Year: 2016
Type: dissertation
Abstract: Alterations in thalamic activity are associated with electrocortical patterns that characterize non-rapid eye movement (non-REM) sleep and general anesthetic-induced sedation and loss-of-consciousness. Both non-REM sleep and general anesthesia are states that are characterized by increased inhibitory Îł aminobutyric acid (GABA)-ergic signaling in the thalamus. There are three forms of GABA type A (GABAA) receptor-mediated inhibition that have been identified in thalamocortical neurons: (1) phasic inhibition mediated by the transient activation of synaptic GABAA receptors, (2) tonic inhibition mediated by the prolonged activation of extrasynaptic GABAA receptors, and (3) spillover inhibition mediated by the transient activation of extrasynaptic GABAA receptors. The separate impact of each of these forms of thalamic GABAergic inhibition on electrocortical activity is unclear and such an understanding would assist in elucidating the thalamic mechanisms mediating the changes in electrocortical activity that signal sedation and loss-of-consciousness. The experiments presented in this thesis identify the electrocortical effects of enhanced thalamic GABAA receptor-mediated tonic and spillover inhibition in vivo. The electrocortical changes elicited by a prototypic GABAA receptor-targeting general anesthetic agent when it is administered directly into the thalamus are characterized and compared to the effects identified with separate manipulations of GABAA receptor-mediated inhibition. These studies show that enhanced thalamic tonic inhibition in mice promotes electrocortical patterns associated with deep non-REM sleep. Specifically, enhanced GABAA receptor-mediated tonic inhibition in the thalamus elicits a state-independent increase in 1-4 Hz electrocortical activity and a decrease in sleep spindle-like oscillations. These effects were altered by blockade of thalamic T-type Ca2+ channels. Importantly, microperfusion of the general anesthetic etomidate into the thalamus elicits changes in electrocortical activity that are distinct form those associated with enhanced thalamic tonic inhibition. Moreover, the action of etomidate at the thalamus is sufficient to elicit an electrocortical signature associated with anesthetic-induced loss-of-consciousness, but only during non-REM sleep. Finally, enhanced GABAA receptor-mediated spillover inhibition in the thalamus fully recapitulates the electrocortical effects identified with etomidate at the thalamus. Together, the findings of this thesis indicate that alterations in thalamic spillover inhibition could underlie the changes in electrocortical activity that signal anesthetic-induced loss-of-consciousness.
Source: TSpace (University of Toronto)
Author: Bahar Lia Mesbah-Oskui
Language: English
Subfield: Anesthesiology and Pain Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2617581920