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: 8615727
• 负责人: Matthew I Banks
• 金额: $ 28.19万
• 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/8615727
• 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; 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; 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; density; drug development; extrastriate visual cortex; hypnotic; insight; microstimulation; prevent; public health relevance; relating to nervous system; research study; response; segregation; sensory stimulus; theories; tool; visual stimulus

Project Summary 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.

项目摘要 阐明麻醉药引起意识丧失的机制将使患者受益 关心并提供对意识的神经基础的洞察力。在这个提议中，我们将测试两个竞争对手， 假设，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对大脑控制中枢至关重要。后者 提出，麻醉剂作用于大脑皮层的广泛区域，以减少网络状态的库 （信息）和连通性（一体化）。我们假设异丙酚，异氟烷和右美托咪定， 作用于不同的分子位点，共享一个共同的皮质机制来产生皮质激素： 在催眠剂量下的刺激表征和皮质-皮质连接的抑制（即那些 导致大脑皮层的分层处理，从而阻止感觉信息的整合。我们将 通过长期记录大鼠的单位活动和局部场电位（LFPs）来验证这些相互竞争的假设 在听觉丘脑听觉和视觉皮层植入多点电极。一个实际的好处， 公共卫生将是基于人口代码和大脑皮层连接的意识检测， 皮质表面记录，其在临床环境中容易获得。 感觉觉知的缺失是一种反映信息传递退化的神经衰弱的表现 在外围和高级皮层之间，但这种分解在哪里以及如何发生尚不清楚。上 目的：研究听觉皮层细胞对感觉刺激的信息反应， 在单细胞水平和群体水平上，以及这些信息在损失后如何变化， 意识恢复（ROC）。通过记录两个丘脑区域的听觉反应，MGv和 MGd，以及它们各自的分层连接的皮质靶点A1和PAF，我们可以确定是否 麻醉剂阻断信息从丘脑到皮层的传递，正如TSH所预测的那样，或者即使在大脑皮层， 维持的丘脑输入皮层反应的面在刺激后变得贫乏， 麻醉剂引起的局部网络活动变化，与IITC一致。在第二和第三个目标中， 我们将研究沿上升和下降的丘脑-皮质通路的连接性沿着。这里我们将 记录整个皮质柱中响应微刺激和听觉的突触和尖峰活动， 视觉感官刺激，以确定在丘脑-皮质突触处的突触/ROC后连接性是否发生变化， TSH预测，或在皮质-皮质突触，与IITC一致。我们将使用来自 这些实验有助于寻求表现在以下的状态转换的电生理学相关性： /ROC，我们将根据人群得出临床上可获得的感觉意识测量值 编码和皮质连接使用最先进的分析和建模技术。