Time and experience differentially affect distinct aspects of hippocampal representational drift.

Hippocampal activity is critical for spatial memory. Within a fixed, familiar environment, hippocampal codes gradually change over timescales of days to weeks-a phenomenon known as representational drift. The passage of time and the amount of experience are two factors that profoundly affect memory. However, thus far, it has remained unclear to what extent these factors drive hippocampal representational drift. Here, we longitudinally recorded large populations of hippocampal neurons in mice while they repeatedly explored two different familiar environments that they visited at different time intervals over weeks. We found that time and experience differentially affected distinct aspects of representational drift: the passage of time drove changes in neuronal activity rates, whereas experience drove changes in the cells' spatial tuning. Changes in spatial tuning were context specific and largely independent of changes in activity rates. Thus, our results suggest that representational drift is a multi-faceted process governed by distinct neuronal mechanisms.

Organization of hippocampal CA3 into correlated cell assemblies supports a stable spatial code.

Hippocampal subfield CA3 is thought to stably store memories in assemblies of recurrently connected cells functioning as a collective. However, the collective hippocampal coding properties that are unique to CA3 and how such properties facilitate the stability or precision of the neural code remain unclear. Here, we performed large-scale Ca2+ imaging in hippocampal CA1 and CA3 of freely behaving mice that repeatedly explored the same, initially novel environments over weeks. CA3 place cells have more precise and more stable tuning and show a higher statistical dependence with their peers compared with CA1 place cells, uncovering a cell assembly organization in CA3. Surprisingly, although tuning precision and long-term stability are correlated, cells with stronger peer dependence exhibit higher stability but not higher precision. Overall, our results expose the three-way relationship between tuning precision, long-term stability, and peer dependence, suggesting that a cell assembly organization underlies long-term storage of information in the hippocampus.

Consistent population activity on the scale of minutes in the mouse hippocampus.

Neurons in the hippocampus fire in consistent sequence over the timescale of seconds during the delay period of some memory experiments. For longer timescales, the firing of hippocampal neurons also changes slowly over minutes within experimental sessions. It was thought that these slow dynamics are caused by stochastic drift or a continuous change in the representation of the episode, rather than consistent sequences unfolding over minutes. This paper studies the consistency of contextual drift in three chronic calcium imaging recordings from the hippocampus CA1 region in mice. Computational measures of consistency show reliable sequences within experimental trials at the scale of seconds as one would expect from time cells or place cells during the trial, as well as across experimental trials on the scale of minutes within a recording session. Consistent sequences in the hippocampus are observed over a wide range of time scales, from seconds to minutes. The hippocampal activity could reflect a scale-invariant spatiotemporal context as suggested by theories of memory from cognitive psychology.

Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models.

Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.

Multiple Maps of the Same Spatial Context Can Stably Coexist in the Mouse Hippocampus.

Hippocampal place cells selectively fire when an animal traverses a particular location and are considered a neural substrate of spatial memory. Place cells were shown to change their activity patterns (remap) across different spatial contexts but to maintain their spatial tuning in a fixed familiar context. Here, we show that mouse hippocampal neurons can globally remap, forming multiple distinct representations (maps) of the same familiar environment, without any apparent changes in sensory input or behavior. Alternations between maps occurred only across separate visits to the environment, implying switching between distinct stable attractors in the hippocampal network. Importantly, the different maps were spatially informative and persistent over weeks, demonstrating that they can be reliably stored and retrieved from long-term memory. Taken together, our results suggest that a memory of a given spatial context could be associated with multiple distinct neuronal representations, rather than just one.

Revealing neural correlates of behavior without behavioral measurements.

Measuring neuronal tuning curves has been instrumental for many discoveries in neuroscience but requires a priori assumptions regarding the identity of the encoded variables. We applied unsupervised learning to large-scale neuronal recordings in behaving mice from circuits involved in spatial cognition and uncovered a highly-organized internal structure of ensemble activity patterns. This emergent structure allowed defining for each neuron an 'internal tuning-curve' that characterizes its activity relative to the network activity, rather than relative to any predefined external variable, revealing place-tuning and head-direction tuning without relying on measurements of place or head-direction. Similar investigation in prefrontal cortex revealed schematic representations of distances and actions, and exposed a previously unknown variable, the 'trajectory-phase'. The internal structure was conserved across mice, allowing using one animal's data to decode another animal's behavior. Thus, the internal structure of neuronal activity itself enables reconstructing internal representations and discovering new behavioral variables hidden within a neural code.

Tracking the Same Neurons across Multiple Days in Ca2+ Imaging Data.

Ca2+ imaging techniques permit time-lapse recordings of neuronal activity from large populations over weeks. However, without identifying the same neurons across imaging sessions (cell registration), longitudinal analysis of the neural code is restricted to population-level statistics. Accurate cell registration becomes challenging with increased numbers of cells, sessions, and inter-session intervals. Current cell registration practices, whether manual or automatic, do not quantitatively evaluate registration accuracy, possibly leading to data misinterpretation. We developed a probabilistic method that automatically registers cells across multiple sessions and estimates the registration confidence for each registered cell. Using large-scale Ca2+ imaging data recorded over weeks from the hippocampus and cortex of freely behaving mice, we show that our method performs more accurate registration than previously used routines, yielding estimated error rates <5%, and that the registration is scalable for many sessions. Thus, our method allows reliable longitudinal analysis of the same neurons over long time periods.

Hippocampal ensemble dynamics timestamp events in long-term memory.

The capacity to remember temporal relationships between different events is essential to episodic memory, but little is currently known about its underlying mechanisms. We performed time-lapse imaging of thousands of neurons over weeks in the hippocampal CA1 of mice as they repeatedly visited two distinct environments. Longitudinal analysis exposed ongoing environment-independent evolution of episodic representations, despite stable place field locations and constant remapping between the two environments. These dynamics time-stamped experienced events via neuronal ensembles that had cellular composition and activity patterns unique to specific points in time. Temporally close episodes shared a common timestamp regardless of the spatial context in which they occurred. Temporally remote episodes had distinct timestamps, even if they occurred within the same spatial context. Our results suggest that days-scale hippocampal ensemble dynamics could support the formation of a mental timeline in which experienced events could be mnemonically associated or dissociated based on their temporal distance.