Abstract
In systems consolidation, encoded memories are replayed by the hippocampus during slow-wave sleep (SWS), and permanently stored in the neocortex. Declarative memory consolidation is believed to benefit from the oscillatory rhythms and low cholinergic tone observed in this sleep stage, but underlying mechanisms remain unclear. To clarify the role of cholinergic modulation and synchronized activity in memory consolidation, we applied repeated electrical stimulation in mature cultures of dissociated rat cortical neurons with high or low cholinergic tone, mimicking the cue replay observed during systems consolidation under distinct cholinergic concentrations. In the absence of cholinergic input, these cultures display activity patterns hallmarked by network bursts, synchronized events reminiscent of the low frequency oscillations observed during SWS. They display stable activity and connectivity, which mutually interact and achieve an equilibrium. Electrical stimulation reforms the equilibrium to include the stimulus response, a phenomenon interpreted as memory trace formation. Without cholinergic input, activity was burst-dominated. First application of a stimulus induced significant connectivity changes, while subsequent repetition no longer affected connectivity. Presenting a second stimulus at a different electrode had the same effect, whereas returning to the initial stimuli did not induce further connectivity alterations, indicating that the second stimulus did not erase the ‘memory trace’ of the first. Distinctively, cultures with high cholinergic tone displayed reduced network excitability and dispersed firing, and electrical stimulation did not induce significant connectivity changes. We conclude that low cholinergic tone facilitates memory formation and consolidation, possibly through enhanced network excitability. Network bursts or SWS oscillations may merely reflect high network excitability.
Highlights
Network or population bursts are a widely observed phenomenon in neuronal ensembles
We show that high cholinergic tone reduces network excitability and the occurrence of network bursts, impeding memory trace formation and consolidation
Carbachol blocks network bursting throughout the 15 h of experiments The carbachol concentration necessary to alter the natural synchronicity of dissociated cortical cultures was assessed by applying accumulating CCh concentrations to the culture bath in three independent cultures at 35 ± 3 d in vitro (DIV)
Summary
Network or population bursts are a widely observed phenomenon in neuronal ensembles. These patterns of synchronized activity occur during early brain development (Teppola et al 2019), certain sleep stages (Steriade and Timofeev 2003) and after various types of brain injury (Fardet et al 2018). Bursting patterns may have different functions: bursts might serve a specific purpose in neural development (Baltz et al 2010), in cognitive performance (Fries 2015), in information transfer (Lisman 1997) or it may be an epiphenomenon occurring whenever networks are insufficiently activated (le Feber et al 2010) Their role has mainly been speculated, with no evidence provided to support these hypotheses. After a newly acquired pattern has been formed as a result of the interaction between several structures within the medial temporal lobe, the encoded information is transferred to the neocortex where it is permanently stored, in a process known as systems consolidation (Axmacher et al 2006) In this stage of SWS, patterns are replayed by the hippocampus, which repeatedly activates neocortical areas (Atherton et al 2015). Limited accessibility to individual neurons and synapses of cortical networks and insufficient afferent input control are major difficulties that hamper highquality experimental data collection in vivo
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