Context-dependent incremental timing cells in the primate hippocampus

Abstract

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.hippocampus | time | primate | associative learning | behavioral learning A fundamental feature of episodic memory is recalling the temporal sequence of events within an episode. Many studies have shown that the hippocampus plays a critical role in such episodic memories in both humans (1-3) and animals (4, 5). For example, the hippocampus is preferentially active in humans tasked to remember the previous order of familiar objects (6, 7), encode sequences of word triplets (8), or learn sequences of key tapping during a reaction time task (9). Further, damage to the hippocampus in humans causes deficits in remembering the temporal order of contextual events in a virtual town (10) and the grouping of sets of words (11). Similarly, animal studies report selective bilateral damage to the hippocampus impairs memory for the sequential order of items in sequence (12)(13)(14).Multiple studies have examined the neurophysiological underpinnings of memory for sequential order in the hippocampus. One study in rodents reported that a population of simultaneously recorded hippocampal CA1 cells signaled timing during an olfactory temporal order memory task by gradual changes in their population response (15). Similarly, populations of primate hippocampal cells signaled incremental timing across a delay interval during a task where subjects were required to remember both what items were shown and in what order (16).Other work in rodents suggests that timing may be supported by individual hippocampal "time cells" that are tuned to particular time intervals within a delay period (17-21). One study attempted to disambiguate the influences of location, time, and distance of these time cells and found that many hippocampal neurons could be differentially separated into one group influenced by time and another group influenced by distance (18). Another study showed that time cells still tracked across a delay period even when rats were not actively locomoting (19).In a prev...

Time, memory, and the legacy of Howard Eichenbaum

“…The findings of time cells in rodents appear to generalize to primates. In monkeys, Suzuki and colleagues (Naya & Suzuki, ; Sakon, Naya, Wirth, & Suzuki, ) have shown that hippocampal neurons track elapsed time in memory tasks, even when the information is task‐irrelevant. Similar to Eichenbaum's work in rats, the findings suggest that the hippocampus may track temporal context as a basis for structuring memory representations as an event unfolds over time.…”

The hippocampus: a special place for time

“…Although most of the work on temporal coding in the hippocampus has been done in rats, Suzuki and colleagues have also demonstrated neural correlates of temporal coding in recordings from the monkey hippocampus. 61,62 In one study, Naya and Suzuki 62 recorded hippocampal activity during a task that required short-term memory for the temporal order of pairs of objects. Hippocampal neurons fired at specific time points during the delay between each object, which they termed an incremental timing signal.…”

“…If this is the case, one would expect that the timing signal of hippocampal neurons should carry sequence-specific information under conditions that encourage learning of consistent associations. Sakon et al 61 tested this prediction in an analysis of hippocampal activity during a test of memory for object-place associations. They found that a subset of hippocampal neurons signaled temporal intervals that were specific to particular object-place associations.…”

Spatial responses, immediate experience, and memory in the monkey hippocampus

“…Neurons that respond during the cues differentiate their activity based on the cue identity [39–42] or the associated response to the cue [39,42–44] indicating that the hippocampus registers non-spatial events as they occur and the neural response is also contingent on the rules of the task. More recently, it has been shown that cue-specific activity can span the delay period before a response, creating a bridge between the events of the task [45,46]. These task-specific responses develop around the time that the animal learns the contingencies of the experimental paradigm [43,47,48], suggesting that the activity of hippocampal neurons may be the direct result of abstracting conditional relationships across task events.…”