Impact of GABA_A and GABA_B Inhibition on Cortical Dynamics and Perturbational Complexity during Synchronous and Desynchronized States

Abstract

Quantitative estimations of spatiotemporal complexity of cortical activity patterns are used in the clinic as a measure of consciousness levels, but the cortical mechanisms involved are not fully understood. We used a version of the Perturbational Complexity Index adapted to multisite recordings from the ferret (either sex) cerebral cortex in vitro (sPCI) to investigate the role of GABAergic inhibition in cortical complexity. We studied two dynamical states: slow-wave activity (synchronous state) and desynchronized activity, that express low and high causal complexity respectively.Progressive blockade of GABAergic inhibition during both regimes revealed its impact on the emergent cortical activity and on sPCI. Gradual GABA A receptor blockade resulted in higher synchronization, being able to drive the network from a desynchronized to a synchronous state, with a progressive decrease of complexity (sPCI). Blocking GABA B receptors also resulted in a reduced sPCI, in particular when in a synchronous, slow wave state. Our findings demonstrate that physiological levels of inhibition contribute to the generation of dynamical richness and spatiotemporal complexity. However, if inhibition is diminished or enhanced, cortical complexity decreases. Using a computational model, we explored a larger parameter space in this relationship and demonstrate a link between excitatory/inhibitory balance and the complexity expressed by the cortical network. 3 Significance statementThe spatiotemporal complexity of the activity expressed by the cerebral cortex is a highly revealing feature of the underlying network's state. Complexity varies with physiological brain states: it is higher during awake than during sleep states. But it also informs about pathological states: in disorders of consciousness, complexity is lower in an unresponsive wakefulness syndrome than in a minimally conscious state. What are the network parameters that modulate complexity? Here we investigate how inhibition, mediated by either GABA A or GABA B -Rs, influences cortical complexity. And we do this departing from two extreme functional states: a highly synchronous, slow-wave state, and a desynchronized one that mimics wakefulness. We find that there is an optimal level of inhibition in which complexity is highest.

Computational Modeling of Information Propagation during the Sleep–Waking Cycle

“…This is in agreement with the morphology of cortical neurons, whereby pyramidal neurons have larger projecting axons with respect to the more local and constrained range of inhibitory axons [36][37][38]. This has also been reflected in numerous computational studies [30,[39][40][41][42].…”

Modeling Synaptic Effects of Anesthesia and its Cortical Cholinergic Reversal

“…For example, in mean field models, GABAergic and glutamatergic synaptic changes are attributed to a single parameter that maps to different concentrations of general anesthesia [27]. Other modelling approaches seek to understand the mechanism of specific anesthetic agents; for example, the effects of propofol have been studied through the modeling of both GABA A and GABA B amplitude/duration and the effects on cortical synchrony and EEG rhythms [18, 28]. Enflurane and isoflurane are other commonly modeled anesthetics where the roles of both glutamatergic receptor binding and GABAergic effects are taken into consideration [28–30].…”

“…Prior experimental studies demonstrated that the behavioral expression of the anesthetic state can be reversed by stimulating the cholinergic system of the brain by various means in vivo and in vitro in both humans and animals [15,17,18,47]. To date, no modelling study has attempted to simulate the reversal of neuronal effects of anesthesia by modulating the interaction between cholinergic and other synaptic effects.…”

“…Recently, reverse dialysis delivery of the acetylcholine agonist carbachol was used to successfully reverse the effect of sevoflurane in rats in vivo [17]. Similar effects were observed in vitro when bathing cortical slices with cholinergic and noradrenergic agonists led to a reversal of slow wave oscillations induced by anesthesia [18]. These studies have shown that various behavioral expressions of the conscious state can be restored by exogenous interventions that aim to counter the pharmacological effect of anesthetics.…”

Spontaneous and Perturbational Complexity in Cortical Cultures

“…Accordingly, perturbations with transcranial magnetic stimulation (TMS) evoke a chain of recurrent, complex activations in the cortex, as measured by electroencephalography (EEG), in wakefulness but not during NREM sleep [ 19 ]. In subsequent studies the complexity of brain responses to direct cortical stimuli, quantified by the perturbational complexity index (PCI) [ 20 ] was tested across many different conditions in humans [ 20 , 21 , 22 ], rodents [ 23 , 24 ], and cortical slices [ 25 , 26 ]. While these experiments provided fundamental insights on the effects of neuromodulation, anesthetics, and brain lesions on PCI, the role of basic cytoarchitectonics and local connectivity has never been explored.…”