All Together Now

THE mechanism by which anesthetics impair consciousness remains one of the most important unsolved mysteries of our specialty—if not of all science. Establishing causal links connecting molecular sites of action with cellular, network, and ultimately behavioral changes will be a formidable challenge. One important approach that can contribute to this effort is the use of mathematical models that can synthesize detailed information about individual channels, cellular properties, and interconnections to yield predictions about the behaviors of complex systems. Experiments can be conducted in silico to investigate how individual components contribute to network properties in a way that is difficult or impossible using in vitro or in vivo approaches. In this issue of ANESTHESIOLOGY, Gottschalk and Miotke make use of this computational approach to investigate how anesthetic modulation of two potentially important molecular targets, -aminobutyric acid type A (GABAA) receptors and T-type calcium channels, might contribute to changes in thalamocortical network properties during anesthesia, with the ultimate goal of explaining how anesthetics render us unconscious. The target of their investigation is a network of inhibitory cells that comprise the reticular nucleus of the thalamus (RTN). The thalamus has long been recognized as the gateway to the cortex, with sensory information transmitted via relay cells, the primary projection neurons of the thalamus, to arrive at primary sensory cortex. More recently, the thalamus has also been recognized to play an important, perhaps even dominant, role in the communication between different regions of the cortex via indirect corticothalamocortical pathways. The cells of the RTN provide an inhibitory input to the relay cells, so they are in an ideal position to control the flow of information to and through the cortex. A remarkable feature of the activity of both RTN and thalamic relay cells is the presence of two distinct firing modes. During alert wakefulness, these neurons are steadily depolarized and respond to excitatory inputs with streams of unitary action potentials, allowing them to relatively faithfully transmit incoming signals in a relatively linear manner. However, during certain network states, such as nonrapid eye movement sleep and anesthesia, they synchronize their own firing and that of their thalamic targets to produce prominent network oscillations that can be observed in the electroencephalogram as sleep spindles, transient bouts of activity that have a dominant frequency of approximately 10 Hz and that occur typically just after the up-state transition during slow wave oscillations of sleep and anesthesia. Two important characteristics that endow them with this ability are (1) -aminobutyric acid–mediated inhibitory synaptic connections that RTN cells make with each other and (2) the presence of low-threshold “transient” T-type Ca channels, which produce a slow calcium spike on which bursts of action potentials ride. The well-recognized transition of electroencephalographic activity during anesthesia from low-amplitude desynchronized activity in the awake state to increasingly synchronous large-amplitude oscillations that mimic those occurring during natural sleep (and in fact may well use many of the same elements) provided the motivation for examining the contributions of anesthetic modulation of GABAA receptors and T-type Ca 2 channels to synchronous activity. The model on which the current study is based was developed using detailed morphologic and electrophysiologic studies of these specific cells and their synapses. It has been used successfully in the past to model spindle generation by the RTN and to demonstrate the role of neuromodulators in switching between firing modes. As demonstrated previously, the model produces a spindle-like rhythm even in the absence of simulated anesthetic effects, though the output is far from synchronous. At first glance, this drug-free characteristic of spindle-like activity seems at odds with a model that is meant to simulate the transition from consciousness to unconsciousness, which is more commonly associated with a transition from tonic to burst firing mode. However, in the quiet resting state, thalamic neurons can respond with bursts to sensory input, and similarities have been noted between sleep spindles and the rhythm, a prominent oscillation seen in the electroencephalogram during quiet wakefulness and that may be produced by a similar mechanism. Therefore, although the model as implemented here does not reproduce the stereotypical transition from tonic to burst firing mode associated with the transition from awake to unconscious, it may nevertheless provide an approximation of quiet waking network activity. An important outstanding question that is particularly applicable to inhaled anesthetics (which can influence essentially any given physiologic process provided that a high enough concentration is administered) is to identify relevant molecular targets and to determine how the typically small effects that are seen at low “sedating” concentrations combine to produce the net effects of This Editorial View accompanies the following article: Gottschalk A, Miotke SA: Volatile anesthetic action in a computational model of the thalamic reticular nucleus. ANESTHESIOLOGY 2009; 110:996–1010.