|Ph.D Student||Kaufman Maya|
|Subject||Neuromodulators in Cortical Networks|
|Department||Department of Medicine||Supervisor||Professor Noam Ziv|
|Full Thesis text|
Neuromodulators, acting over a range of time scales, shape diverse aspects of neuronal properties including neuronal excitability, synaptic transmission and the coordination of neuronal firing. Changes in neuromodulatory tone occurring over circadian time scales play crucial roles in regulating arousal and underlying cortical activity patterns which, in turn, have been suggested to regulate homeostatic synaptic remodeling. However, the long term effects neuromodulators have on synaptic remodeling and possible interactions with adaptive and homeostatic processes have rarely been explored. Here we used multi-electrode array recordings combined with automated microscopy to examine the long-term relationships between cholinergic tone, synaptic remodeling and network activity characteristics in networks of dissociated cortical neurons maintained ex-vivo. Experimental elevations of cholinergic tone, either continuously or in a semi-phasic regime, led to an abrupt desynchronization of network activity followed (in the case of continuous tone) by a gradual growth of excitatory synapses over hours. Both effects were reversed by subsequent blockage of cholinergic receptors. Intriguingly, sustained elevations of cholinergic tone were associated with a gradual recovery of network synchrony but not with a reversal of synaptic growth. These findings show that cholinergic tone can strongly affect synaptic remodeling and synchronous activity, but do not support a strict coupling between the two. Introducing feedback between cholinergic input and network synchrony enabled the stabilization of a desynchronized state, at the cost of a gradually increasing cholinergic input, which ultimately failed to prevent the reemergence of synchronous activity. However, periodic withdrawals of cholinergic input restored its efficacy. In light of the critical role neuromodulators play in maintaining arousal as well as in many cognitive functions, it seems that 'withdrawal' periods are crucially needed for restoring neuromodulatory efficacy. We hypothesize that this withdrawal is best achieved during sleep, which is thus viewed as an unavoidable price of prolonged neuromodulator-driven arousal.