Potential factors influencing replay across CA1 during sharp-wave ripples

Abstract

Sharp-wave ripples are complex neurophysiological events recorded along the trisynaptic hippocampal circuit (i.e. from CA3 to CA1 and the subiculum) during slow-wave sleep and awake states. They arise locally but scale brain-wide to the hippocampal target regions at cortical and subcortical structures. During these events, neuronal firing sequences are replayed retrospectively or prospectively and in the forward or reverse order as defined by experience. They could reflect either pre-configured firing sequences, learned sequences or an option space to inform subsequent decisions. How can different sequences arise during sharp-wave ripples? Emerging data suggest the hippocampal circuit is organized in different loops across the proximal (close to dentate gyrus) and distal (close to entorhinal cortex) axis. These data also disclose a so-far neglected laminar organization of the hippocampal output during sharp-wave events. Here, I discuss whether by incorporating cell-type-specific mechanisms converging on deep and superficial CA1 sublayers along the proximodistal axis, some novel factors influencing the organization of hippocampal sequences could be unveiled. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

Keywords: deep–superficial; preplay; replay; ripples.

Figure 1.

Miscellaneous patterns of replay potentially underlying different processes of memory consolidation, retrieval, planning and imagination. As the animal experiences a succession of events (represented by letters), some hippocampal neurons fire selectivity to build an abstract representation or cognitive map. During periods associated with sleep and immobility, sequences of these ‘place cells’ are co-activated in an orderly manner coordinated by sharp-wave ripples (SPW-ripples). The order of replay reveals the multifactorial influence of brain state and microcircuit physiology, as well as other procedural and cognitive factors. According to use, replay can be retrospective (engaging sequences already experienced) or prospective (engaging sequences ahead in time). According to the order, replay can be forward (in the same order as experienced) or reverse (opposite to experienced). Some sequences are not linked to experience and reflect a sort of preplay of events never seen before. Finally, according to the subject ‘location’ in the event space, replay can be local or remote. (a) Forward retrospective replay occurring remotely during sleep was the first form of replay reported in the literature [28,29]. Later reports showed it is also present locally during awake immobility and exploratory pauses [30] (b) Reverse retrospective replay is more typically present in awake conditions [6,30] and strongly influenced by novelty, reward values or goal-oriented tasks [31]. Forward and reverse replay can be concatenated along several sharp-wave ripples to accommodate extended experience [32]. (c) Forward prospective replay of already experienced neuronal sequences is typically seen before running for a goal or during choice learning [30,33,34]. (d) Preplay depicts sequences never experienced before and is correlated to or predictive of the activity during the future experience [35,36]. Preplay, which can be forward or reverse, is detectable in awake rest and in slow-wave sleep, and it has been proposed to play a major role in rapid encoding of novel information. (Online version in colour.)

Figure 2.

Flexibility of neuronal firing from CA1 pyramidal cells during sharp-wave ripples (SPW-ripples). (a) Unsupervised classification of individual sharp-wave ripple events clusters of similar local field potential signatures to be identified. The number of events in each group is indicated. Clusters of groups with topological similarities in the high-dimensional space are identified by colours in the inset scheme. (b) Single CA1 pyramidal cells were recorded juxtacellularly during sharp-wave ripples and their firing was grouped per cluster. Note different timing of the same cell in the orange and blue cluster indicated before. (c) Juxtacellular recorded cells are labelled for morphological identification with streptavidin, and classified as deep or superficial depending on their location within the calbindin-positive sublayer. (d) Distribution of the preferred firing phase during the sharp-wave from different clusters in deep and superficial cells. Note wider distribution in deep cells indicating more flexibility. Data from [86]. (Online version in colour.)

Figure 3.

Biases of hippocampal replay can affect deep and superficial (sup.) CA1 pyramidal cells differently. (a) Known deep superficial local microcircuit motifs. Deep cells are more strongly activated by inputs from CA2 (at basal dendrites) and the medial entorhinal cortex. Inputs from CA3 cells onto deep cells are strongly interfaced by feed-forward inhibition. Superficial cells receive more innervation from the lateral entorhinal cortex and direct CA3 inputs. Importantly, lateral and medial entorhinal inputs to deep and superficial cells organize proximodistally along the traverse CA1 axis. Superficial cells mainly recruit PV+ basket cells whereas deep cells are biased for SOM+ interneurons. In return, innervation by PV+ basket cells is larger over deep cells while CCK+ basket cells preferentially target superficial cells. (b) Differential transcriptomic expression of serotoninergic (Htr) and cholinergic receptor genes (Chrn) along the deep and superficial layers. Normalized gene expression values from three different replicates are shown. Data from https://hipposeq.janelia.org/ [92]. (c) Multifactorial axes biasing the content and organization of replays during sharp-wave ripples. Different influences on deep and superficial CA1 pyramidal cells have been reported along these axes (grey boxes). The relative axis length is not necessarily informative [,,,–,,,–,,,,,–,–98]. PC, pyramidal cell, SOM+, somatostatin-positive interneuron; PV+, parvalbumin-positive basket cell; CCK+, cholecystokinin-positive basket cell; MECIII, medial entorhinal cortex layer III; LECIII, lateral entorhinal cortex layer III. (Online version in colour.)

Figure 4.

Potential mechanisms for sequence orthogonalization across deep and superficial CA1 sublayers. Different responsiveness of deep and superficial (sup.) cells to a collection of pre-synaptic inputs from CA2 to CA3 regions may support different timing for activation in a sequence, which together with dedicated inhibitory control will determine firing selection across CA1 sublayers. Entorhinal inputs converging differently in deep and superficial cells across the proximodistal axis could additionally bias firing depending on the animal location and salient sensory information. State and emotional factors represent additional orthogonalizing factors.