Elucidating the mechanism by which anesthetics cause loss of consciousness (LOC) will benefit patient care and provide insight into the neural basis of consciousness. In this proposal, we will test two competing hypotheses, the thalamic switch hypothesis (TSH) and the information integration theory of consciousness (IITC). In the former, disruption of thalamo-cortical information transfer is thought critical for LOC. The latter proposes that anesthetics act across wide areas of cortex to reduce the repertoire of network states (information) and connectivity (integration). We postulate that propofol, isoflurane and dexmedetomidine, acting at diverse molecular loci, share a common cortical mechanism for producing LOC: degradation of stimulus representation and suppression of cortico-cortical connectivity at just-hypnotic doses (i.e. those just causing LOC), which prevent incorporation of sensory information into cortical hierarchical processing. We will test these competing hypotheses by recording unit activity and local field potentials (LFPs) in rats chronically implanted with multisite electrodes in auditory thalamus and auditory and visual cortex. A practical benefit to public health will be assays of consciousness based on population codes and cortical connectivity derived from cortical surface recordings, which are readily obtained in clinical settings. The absence of sensory awareness is a manifestation of LOC that reflects degraded information transfer between the periphery and high order cortex, but where and how this breakdown occurs is unclear. In the first Aim, we will focus on how much information responses of cells in auditory cortex carry about sensory stimuli, both at the single cell level and at the population level, and how this information changes upon loss and recovery of consciousness (LOC/ROC). By recording auditory responses in two thalamic areas, MGv and MGd, and their respective hierarchically connected cortical targets, A1 and PAF, we can determine whether anesthetics block information transfer from thalamus to cortex, as predicted by the TSH, or whether even in the face of maintained thalamic input cortical responses become impoverished upon LOC due to observed changes in local network activity caused by anesthetics, consistent with the IITC. In the second and third Aims, we will investigate connectivity along the ascending and descending thalamo-cortical pathway. Here we will record synaptic and spiking activity in entire cortical columns in response to microstimulation and auditory and visual sensory stimuli to determine if connectivity changes upon LOC/ROC at thalamo-cortical synapses, as predicted by the TSH, or at cortico-cortical synapses, consistent with the IITC. We will use the information from these experiments to aid in seeking electrophysiological correlates of the state transitions manifested in LOC/ROC, and we will derive clinically accessible measures of sensory awareness based on population coding and cortical connectivity using state of the art analysis and modeling techniques.
Although in widespread use for >150 years, how general anesthetics cause loss of consciousness remains one of the great mysteries of biomedical science. Understanding these mechanisms would benefit patient care through development of drugs specifically targeted towards causing loss of consciousness with fewer side effects compared to current agents, and allowing for the development of noninvasive monitors of awareness for use in the operating room and as diagnostic tools for patients in vegetative or minimally conscious states. This proposal seeks to understand these mechanisms using electrophysiological and modeling techniques in rats.
|Raz, Aeyal; Grady, Sean M; Krause, Bryan M et al. (2014) Preferential effect of isoflurane on top-down vs. bottom-up pathways in sensory cortex. Front Syst Neurosci 8:191|