Mechanisms and modulation of cortical rhythms and complexity

Abstract

Throughout various brain states, billions of neurons interact resulting in a variety of cortical rhythms accompanied by switches between behavioral states (Gervasoni et al., 2004). As a result of the specific (1) structure (layers and columns), (2) connections and (3) components (excitatory and inhibitory neurons expressing receptors and ion channels) within the cortical networks, switches in the cortical network state are possible. From synchronized cortical regimes of slow wave activity (SWA) during deep sleep or anesthesia (Steriade et al., 2001), global activity can change to irregular and spatiotemporally complex cortical activity during arousal states (Duarte et al., 2017; Steriade et al., 2001). If the underlying cellular or molecular regulatory mechanisms of these transitions are altered, aberrant cortical rhythms and behavioral states may appear (e.g., epilepsy or consciousness disorders). Thus, healthy and altered patterns of cortical activity correlate with behavioral states. Many methods have been used to detect the level of consciousness based on cortical activity (spontaneous or evoked activity). The Perturbational Complexity Index (PCI) (Casali et al., 2013) can effectively detect the level of complexity in humans and also in cortical slices in vitro (sPCI) (D'Andola et al., 2017) based on the cortical evoked responses after electrical stimulation. Because (1) cortical activity patterns can be simulated in in vitro preparations (Compte, 2003; Sanchez-Vives et al., 2010), (2) shifting between cortical rhythms can occur independently of thalamic

inputs, and (3) as a result of neuromodulators acting directly on cortex(Constantinople and Bruno, 2011), we can specifically activate or inactivate ion channels or receptors in order to induce changes in the spontaneous or evoked activity (sPCI) and provide insights into the underlying mechanisms controlling the transition between different cortical rhythms and complexity.

To investigate these, (1) we replicated SWA and awake-like regimes to validate isolated cortical slices as a model of brain states and analyzed sPCI as a methodological tool to quantify network complexity; (2) we studied the contribution of excitatory and inhibitory components to the different cortical network rhythms and complexity; and (3) we identified cellular mechanisms underlying the modulation of cortical states by regulating the levels of different neurotransmitters involved in brain state transitions and complexity.

The main methods used during this doctoral thesis consisted of an in vitro preparation of cortical brain slices from ferrets, which spontaneously display SWA. We recorded the cortical activity with a 16-channel array, and modulated the spontaneous and evoked cortical activity by the bath application of agonist/antagonists of ion channels/receptors. We also modulate cortical activity using electrical tools (through direct current stimulation) or photopharmacology tools.

The results exposed within this thesis revealed that isolated cortical slices can display different cortical activity patterns and levels of complexity detected by sPCI (D'Andola et al., 2017). Using this model, we demonstrated that the disruption of inhibitory and excitatory balances has important effects over the regime of cortical activity and the cortical complexity. We demonstrated that inhibition (fast and slow) maintains cortical activity patterns through the modulation of excitability and their oscillatory frequency. In addition, we demonstrated that certain levels of excitability are required to induce higher complexity states. When we induced changes in excitability through (1) K+ channels or muscarinic acetylcholine receptors; (2) or with inactivation of K+ channels or blocking

inhibition, the network shifts from the bistable response to more heterogeneous responses (increasing network complexity states) or to a homogeneous epileptic response (decreasing network complexity states), respectively. Thus, these findings suggest that the maintenance of cortical rhythms and neural complexity at physiological levels requires the coordinated contribution of the balance between excitation and inhibition and excitability, parameters that can be modulated by different mechanisms, like neurotransmitters, drugs or exogenous stimulation.