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Impact of background input on memory consolidation in In-Vitro neural networks

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May 22, 2024 version files 21.65 GB

Abstract

Memory consolidation is a complex process, that can be divided into two stages: first, memories are temporary stored in hippocampus and in the second stage, repeated replay slowly transfers memories to the neo-cortex for long-term consolidation. This 2nd stage occurs during slow wave sleep, a phase characterized in the cortex by low cholinergic tone and low afferent input.  A recent in-vitro study showed that high cholinergic tone hampers memory consolidation, probably due to lowered network excitability (defined as the mean network response to one neuron spiking). Here we investigate whether low background input contributes to memory consolidation.

We used cortical neuronal networks on multi electrode arrays to study memory. When input deprived, these networks develop an activity-connectivity balance. Focal stimuli initially disrupt the existing balance,  inducing connectivity changes. When repeated, this effect fades and the response becomes part of spontaneous patterns (memory formation). Application of the same stimulus hours later does not affect connectivity indicating that memory was consolidated.

We applied five periods (10 min each) of focal electrical stimulation at different electrodes (A B A), separated by 1 hour of spontaneous activity . Some cultures were transfected to express channelrhopsins (ChR2) enabling global optogenetic background stimulation. We used 12 control, 15 ChR2 cultures with no background input and 8 ChR2 cultures with superimposed random optogenetic stimulation during electrical stimulation periods (fmean=5 Hz) to mimic afferent input.

Background stimulation acutely reduced network excitability during stimulation without persisting effects after cessation. ChR2 cultures showed significantly more dispersed spiking outside network bursts, and network excitability tended to be lower than in control cultures. Stimulation at electrodes A and B induced memory traces in control cultures. Return to electrode A did not further affect connectivity, showing that memory trace A had been consolidated. Background stimulation impeded the formation of memory traces following electrical stimulation at either electrode. ChR2 expression alone also obstructed memorization.

These findings confirm the importance of low background afferent input for memory consolidation. The presence of background afferent inputs reduced network excitability, similar to high cholinergic tone. This leads to the conclusion that sufficient network excitability is crucial for memory consolidation, and high network excitability may be a critical feature of  slow wave sleep that makes it more suitable for memory consolidation than the awake state.