Thalamic and cortical mechanisms of anesthetic-induced unconsciousness

描述(由申请人提供)：阐明麻醉药导致意识丧失(LOC)的机制将有利于患者的护理，并提供对意识的神经基础的洞察。在这个提案中，我们将检验两个相互竞争的假说，丘脑开关假说(TSH)和意识的信息整合理论(IITC)。在前者中，丘脑-皮质信息传递的中断被认为是LOC的关键。后者 建议麻醉剂作用于皮质的广泛区域，以减少网络状态(信息)和连接性(整合)的保留。我们推测，异丙酚、异氟醚和右美托咪定作用于不同的分子位点，具有共同的产生LOC的皮层机制：在刚刚催眠的剂量下(即那些只引起LOC的)，刺激表征的退化和皮质-皮质连接性的抑制，这阻止了感觉信息被整合到皮质分级处理中。我们将通过记录长期植入听觉丘脑、听觉和视觉皮质多部位电极的大鼠的单位活动和局部场电位(LFP)来检验这些相互竞争的假说。对公众健康的一个实际好处将是基于人群代码和皮质表面记录得出的皮质连接性的意识分析，这些都很容易在临床环境中获得。感觉意识的缺乏是LOC的一种表现，它反映了外周和高级皮质之间信息传递的退化，但这种崩溃发生在哪里以及如何发生尚不清楚。在第一个目标中，我们将重点研究听觉皮层细胞在单个细胞水平和群体水平上对感觉刺激的信息反应，以及这些信息在意识丧失和恢复时是如何变化的(LOC/ROC)。通过记录丘脑的两个区域MGV和MGD的听觉反应，以及它们各自的分级连接的皮质靶点A1和PAF，我们可以确定麻醉剂是否像TSH预测的那样阻断了信息从丘脑到皮质的传递，或者即使面对维持丘脑输入的情况，皮质反应是否由于观察到麻醉剂引起的局部网络活动的变化而变得贫乏，与IITC一致。在第二个和第三个目标中，我们将研究丘脑皮质上行和下行通路的连通性。在这里，我们将记录整个皮质柱对微刺激和听觉和视觉刺激的突触和棘波活动，以确定是否如TSH预测的那样，在丘脑-皮质突触的LOC/ROC上，或者在皮质-皮质突触上，与IITC一致。我们将使用这些实验中的信息来帮助寻找LOC/ROC中显示的状态转换的电生理学关联，并将使用最先进的分析和建模技术，基于群体编码和皮质连接得出临床可访问的感觉意识测量指标。

DESCRIPTION (provided by applicant): 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 an 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.