrast, the PRW was attenuated with activity from low firing rate cells and enhanced with activity from high firing rate cells, with putative IN spikes during ripples leading to the most prominent PRW peaks. The selective changes in SWR features as a function of time window, cell type, and cognitive/vigilance states suggest that this mesoscopic field event can offer additional information about the local network and animal's state than would be appreciated from SWR event rates alone.

Sharp-Wave Ripples in Primates Are Enhanced near Remembered Visual Objects.

The hippocampus plays an important role in memory for events that are distinct in space and time. One of the strongest, most synchronous neural signals produced by the hippocampus is the sharp-wave ripple (SWR), observed in a variety of mammalian species during offline behaviors, such as slow-wave sleep [1-3] and quiescent waking and pauses in exploration [4-8], leading to long-standing and widespread theories of its contribution to plasticity and memory during these inactive or immobile states [9-14]. Indeed, during sleep and waking inactivity, hippocampal SWRs in rodents appear to support spatial long-term and working memory [4, 15-23], but so far, they have not been linked to memory in primates. More recently, SWRs have been observed during active, visual scene exploration in macaques [24], opening up the possibility that these active-state ripples in the primate hippocampus are linked to memory for objects embedded in scenes. By measuring hippocampal SWRs in macaques during search for scene-contextualized objects, we found that SWR rate increased with repeated presentations. Furthermore, gaze during SWRs was more likely to be near the target object on repeated than on novel presentations, even after accounting for overall differences in gaze location with scene repetition. This proximity bias with repetition occurred near the time of target object detection for remembered targets. The increase in ripple likelihood near remembered visual objects suggests a link between ripples and memory in primates; specifically, SWRs may reflect part of a mechanism supporting the guidance of search based on past experience.

Hippocampal gamma-band Synchrony and pupillary responses index memory during visual search.

Memory for scenes is supported by the hippocampus, among other interconnected structures, but the neural mechanisms related to this process are not well understood. To assess the role of the hippocampus in memory-guided scene search, we recorded local field potentials and multiunit activity from the hippocampus of macaques as they performed goal-directed search tasks using natural scenes. We additionally measured pupil size during scene presentation, which in humans is modulated by recognition memory. We found that both pupil dilation and search efficiency accompanied scene repetition, thereby indicating memory for scenes. Neural correlates included a brief increase in hippocampal multiunit activity and a sustained synchronization of unit activity to gamma band oscillations (50-70 Hz). The repetition effects on hippocampal gamma synchronization occurred when pupils were most dilated, suggesting an interaction between aroused, attentive processing and hippocampal correlates of recognition memory. These results suggest that the hippocampus may support memory-guided visual search through enhanced local gamma synchrony. © 2016 Wiley Periodicals, Inc.

Pupillary responses and memory-guided visual search reveal age-related and Alzheimer's-related memory decline.

Episodic memory - composed of memory for unique spatiotemporal experiences - is known to decline with aging, and even more severely in Alzheimer 's disease (AD). Memory for trial-unique objects in spatial scenes depends on the integrity of the hippocampus and interconnected structures that are among the first areas affected in AD. We reasoned that memory for objects-in-scenes would be impaired with aging, and that further impairments would be observed in AD. We asked younger adults, healthy older adults, older adults at-risk for developing cognitive impairments, and older adults with probable early AD to find changing items ('targets') within images of natural scenes, measuring repeated-trial changes in search efficiency and pupil diameter. Compared to younger adults, older adults took longer to detect target objects in repeated scenes, they required more fixations and those fixations were more dispersed. Whereas individuals with AD showed some benefit of memory in this task, they had substantially longer detection times, and more numerous, dispersed fixations on repeated scenes compared to age-matched older adults. Correspondingly, pupillary responses to novel and repeated scenes were diminished with aging and further in AD, and the memory-related changes were weaker with aging and absent in AD. Our results suggest that several nonverbal measures from memory-guided visual search tasks can index aging and Alzheimer's disease status, including pupillary dynamics. The task measurements are sensitive to the integrity of brain structures that are associated with Alzheimer's-related neurodegeneration, the task is well tolerated across a range of abilities, and thus, it may prove useful in early diagnostics and longitudinal tracking of memory decline.

Sharp Wave Ripples during Visual Exploration in the Primate Hippocampus.

Hippocampal sharp-wave ripples (SWRs) are highly synchronous oscillatory field potentials that are thought to facilitate memory consolidation. SWRs typically occur during quiescent states, when neural activity reflecting recent experience is replayed. In rodents, SWRs also occur during brief locomotor pauses in maze exploration, where they appear to support learning during experience. In this study, we detected SWRs that occurred during quiescent states, but also during goal-directed visual exploration in nonhuman primates (Macaca mulatta). The exploratory SWRs showed peak frequency bands similar to those of quiescent SWRs, and both types were inhibited at the onset of their respective behavioral epochs. In apparent contrast to rodent SWRs, these exploratory SWRs occurred during active periods of exploration, e.g., while animals searched for a target object in a scene. SWRs were associated with smaller saccades and longer fixations. Also, when they coincided with target-object fixations during search, detection was more likely than when these events were decoupled. Although we observed high gamma-band field potentials of similar frequency to SWRs, only the SWRs accompanied greater spiking synchrony in neural populations. These results reveal that SWRs are not limited to off-line states as conventionally defined; rather, they occur during active and informative performance windows. The exploratory SWR in primates is an infrequent occurrence associated with active, attentive performance, which may indicate a new, extended role of SWRs during exploration in primates. SIGNIFICANCE STATEMENT: Sharp-wave ripples (SWRs) are high-frequency oscillations that generate highly synchronized activity in neural populations. Their prevalence in sleep and quiet wakefulness, and the memory deficits that result from their interruption, suggest that SWRs contribute to memory consolidation during rest. Here, we report that SWRs from the monkey hippocampus occur not only during behavioral inactivity but also during successful visual exploration. SWRs were associated with attentive, focal search and appeared to enhance perception of locations viewed around the time of their occurrence. SWRs occurring in rest are noteworthy for their relation to heightened neural population activity, temporally precise and widespread synchronization, and memory consolidation; therefore, the SWRs reported here may have a similar effect on neural populations, even as experiences unfold.

Saccades during visual exploration align hippocampal 3-8 Hz rhythms in human and non-human primates.

Visual exploration in primates depends on saccadic eye movements (SEMs) that cause alternations of neural suppression and enhancement. This modulation extends beyond retinotopic areas, and is thought to facilitate perception; yet saccades may also influence brain regions critical for forming memories of these exploratory episodes. The hippocampus, for example, shows oscillatory activity that is generally associated with encoding of information. Whether or how hippocampal oscillations are influenced by eye movements is unknown. We recorded the neural activity in the human and macaque hippocampus during visual scene search. Across species, SEMs were associated with a time-limited alignment of a low-frequency (3-8 Hz) rhythm. The phase alignment depended on the task and not only on eye movements per se, and the frequency band was not a direct consequence of saccade rate. Hippocampal theta-frequency oscillations are produced by other mammals during repetitive exploratory behaviors, including whisking, sniffing, echolocation, and locomotion. The present results may reflect a similar yet distinct primate homologue supporting active perception during exploration.

How macaques view familiarity and gaze in conspecific faces.

The pattern of visual fixations on an image depends not only on the image content but also on the viewer's disposition and on the function (or pathology) of underlying neural circuitry. For example, human viewers display changes in viewing patterns toward face images that differ in gaze direction or in the viewer's familiarity with the face. Macaques share many face processing abilities with humans, and their neural circuitry is used to understand perception across species, yet their viewing responses to gaze and familiarity of faces is poorly understood. In this study, rhesus macaques passively viewed faces of familiar and unfamiliar conspecifics whose head-and-eye gaze was directed either toward or away from the viewing monkey. The eyes of faces were viewed more than any other feature; furthermore, familiar eyes were viewed more than unfamiliar eyes. In contrast, ears, though not as salient as eyes, were viewed about twice as often for unfamiliar faces as familiar faces. Directed-gaze eyes were fixated earlier, and for a greater proportion of saccades than were the eyes of averted-gaze faces, suggesting that mutual gaze attracts a more immediate and sustained scanning of the eyes. Ears and external features were more salient for averted, as compared with directed gaze. In general, effects were more robust (within and across subjects) for the gaze contrast than for familiarity, perhaps as a consequence of the greater image-based differences for the gaze than the familiarity stimuli used in this study.