Real-time closed-loop electrophysiology: towards new frontiers in in vitro investigations in the neurosciences.

Reflected at any level of organization of the central nervous system, most of the processes ranging from ion channels to neuronal networks occur in a closed loop, where the input to the system depends on its output. In contrast, most in vitro preparations and experimental protocols operate autonomously, and do not depend on the output of the studied system. Thanks to the progress in digital signal processing and real-time computing, it is now possible to artificially close the loop and investigate biophysical processes and mechanisms under increased realism. In this contribution, we review some of the most relevant examples of a new trend in in vitro electrophysiology, ranging from the use of dynamic-clamp to multi-electrode distributed feedback stimulation. We are convinced these represents the beginning of new frontiers for the in vitro investigation of the brain, promising to open the still existing borders between theoretical and experimental approaches while taking advantage of cutting edge technologies.

Single-neuron discharge properties and network activity in dissociated cultures of neocortex.

Cultures of neurons from rat neocortex exhibit spontaneous, temporally patterned, network activity. Such a distributed activity in vitro constitutes a possible framework for combining theoretical and experimental approaches, linking the single-neuron discharge properties to network phenomena. In this work, we addressed the issue of closing the loop, from the identification of the single-cell discharge properties to the prediction of collective network phenomena. Thus, we compared these predictions with the spontaneously emerging network activity in vitro, detected by substrate arrays of microelectrodes. Therefore, we characterized the single-cell discharge properties to Gauss-distributed noisy currents, under pharmacological blockade of the synaptic transmission. Such stochastic currents emulate a realistic input from the network. The mean (m) and variance (s(2)) of the injected current were varied independently, reminiscent of the extended mean-field description of a variety of possible presynaptic network organizations and mean activity levels, and the neuronal response was evaluated in terms of the steady-state mean firing rate (f). Experimental current-to-spike-rate responses f(m, s(2)) were similar to those of neurons in brain slices, and could be quantitatively described by leaky integrate-and-fire (IF) point neurons. The identified model parameters were then used in numerical simulations of a network of IF neurons. Such a network reproduced a collective activity, matching the spontaneous irregular population bursting, observed in cultured networks. We finally interpret such a collective activity and its link with model details by the mean-field theory. We conclude that the IF model is an adequate minimal description of synaptic integration and neuronal excitability, when collective network activities are considered in vitro.