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: 8990491
• 负责人: Matthew I Banks
• 金额: $ 28.91万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990491
• 关键词: Adverse effects; Anesthesia procedures; Anesthetics; Area; Auditory; Auditory area; Awareness; Biological Assay; Brain Stem; Cell Nucleus; Cells; Clinical; Code; Conscious; Cortical Column; Data; Development; Dexmedetomidine; Diagnostic; Dose; Electrodes; Electrophysiology (science); General anesthetic drugs; Health; Implant; Ipsilateral; Isoflurane; Link; Measures; Midbrain structure; Minimally Conscious States; Modality; Modeling; Molecular; Monitor; Operating Rooms; Output; Pathway interactions; Patient Care; Patients; Population; Process; Propofol; Public Health; Rattus; Recovery; Science; Sensory; Source; Stimulus; Surface; Synapses; Techniques; Testing; Thalamic structure; Unconscious State; Visual; Visual Cortex; auditory stimulus; awake; base; causal model; density; drug development; extrastriate visual cortex; hypnotic; insight; microstimulation; prevent; relating to nervous system; research study; 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）：阐明麻醉药导致意识丧失（LOC）的机制将使患者护理受益，并提供对意识神经基础的见解。在此提案中，我们将检验两个相互竞争的假设：丘脑开关假设（TSH）和意识的信息整合理论（IITC）。在前者中，丘脑 - 皮层信息转移的破坏对于LOC来说至关重要。后者 建议麻醉药在皮质的广泛地区起作用，以减少网络状态（信息）和连接性（集成）的曲目。 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.我们将通过记录单位活动和局部田间电位（LFP）来测试这些竞争假设，并在听觉丘脑和听觉和视觉皮层中慢性植入的大鼠中。公共卫生的实际好处将是基于人口代码和从皮质表面记录得出的皮质连通性的意识测定，这些连通性在临床环境中很容易获得。 缺乏感官意识是LOC的一种表现，它反映了外围和高阶皮层之间的降级信息传递，但是这种崩溃的发生尚不清楚。在第一个目标中，我们将重点介绍在听觉皮层中细胞对感官刺激的信息响应，包括在人群水平的单细胞水平A处，以及该信息随着意识的丧失和恢复而发生变化（LOC/ROC）。通过记录两个丘脑区域的听觉响应，MGV和MGD及其各自的层次连接的皮质靶标A1和PAF，我们可以确定麻醉剂的信息是否会从丘脑转移到丘脑到皮质的信息是否被TSH预测，即使是在维持丘脑输入的互联网上，也会导致丘脑的互联网，这是否会导致丘脑的影响。与IITC一致。在第二和第三目标中，我们将研究沿着上升和下降的丘脑皮层途径的连通性。在这里，我们将记录整个皮质柱中的突触和峰值活性，以响应微刺激，听觉和视觉感觉刺激，以确定TSH或Cortico-cortical-cortical-portical Synapses在THALAMO-Cortical Synapses处的LOC/ROC上的连通性是否变化，与IITC一致。我们将使用这些实验中的信息来帮助寻求LOC/ROC中表现出的状态转变的电生理相关性，我们将使用艺术分析和建模技术的状态基于种群编码和皮质连接性来得出基于种群编码和皮质连接性的临床上访问感官意识的测量。