Memory trace replay: the shaping of memory consolidation by neuromodulation

Abstract

The consolidation of memories for places and events is thought to rely, at the network level, on the replay of spatially tuned neuronal firing patterns representing discrete places and spatial trajectories. This occurs in the hippocampal-entorhinal circuit during sharp wave ripple events (SWRs) that occur during sleep or rest. Here, we review theoretical models of lingering place cell excitability and behaviorally induced synaptic plasticity within cell assemblies to explain which sequences or places are replayed. We further provide new insights into how fluctuations in cholinergic tone during different behavioral states might shape the direction of replay and how dopaminergic release in response to novelty or reward can modulate which cell assemblies are replayed.

Keywords: acetylcholine; dopamine; hippocampus; replay; sharp-wave ripples; synaptic plasticity.

Figure 1

Lingering excitability model. The firing rate of a place cell (colored distributions) can be considered as a symmetrical distribution centered on the middle of the place field of the cell , . Normal spike thresholds along the track mean that the firing of each cell is turned on and then off as an animal traverses the place field of the cell. However, at the end of the track, where sharp wave ripples (SWRs) may occur as the animal slows down, the hippocampal network moves into a state where inhibitory inputs impinging onto pyramidal cells are temporally redistributed; inhibition at the axon initial segment is removed, effectively reducing the spike threshold of pyramidal cells compared with waking periods outside of SWRs . This then reveals the tails of the firing distributions of the spatially tuned cells so that, during SWRs, the cells fire in an order dictated by these distributions (i.e., forward if the animal was at the start of the trajectory sequence but in reverse if the animal was at the end of the trajectory sequence).

Figure 2

Synaptic plasticity model. In this model, the spatial overlap between the place fields mapping a trajectory in an environment facilitates the strengthening of the excitatory synaptic connections between the transiently co-active place cells. Subsequently, when pyramidal cells are disinhibited during sharp wave ripples (SWRs), the firing of an initiator cell (e.g., the red one) leads to replay of the entire sequence of cells (e.g., the blue, yellow, green, and pink ones) that were previously paired together.

Figure 3

Behavioral state model. During exploration, there are sensory inputs to the hippocampus, place cells are active, and the high cholinergic tone depolarizes cells. These factors all favor predominantly backward replay in exploration sharp wave ripples (eSWRs) , , in accordance with the model of lingering excitability. It is predicted that this backward replay in eSWRs and the forward activation of place cells during exploration, in the presence of high cholinergic tone, both lead to synaptic plasticity between the active place cells with overlapping place fields . An important assumption is that plasticity induced from environmental exploration is greater than that induced by activity in eSWRs and, therefore, there is a bias in subsequent SWRs for forward replay over backward replay. During longer periods of immobility, this plasticity-dependent forward replay bias is balanced by the lingering excitability of place cells, which, although reduced due to slightly lower levels of acetylcholine and a longer time spent immobile, is still capable of providing an initiation bias to the current position , , that can drive backward replay. Consequently, during immobility (i)SWRs, there is an equal balance of forward and backward replay . However, since there is a lower level of cholinergic tone, it is predicted that replay during iSWRs induces less plasticity than the replay in eSWRs. Hence, the plasticity-dependent bias for forward replay is maintained. Thus, when the animal sleeps and the lingering excitability and sensory drive to place cells are removed, replay now occurs solely through the plasticity-dependent mechanism and there is more forward than backward replay , .

Figure 4

Novelty and/or reward based model. Dopamine release in response to novelty or reward facilitates the formation of stable place cell assemblies through synaptic plasticity (note the stronger connection within the network between the yellow, green, and pink fields compared with the orange, red, and blue fields). This increases the likelihood of replay of cell assemblies active during novel or rewarding environments via the synaptic plasticity model.

Figure I

Hippocampal network activity during sleep epochs. (A) Mean sharp wave ripple (SWR)-triggered local field potential from four separate tetrodes located just above and within the stratum pyramidale (first three waveforms) and below in the stratum radiatum (bottom waveform). (B) SWR firing responses of CA1 pyramidal cells during sleep. Top trace, wide-band (1 H–5 kHz) local field potential recorded in the pyramidal cell layer. Bottom trace, 140–250 Hz band pass-filtered local field potential highlighting ripple frequency events. Raster plots, spike times (vertical tics) of simultaneously recorded CA1 pyramidal cells (one cell per row). Note the firing synchrony during ripple events. Data from .

Figure I

Replay of place cell activity in sharp wave ripples (SWRs).