Hippocampal sharp‐wave ripples (SWRs) support the reactivation of memory representations, relaying information to neocortex during “offline” and sleep‐dependent memory consolidation. While blockade of NMDA receptors (NMDAR) is known to affect both learning and subsequent consolidation, the specific contributions of NMDAR activation to SWR‐associated activity remain unclear. Here, we combine biophysical modeling with in vivo local field potential (LFP) and unit recording to quantify changes in SWR dynamics following inactivation of NMDAR. In a biophysical model of CA3‐CA1 SWR activity, we find that NMDAR removal leads to reduced SWR density, but spares SWR properties such as duration, cell recruitment and ripple frequency. These predictions are confirmed by experiments in which NMDAR‐mediated transmission in rats was inhibited using three different NMDAR antagonists, while recording dorsal CA1 LFP. In the model, loss of NMDAR‐mediated conductances also induced a reduction in the proportion of cell pairs that co‐activate significantly above chance across multiple events. Again, this prediction is corroborated by dorsal CA1 single‐unit recordings, where the NMDAR blocker ketamine disrupted correlated spiking during SWR. Our results are consistent with a framework in which NMDA receptors both promote activation of SWR events and organize SWR‐associated spiking content. This suggests that, while SWR are short‐lived events emerging in fast excitatory‐inhibitory networks, slower network components including NMDAR‐mediated currents contribute to ripple density and promote consistency in the spiking content across ripples, underpinning mechanisms for fine‐tuning of memory consolidation processes.
- Award ID(s):
- 1844935
- NSF-PAR ID:
- 10145134
- Date Published:
- Journal Name:
- Philosophical Transactions of the Royal Society B: Biological Sciences
- Volume:
- 375
- Issue:
- 1799
- ISSN:
- 0962-8436
- Page Range / eLocation ID:
- 20190238
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract During spatial exploration, neural circuits in the hippocampus store memories of sequences of sensory events encountered in the environment. When sensory information is absent during ‘offline’ resting periods, brief neuronal population bursts can ‘replay’ sequences of activity that resemble bouts of sensory experience. These sequences can occur in either forward or reverse order, and can even include spatial trajectories that have not been experienced, but are consistent with the topology of the environment. The neural circuit mechanisms underlying this variable and flexible sequence generation are unknown. Here we demonstrate in a recurrent spiking network model of hippocampal area CA3 that experimental constraints on network dynamics such as population sparsity, stimulus selectivity, rhythmicity and spike rate adaptation, as well as associative synaptic connectivity, enable additional emergent properties, including variable offline memory replay. In an online stimulus‐driven state, we observed the emergence of neuronal sequences that swept from representations of past to future stimuli on the timescale of the theta rhythm. In an offline state driven only by noise, the network generated both forward and reverse neuronal sequences, and recapitulated the experimental observation that offline memory replay events tend to include salient locations like the site of a reward. These results demonstrate that biological constraints on the dynamics of recurrent neural circuits are sufficient to enable memories of sensory events stored in the strengths of synaptic connections to be flexibly read out during rest and sleep, which is thought to be important for memory consolidation and planning of future behaviour.
image Key points A recurrent spiking network model of hippocampal area CA3 was optimized to recapitulate experimentally observed network dynamics during simulated spatial exploration.
During simulated offline rest, the network exhibited the emergent property of generating flexible forward, reverse and mixed direction memory replay events.
Network perturbations and analysis of model diversity and degeneracy identified associative synaptic connectivity and key features of network dynamics as important for offline sequence generation.
Network simulations demonstrate that population over‐representation of salient positions like the site of reward results in biased memory replay.
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1098/rstb.2019.0238
