Two photon interrogation of hippocampal subregions CA1 and CA3 during spatial behaviour

The hippocampus is crucial for spatial navigation and episodic memory formation. Hippocampal place cells exhibit spatially selective activity within an environment and form the neural basis of a cognitive map of space which supports these mnemonic functions. Hebb’s (1949) postulate regarding the creation of cell assemblies is seen as the pre-eminent model of learning in neural systems. Investigating changes to the hippocampal representation of space during an animal’s exploration of its environment provides an opportunity to observe Hebbian learning at the population and single cell level. When exploring new environments animals form spatial memories that are updated with experience and retrieved upon re-exposure to the same environment, but how this is achieved by different subnetworks in hippocampal CA1 and CA3, and how these circuits encode distinct memories of similar objects and events remains unclear. To test these ideas, we developed an experimental strategy and detailed protocols for simultaneously recording from CA1 and CA3 populations with 2P imaging. We also developed a novel all-optical protocol to simultaneously activate and record from ensembles of CA3 neurons. We used these approaches to show that targeted activation of CA3 neurons results in an increasing excitatory amplification seen only in CA3 cells when stimulating other CA3 cells, and not in CA1, perhaps reflecting the greater number of recurrent connections in CA3. To probe hippocampal spatial representations, we titrated input to the network by morphing VR environments during spatial navigation to assess the local CA3 as well as downstream CA1 responses. To this end, we found CA1 and CA3 neural population responses behave nonlinearly, consistent with attractor dynamics associated with the two stored representations. We interpret our findings as supporting classic theories of Hebbian learning and as the beginning of uncovering the relationship between hippocampal neural circuit activity and the computations implemented by their dynamics. Establishing this relationship is paramount to demystifying the neural underpinnings of cognition

Spatial Representations in the Entorhino-Hippocampal Circuit

After a general introduction and a brief review of the available experimental data on spatial representations (chapter 2), this thesis is divided into two main parts. The first part, comprising the chapters from 3 to 6, is dedicated to grid cells. In chapter 3 we present and discuss the various models proposed for explaining grid cells formation. In chapter 4 and 5 we study our model of grid cells generation based on adaptation in the case of non-planar environments, namely in the case of a spherical environment and of three-dimensional space. In chapter 6 we propose a variant of the model where the alignment of the grid axes is induced through reciprocal inhibition, and we suggest that that the inhibitory connections obtained during this learning process can be used to implement a continuous attractor in mEC. The second part, comprising chapters from 7 to 10 is instead focused on place cell representations. In chapter 7 we analyze the differences between place cells and grid cells in terms on information content, in chapter 8 we describe the properties of attractor dynamics in our model of the Ca3 net- work, and in the following chapter we study the effects of theta oscillations on network dynamics. Finally, in Chapter 10 we analyze to what extent the learning of a new representation, can preserve the topology and the exact metric of physical space

Human episodic memory retrieval is accompanied by a neural contiguity effect

Cognitive psychologists have long hypothesized that experiences are encoded in a temporal context that changes gradually over time. When an episodic memory is retrieved, the state of context is recovered—a jump back in time. We recorded from single units in the MTL of epilepsy patients performing an item recognition task. The population vector changed gradually over minutes during presentation of the list. When a probe from the list was remembered with high confidence, the population vector reinstated the temporal context of the original presentation of that probe during study—a neural contiguity effect that provides a possible mechanism for behavioral contiguity effects. This pattern was only observed for well-remembered probes; old probes that were not well-remembered showed an anti-contiguity effect. These results constitute the first direct evidence that recovery of an episodic memory in humans is associated with retrieval of a gradually-changing state of temporal context—a neural “jump-back-in-time” that parallels the act of remembering

Reactivation of rate remapping in CA3

Sherpa Romeo yellow journal. Open access article. Creative Commons Attribution 4.0 International License (CC BY 4.0) appliesThe hippocampus is thought to contribute to episodic memory by creating, storing, and reactivating patterns that are unique to each experience, including different experiences that happen at the same location. Hippocampus can combine spatial and contextual/episodic information using a dual coding scheme known as “global” and “rate” remapping. Global remapping selects which set of neurons can activate at a given location. Rate remapping readjusts the firing rates of this set depending on current experience, thus expressing experience-unique patterns at each location. But can the experience-unique component be retrieved spontaneously? Whereas reactivation of recent, spatially selective patterns in hippocampus is well established, it is never perfect, raising the issue of whether the experiential component might be absent. This question is key to the hypothesis that hippocampus can assist memory consolidation by reactivating and broadcasting experience-specific “index codes” to neocortex. In CA3, global remapping exhibits attractor-like dynamics, whereas rate remapping apparently does not, leading to the hypothesis that only the former can be retrieved associatively and casting doubt on the general consolidation hypothesis. Therefore, we studied whether the rate component is reactivated spontaneously during sleep. We conducted neural ensemble recordings from CA3 while rats ran on a circular track in different directions (in different sessions) and while they slept. It was shown previously that the two directions of running result in strong rate remapping. During sleep, the most recent rate distribution was reactivated preferentially. Therefore, CA3 can retrieve patterns spontaneously that are unique to both the location and the content of recent experience.Ye

Sensory Feedback, Error Correction, and Remapping in a Multiple Oscillator Model of Place-Cell Activity

Mammals navigate by integrating self-motion signals (“path integration”) and occasionally fixing on familiar environmental landmarks. The rat hippocampus is a model system of spatial representation in which place cells are thought to integrate both sensory and spatial information from entorhinal cortex. The localized firing fields of hippocampal place cells and entorhinal grid-cells demonstrate a phase relationship with the local theta (6–10 Hz) rhythm that may be a temporal signature of path integration. However, encoding self-motion in the phase of theta oscillations requires high temporal precision and is susceptible to idiothetic noise, neuronal variability, and a changing environment. We present a model based on oscillatory interference theory, previously studied in the context of grid cells, in which transient temporal synchronization among a pool of path-integrating theta oscillators produces hippocampal-like place fields. We hypothesize that a spatiotemporally extended sensory interaction with external cues modulates feedback to the theta oscillators. We implement a form of this cue-driven feedback and show that it can retrieve fixed points in the phase code of position. A single cue can smoothly reset oscillator phases to correct for both systematic errors and continuous noise in path integration. Further, simulations in which local and global cues are rotated against each other reveal a phase-code mechanism in which conflicting cue arrangements can reproduce experimentally observed distributions of “partial remapping” responses. This abstract model demonstrates that phase-code feedback can provide stability to the temporal coding of position during navigation and may contribute to the context-dependence of hippocampal spatial representations. While the anatomical substrates of these processes have not been fully characterized, our findings suggest several signatures that can be evaluated in future experiments

IST Austria Thesis

The hippocampus is a key brain region for spatial memory and navigation and is needed at all stages of memory, including encoding, consolidation, and recall. Hippocampal place cells selectively discharge at specific locations of the environment to form a cognitive map of the space. During the rest period and sleep following spatial navigation and/or learning, the waking activity of the place cells is reactivated within high synchrony events. This reactivation is thought to be important for memory consolidation and stabilization of the spatial representations. The aim of my thesis was to directly test whether the reactivation content encoded in firing patterns of place cells is important for consolidation of spatial memories. In particular, I aimed to test whether, in cases when multiple spatial memory traces are acquired during learning, the specific disruption of the reactivation of a subset of these memories leads to the selective disruption of the corresponding memory traces or through memory interference the other learned memories are disrupted as well. In this thesis, using a modified cheeseboard paradigm and a closed-loop recording setup with feedback optogenetic stimulation, I examined how the disruption of the reactivation of specific spiking patterns affects consolidation of the corresponding memory traces. To obtain multiple distinctive memories, animals had to perform a spatial task in two distinct cheeseboard environments and the reactivation of spiking patterns associated with one of the environments (target) was disrupted after learning during four hours rest period using a real-time decoding method. This real-time decoding method was capable of selectively affecting the firing rates and cofiring correlations of the target environment-encoding cells. The selective disruption led to behavioural impairment in the memory tests after the rest periods in the target environment but not in the other undisrupted control environment. In addition, the map of the target environment was less stable in the impaired memory tests compared to the learning session before than the map of the control environment. However, when the animal relearned the task, the same map recurred in the target environment that was present during learning before the disruption. Altogether my work demonstrated that the reactivation content is important: assembly-related disruption of reactivation can lead to a selective memory impairment and deficiency in map stability. These findings indeed suggest that reactivated assembly patterns reflect processes associated with the consolidation of memory traces