Thalamic and cortical mechanisms of anesthetic-induced unconsciousness

麻醉引起无意识的丘脑和皮质机制

• 批准号: 9189624
• 负责人: Matthew I Banks
• 金额: $ 28.63万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189624
• 关键词: Adverse effects; Anesthesia procedures; Anesthetics; Area; Auditory; Auditory area; Awareness; Biological Assay; Brain Stem; Cell Nucleus; Cells; Chronic; Clinical; Code; Conscious; Cortical Column; Data; Development; Dexmedetomidine; Diagnostic; Dose; Electrodes; Electrophysiology (science); General anesthetic drugs; Implant; Ipsilateral; Isoflurane; Link; Measures; Midbrain structure; Minimally Conscious States; Modality; Modeling; Molecular; Monitor; Operating Rooms; Output; Pathway interactions; Patient Care; Patients; Population; Propofol; Public Health; Rattus; Recovery; Science; Sensory; Source; Stimulus; Surface; Synapses; Techniques; Testing; Thalamic structure; Unconscious State; Visual; Visual Cortex; auditory stimulus; auditory thalamus; awake; base; causal model; density; drug development; experimental study; extrastriate visual cortex; hypnotic; insight; microstimulation; prevent; public health relevance; relating to nervous system; response; segregation; sensory input; sensory stimulus; theories; tool; visual stimulus

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.

描述（由申请人提供）：阐明麻醉剂导致意识丧失（LOC）的机制将有利于患者护理并提供对意识神经基础的深入了解。在这个提案中，我们将测试两个相互竞争的假设，即丘脑开关假说（TSH）和意识信息整合理论（IITC）。对于前者，丘脑皮质信息传递的破坏被认为对于 LOC 至关重要。后者 提出麻醉剂作用于大脑皮层的广泛区域，以减少网络状态（信息）和连接（整合）的全部内容。我们假设丙泊酚、异氟烷和右美托咪定作用于不同的分子位点，具有产生 LOC 的共同皮质机制：在刚好催眠剂量（即仅引起 LOC 的剂量）下刺激表征的退化和皮质-皮质连接的抑制，从而防止将感觉信息纳入皮质分层处理。我们将通过记录在听觉丘脑以及听觉和视觉皮层长期植入多部位电极的大鼠的单位活动和局部场电位（LFP）来测试这些相互竞争的假设。对公共健康的实际好处将是基于人口代码和皮层连接性的意识分析，这些代码和皮层连接性源自皮层表面记录，这些记录在临床环境中很容易获得。 感觉意识的缺失是 LOC 的一种表现，反映了外周皮层和高阶皮层之间信息传递的退化，但这种故障发生在哪里以及如何发生尚不清楚。在第一个目标中，我们将重点关注听觉皮层细胞在单细胞水平和群体水平上携带多少关于感觉刺激的信息反应，以及这些信息在意识丧失和恢复时如何变化（LOC/ROC） ）。通过记录两个丘脑区域 MGv 和 MGd 的听觉反应，以及它们各自分层连接的皮质目标 A1 和 PAF，我们可以确定麻醉剂是否会像 TSH 预测的那样阻碍从丘脑到皮质的信息传输，或者甚至在面部维持的丘脑输入皮层反应在 LOC 时变得贫乏，因为观察到麻醉药引起的局部网络活动发生变化，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升和下降通路的连通性。在这里，我们将记录整个皮质柱中响应微刺激以及听觉和视觉感觉刺激的突触和尖峰活动，以确定丘脑-皮质突触的 LOC/ROC 连接是否发生变化，如 TSH 预测的那样，或皮质-皮质突触，与 IITC 一致。我们将使用这些实验中的信息来帮助寻找 LOC/ROC 中表现的状态转换的电生理学相关性，并且我们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，得出临床上可访问的感觉意识测量方法。