Differential effects of cholinergic and noradrenergic neuromodulation on spontaneous cortical network dynamics

Adaptation to prolonged neuromodulation in cortical cultures: an invariable return to network synchrony

“…These ranged from near continuous tonic firing, through intermittent tonic firing, through sporadic firing to near silence. Importantly, and in excellent agreement with prior in vitro [35,[62][63][64][65] and in vivo [50,57,61] studies, the network-wide synchrony of neural activity was strongly reduced. To quantify the effects of ACh on network synchrony we developed a robust measure that was termed the 'Sync Ratio' which ranges from 0 to 1 (completely asynchronous to completely synchronous activity, respectively; see Methods and Additional file 3: Figure S3 for a full explanation of this measure's rational and derivation).…”

“…Both in vivo [10,15,17,21,44] and in vitro [27,33,34,37,[45][46][47] experiments, as well as modeling studies [21,39,40,48,49], indicate that these forms of synchrony are not imposed by some external circuitry, global inhibition or pacemaker cells, but probably arise from the interplay of spontaneous synaptic activity, nonlinear neuronal recruitment cascades, refractoriness and network wide synaptic depression (summarized in [17]), effectively giving rise to a default activity mode, as it has been referred to [35,36] (see also [39]). Furthermore, and in full concordance with their activities in vivo [44,[50][51][52][53][54][55][56][57][58][59][60][61], cholinergic and adrenergic agonists suppress network synchrony in cell culture and slice preparations, shifting spontaneous activity away from this 'default' mode towards desynchronized, tonic firing modes [35,36,[62][63][64][65]. Thus, while synchrony in networks of cultured cortical neurons does not fully replicate the forms of synchrony related to low neuromodulatory tone in the intact brain, the similarities in underlying mechanisms and the comparable effects of neuromodulation suggest that this preparation is a useful mode...…”

“…As shown in Figure 5a,b and Additional file 10: Video S3, the addition of NA (20 μM [36,65]) to the MEA dish (and perfusion media) resulted in an immediate reduction in network synchrony which was reflected in drastically reduced Sync Ratio values. Unlike ACh, however, the suppression of network synchrony was also accompanied by an immediate and significant reduction in total firing rates (data not shown), in excellent agreement with a recent in vivo study concerning NA, cortical synchrony and firing rates [61].…”

“…Thus, for example, it is well established that prolonged exposure to cholinergic agonists is associated with the internalization and, ultimately, down-regulation (degradation and/or reduced synthesis) of muscarinic receptors, which seem to be the major mediators of cholinergic-driven network desynchronization [16,18,57,62] (in particular M1 receptors [65,83]). Where examined, however, internalization was observed to occur rapidly, with membrane receptor levels plateauing within minutes or at most one to three hours following chronic exposure to muscarinic agonists [84][85][86].…”

“…Consequently, and if synchrony represents a strong attractor as prior studies suggest [39,49], escaping it might depend on finely tuned combinations of multiple factors, such as neuronal membrane potential, excitability, probability of neurotransmitter release and synaptic depression. All these (and others) have been previously shown to be affected by (cholinergic) neuromodulation in complex and intricate manners [26,40,55,57,62,65,83,[91][92][93][94][95] which differ from one cell type to another [96]. Consequently, the (homeostatic) recovery [25,38] of one or more of these finely tuned factors, in one or more neuronal types, might move the system back into a parameter space within which synchrony naturally emerges [49].…”