Abstract
BackgroundProlonged neuromodulatory regimes, such as those critically involved in promoting arousal and suppressing sleep-associated synchronous activity patterns, might be expected to trigger adaptation processes and, consequently, a decline in neuromodulator-driven effects. This possibility, however, has rarely been addressed.ResultsUsing networks of cultured cortical neurons, acetylcholine microinjections and a novel closed-loop ‘synchrony-clamp’ system, we found that acetylcholine pulses strongly suppressed network synchrony. Over the course of many hours, however, synchrony invariably reemerged, even when feedback was used to compensate for declining cholinergic efficacy. Network synchrony also reemerged following its initial suppression by noradrenaline, but this did not occlude the suppression of synchrony or its gradual reemergence following subsequent cholinergic input. Importantly, cholinergic efficacy could be restored and preserved over extended time scales by periodically withdrawing cholinergic input.ConclusionsThese findings indicate that the capacity of neuromodulators to suppress network synchrony is constrained by slow-acting, reactive processes. A multiplicity of neuromodulators and ultimately neuromodulator withdrawal periods might thus be necessary to cope with an inevitable reemergence of network synchrony.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-014-0083-3) contains supplementary material, which is available to authorized users.
Highlights
Prolonged neuromodulatory regimes, such as those critically involved in promoting arousal and suppressing sleep-associated synchronous activity patterns, might be expected to trigger adaptation processes and, a decline in neuromodulator-driven effects
Rational and experimental approach To examine relationships between prolonged cholinergic input and network synchrony we developed an experimental system which allowed us to tightly control and manipulate cholinergic input, measure its effects on network activity and synchrony, and assay changes in its capacity to suppress synchrony, with the latter serving as a measure of adaptive or homeostatic reactions occurring in the same networks
Pulsed ACh applications effectively suppress network synchrony, but synchrony eventually reemerges Under baseline conditions, and in agreement with many reports [27,30,31,32,33,34,35,36,70], spontaneous activity in the cortical networks used here occurs as periods of synchronous, network-wide bursting activity which lasts for several hundreds of milliseconds, separated by longer periods (1 to 10 seconds) of near-complete quiescence or sparse, asynchronous action potentials (Figure 2a)
Summary
Prolonged neuromodulatory regimes, such as those critically involved in promoting arousal and suppressing sleep-associated synchronous activity patterns, might be expected to trigger adaptation processes and, a decline in neuromodulator-driven effects. Some of the most important long-term neuromodulatory processes in the mammalian brain are those that regulate a striking form of cortical synchrony known as ‘slow oscillations’, ‘slow wave’ or ‘slow rhythmic’ activity This activity pattern is characterized by transitions between periods of neuronal discharges (‘on’ periods) and periods of near-complete quiescence (‘off’ periods) which occur in remarkably synchronous fashion in large cortical domains. Note that in this context synchrony does not refer to the degree to which multiple neurons fire action potentials simultaneously at millisecond time precision
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
