Abstract
The mechanism of loss of consciousness (LOC) under anesthesia is unknown. Because consciousness depends on activity in the cortico-thalamic network, anesthetic actions on this network are likely critical for LOC. Competing theories stress the importance of anesthetic actions on bottom-up “core” thalamo-cortical (TC) vs. top-down cortico-cortical (CC) and matrix TC connections. We tested these models using laminar recordings in rat auditory cortex in vivo and murine brain slices. We selectively activated bottom-up vs. top-down afferent pathways using sensory stimuli in vivo and electrical stimulation in brain slices, and compared effects of isoflurane on responses evoked via the two pathways. Auditory stimuli in vivo and core TC afferent stimulation in brain slices evoked short latency current sinks in middle layers, consistent with activation of core TC afferents. By contrast, visual stimuli in vivo and stimulation of CC and matrix TC afferents in brain slices evoked responses mainly in superficial and deep layers, consistent with projection patterns of top-down afferents that carry visual information to auditory cortex. Responses to auditory stimuli in vivo and core TC afferents in brain slices were significantly less affected by isoflurane compared to responses triggered by visual stimuli in vivo and CC/matrix TC afferents in slices. At a just-hypnotic dose in vivo, auditory responses were enhanced by isoflurane, whereas visual responses were dramatically reduced. At a comparable concentration in slices, isoflurane suppressed both core TC and CC/matrix TC responses, but the effect on the latter responses was far greater than on core TC responses, indicating that at least part of the differential effects observed in vivo were due to local actions of isoflurane in auditory cortex. These data support a model in which disruption of top-down connectivity contributes to anesthesia-induced LOC, and have implications for understanding the neural basis of consciousness.
Highlights
In widespread use for >150 years, how anesthetics cause loss of consciousness (LOC) remains one of the great unsolved mysteries in biomedical science
IN VIVO ELECTROPHYSIOLOGY The data presented here were obtained from 10 animals in which probes were localized to a primary auditory field (Figures 1A,B), probes penetrated at least to layer 5 (Figure 1A) and responses to both auditory and visual stimuli could be identified in the Local field potentials (LFPs) (Figure 1C)
Shortest latency of significant LFP responses (12.3 ± 2.2 ms) were observed in the middle layers (0.9 ± 0.3 mm), as expected for responses mediated by core TC afferents (Scheel, 1988; Roger and Arnault, 1989; Romanski and Ledoux, 1993; Winer et al, 1999; Polley et al, 2007; Storace et al, 2010; Smith et al, 2012)
Summary
In widespread use for >150 years, how anesthetics cause loss of consciousness (LOC) remains one of the great unsolved mysteries in biomedical science. Elucidating these mechanisms would benefit patient care in terms of improved monitoring and more selective anesthetic agents, and would provide insight into neural mechanisms of consciousness. Because TC information transfer has been hypothesized as the key mediator for consciousness (Llinas et al, 1998), these observations formed the basis of the thalamic switch hypothesis of anesthetic-induced LOC (Alkire et al, 2000).
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