The role of medial entorhinal cortex activity in hippocampal CA1 spatiotemporally correlated sequence generation and object selectivity for memory function

The hippocampus is crucial for episodic memory and certain forms of spatial navigation. Firing activity of hippocampal principal neurons contains environmental information, including the presence of specific objects, as well as the animal’s spatial and temporal position relative to environmental and behavioral cues. The organization of these firing correlates may allow the formation of memory traces through the integration of object and event information onto a spatiotemporal framework of cell assemblies. Characterizing how external inputs guide internal dynamics in the hippocampus to enable this process across different experiences is crucial to understanding hippocampal function. A body of literature implicates the medial entorhinal cortex (MEC) in supplying spatial and temporal information to the hippocampus. Here we develop a protocol utilizing bilaterally implanted custom designed triple fiber optic arrays and the red-shifted inhibitory opsin JAWS to transiently inactivate large volumes of MEC in freely behaving rats. This was coupled with extracellular tetrode recording of ensembles in CA1 of the hippocampus during a novel memory task involving temporal, spatial and object related epochs, in order to assess the importance of MEC activity for hippocampal feature selectivity during a rich and familiar experience. We report that inactivation of MEC during a mnemonic temporal delay disrupts the existing temporal firing field sequence in CA1 both during and following the inactivation period. Neurons with firing fields prior to the inactivation on each trial remained relatively stable. The disruption of CA1 temporal firing field sequences was accompanied by a behavioral deficit implicating MEC activity and hippocampal temporal field sequences in effective memory across time. Inactivating MEC during the object or spatial epochs of the task did not significantly alter CA1 object selective or spatial firing fields and behavioral performance remained stable. Our findings suggest that MEC is crucial specifically for temporal field organization and expression during a familiar and rich experience. These results support a role for MEC in guiding hippocampal cell assembly sequences in the absence of salient changing stimuli, which may extend to the navigation of cognitive organization in humans and support memory formation and retrieval

The role of experience in memory consolidation

The hippocampus is believed to play a key role in long-term consolidation during sleep. Additionally, hippocampal place cells - pyramidal neurons that fire in discrete locations in the space - have been used as a reliable behavioural correlate to study learning and memory of spatial tasks. To date, most studies investigating memory consolidation focus on recordings from neural data obtained during tasks the subjects have been previously overexposed to. While this strategy guarantees a higher stability of the spatial map encoding for that specific experience, the reality of more naturalistic settings is that both humans and other animals can encounter multiple events of diverse duration and relevance on a daily basis. Yet, it remains unclear how the brain prioritizes and successfully stores multiple novel events. To address this question, we exposed a group of rats to pairs of novel linear tracks across different days. Each day, rats were allowed to run in each track for a different fixed number of laps, and the experience was preceded and followed by a sleep session. We found that the hippocampus was able to discriminate the different spatial maps even for short exposures with unstable place fields. We also observed awake and sleep hippocampal replay of all tracks regardless of the stability of their spatial representations. However, when presented with similar experiences of different duration in the novel tracks, the hippocampus prioritised the consolidation of the longer experience if the spatial representation of the shorter one was still unstable. Finally, we found that both awake hippocampal replay and theta sequences influenced the levels of subsequent sleep replay. These results aim to add further understanding of how experience shapes the encoding of different spatial trajectories, and how offline activity contributes to the consolidation of their memory representations

Neural processes underpinning episodic memory

Episodic memory is the memory for our personal past experiences. Although numerous functional magnetic resonance imaging (fMRI) studies investigating its neural basis have revealed a consistent and distributed network of associated brain regions, surprisingly little is known about the contributions individual brain areas make to the recollective experience. In this thesis I address this fundamental issue by employing a range of different experimental techniques including neuropsychological testing, virtual reality environments, whole brain and high spatial resolution fMRI, and multivariate pattern analysis. Episodic memory recall is widely agreed to be a reconstructive process, one that is known to be critically reliant on the hippocampus. I therefore hypothesised that the same neural machinery responsible for reconstruction might also support ‘constructive’ cognitive functions such as imagination. To test this proposal, patients with focal damage to the hippocampus bilaterally were asked to imagine new experiences and were found to be impaired relative to matched control participants. Moreover, driving this deficit was a lack of spatial coherence in their imagined experiences, pointing to a role for the hippocampus in binding together the disparate elements of a scene. A subsequent fMRI study involving healthy participants compared the recall of real memories with the construction of imaginary memories. This revealed a fronto-temporo-parietal network in common to both tasks that included the hippocampus, ventromedial prefrontal, retrosplenial and parietal cortices. Based on these results I advanced the notion that this network might support the process of ‘scene construction’, defined as the generation and maintenance of a complex and coherent spatial context. Furthermore, I argued that this scene construction network might underpin other important cognitive functions besides episodic memory and imagination, such as navigation and thinking about the future. It is has been proposed that spatial context may act as the scaffold around which episodic memories are built. Given the hippocampus appears to play a critical role in imagination by supporting the creation of a rich coherent spatial scene, I sought to explore the nature of this hippocampal spatial code in a novel way. By combining high spatial resolution fMRI with multivariate pattern analysis techniques it proved possible to accurately determine where a subject was located in a virtual reality environment based solely on the pattern of activity across hippocampal voxels. For this to have been possible, the hippocampal population code must be large and non-uniform. I then extended these techniques to the domain of episodic memory by showing that individual memories could be accurately decoded from the pattern of activity across hippocampal voxels, thus identifying individual memory traces. I consider these findings together with other recent advances in the episodic memory field, and present a new perspective on the role of the hippocampus in episodic recollection. I discuss how this new (and preliminary) framework compares with current prevailing theories of hippocampal function, and suggest how it might account for some previously contradictory data

Electrophysiological evidence for memory schemas in the rat hippocampus

According to Piaget and Bartlett, learning involves both assimilation of new memories into networks of preexisting knowledge and alteration of existing networks to accommodate new information into existing schemas. Recent evidence suggests that the hippocampus integrates related memories into schemas that link representations of separately acquired experiences. In this thesis, I first review models for how memories of individual experiences become consolidated into the structure of world knowledge. Disruption of consolidated memories can occur during related learning, which suggests that consolidation of new information is the reconsolidation of related memories. The accepted role of the hippocampus during memory consolidation and reconsolidation suggests that it is also involved in modifying appropriate schemas during learning. To study schema development, I trained rats to retrieve rewards at different loci on a maze while recording hippocampal calls. About a quarter of cells were active at multiple goal sites, though the ensemble as a whole distinguished goal loci from one another. When new goals were introduced, cells that had been active at old goal locations began firing at the new locations. This initial generalization decreased in the days after learning. Learning also caused changes in firing patterns at well-learned goal locations. These results suggest that learning was supported by modification of an active schema of spatially related reward loci. In another experiment, I extended these findings to explore a schema of object and place associations. Ensemble activity was influenced by a hierarchy of task dimensions which included: experimental context, rat's spatial location, the reward potential and the identity of sampled objects. As rats learned about new objects, the cells that had previously fired for particular object-place conjunctions generalized their firing patterns to new conjunctions that similarly predicted reward. In both experiments, I observed highly structured representations for a set of related experiences. This organization of hippocampal activity counters key assumptions in standard models of hippocampal function that predict relative independence between memory traces. Instead, these findings reveal neural mechanisms for how the hippocampus develops a relational organization of memories that could support novel, inferential judgments between indirectly related events

Threat learning impairs subsequent associative inference

Despite it being widely acknowledged that the most important function of memory is to facilitate the prediction of significant events in a complex world, no studies to date have investigated how our ability to infer associations across distinct but overlapping experiences is affected by the inclusion of threat memories. To address this question, participants (n = 35) encoded neutral predictive associations (A → B). The following day these memories were reactivated by pairing B with a new aversive or neutral outcome (B → C(THREAT/NEUTRAL)) while pupil dilation was measured as an index of emotional arousal. Then, again 1 day later, the accuracy of indirect associations (A → C?) was tested. Associative inferences involving a threat learning memory were impaired whereas the initial memories were retroactively strengthened, but these effects were not moderated by pupil dilation at encoding. These results imply that a healthy memory system may compartmentalize episodic information of threat, and so hinders its recall when cued only indirectly. Malfunctioning of this process may cause maladaptive linkage of negative events to distant and benign memories, and thereby contribute to the development of clinical intrusions and anxiety

Network analysis of the cellular circuits of memory

Intuitively, memory is conceived as a collection of static images that we accumulate as we experience the world. But actually, memories are constantly changing through our life, shaped by our ongoing experiences. Assimilating new knowledge without corrupting pre-existing memories is then a critical brain function. However, learning and memory interact: prior knowledge can proactively influence learning, and new information can retroactively modify memories of past events. The hippocampus is a brain region essential for learning and memory, but the network-level operations that underlie the continuous integration of new experiences into memory, segregating them as discrete traces while enabling their interaction, are unknown. Here I show a network mechanism by which two distinct memories interact. Hippocampal CA1 neuron ensembles were monitored in mice as they explored a familiar environment before and after forming a new place-reward memory in a different environment. By employing a network science representation of the co-firing relationships among principal cells, I first found that new associative learning modifies the topology of the cells’ co-firing patterns representing the unrelated familiar environment. I fur- ther observed that these neuronal co-firing graphs evolved along three functional axes: the first segregated novelty; the second distinguished individual novel be- havioural experiences; while the third revealed cross-memory interaction. Finally, I found that during this process, high activity principal cells rapidly formed the core representation of each memory; whereas low activity principal cells gradually joined co-activation motifs throughout individual experiences, enabling cross-memory in- teractions. These findings reveal an organizational principle of brain networks where high and low activity cells are differentially recruited into coactivity motifs as build- ing blocks for the flexible integration and interaction of memories. Finally, I employ a set of manifold learning and related approaches to explore and characterise the complex neural population dynamics within CA1 that underlie sim- ple exploration.Open Acces

Retrieval dynamics in episodic memory – from computations to representations

Understanding how our experiences are retrieved from long-term memory is fundamental in cognitive neuroscience. In this doctoral thesis I explore two essential questions regarding the temporal dynamics of episodic memory retrieval. First, I investigate how rapidly distinct components of a visual object representation (i.e., perceptual and conceptual aspects) are reactivated during retrieval, and how this temporal sequence evolves compared to visual encoding. Findings from a series of behavioural, scalp electroencephalography (EEG) and intracranial EEG experiments, using reaction times and time- resolved decoding analyses, suggest that retrieval is a hierarchical, multi- layered process that follows the reverse order compared to encoding, prioritizing semantic information over perceptual details. Second, I explore whether memories are reactivated following a specific oscillatory rhythm. Computational models, based on studies in rodents, suggest that encoding and retrieval processes occur at opposing phases of hippocampal theta oscillations. Evidence for such phase modulation in humans is still sparse. The present findings suggest that in humans, neural signatures of memory retrieval fluctuate with, and are time-locked to, the phase of theta oscillations. Altogether, this doctoral thesis supports the view that retrieval is an oscillatory process and the elements that form our memories are retrieved following a biased and sequential order

Predicting memory formation over multiple study episodes

Repeated study typically improves episodic memory performance. Two different types of explanations of this phenomenon have been put forward: 1) reactivating the same representations strengthens and stabilizes memories, or 2) greater encoding variability benefits memory by promoting richer traces. The present experiment directly compared these predictions in a design with multiple repeated study episodes, allowing to dissociate memory for studied items and their context of study. Participants repeatedly encoded names of famous people four times, either in the same task, or in different tasks. During the test phase, an old/new judgement task was used to assess item memory, followed by a source memory judgement about the encoding task. Consistent with predictions from the encoding variability view, encoding stimulus in different contexts resulted in higher item memory. In contrast, consistent with the reactivation view, source memory performance was higher when participants encoded stimuli in the same task repeatedly. Taken together, our findings indicate that encoding variability benefits episodic memory, by increasing the number of items that are recalled. These benefits are however at the expenses of source recollection and memory for details, which are decreased, likely due to interference and generalisation across contexts