We have proposed that general anesthetics, irrespective of their precise mechanism of action, induce loss of consciousness when they bring about the breakdown of information integration within the corticothalamic system. Here, we will test this proposal using animal models in which we can investigate the role of different neuronal populations in anesthetic unconsciousness. Specifically, it is unclear whether anesthetic loss/recovery of consciousness (LOC/ROC) relies on a thalamic switch or a direct action on cortical cells. Within cortex, it is not known whether anesthetic LOC/ROC is a global phenomenon or is due to specific neural populations and fiber pathways. We hypothesize that pyramidal cells in supragranular (SG) layers, which form a highly integrated network both within and across cortical areas, are ideally poised to support information integration and thereby consciousness. The roles of different thalamic populations in modulating cortical interactions are also unknown. We hypothesize that thalamic matrix cells, with their widespread cortical projections focused especially in SG layers, enable cortical information integration. In addition t actions on specific cell types, we propose that anesthetics target specific synaptic pathways, suppressing cortico-cortical (CC) and matrix thalamo-cortical (TC) synaptic connections, while leaving core TC connections intact. To test these hypotheses, we will take advantage of recent developments in laminar multiunit recordings in freely- moving rodents to examine the neural correlates of LOC/ROC, and recordings of network activity in brain slices to investigate the cellular and circuit mechanisms of these correlates. Moreover, we will use optogenetic and pharmacogenetic methods to transiently activate/inactivate specific cortical layers and thalamic populations and explore their causal involvement in LOC/ROC.
How anesthetics produce unconsciousness remains mysterious, but both empirical and theoretical considerations indicate that consciousness requires a high level of information integration in specific brain regions. In this project we will test in mice the hypothesis that general anesthetics, irrespective of their precise mechanism of action, induce loss of consciousness when they bring about the breakdown of information integration in specific neuronal populations within the corticothalamic system.
