Elucidating dynamic reorganization of whole-brain networks during anesthetic-induced unconsciousness

阐明麻醉引起的无意识期间全脑网络的动态重组

• 批准号: 10460502
• 负责人: Nanyin Zhang
• 金额: $ 33.22万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-02 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460502
• 关键词: Altered Level of Consciousness; Anesthesia procedures; Anesthetics; Animal Behavior; Animal Model; Animals; Biological Markers; Brain; Characteristics; Claustral structure; Conscious; Data; Development; Dexmedetomidine; Dose; Electrophysiology (science); Functional Magnetic Resonance Imaging; Goals; Grant; Graph; Immobilization; Individual; Isoflurane; Ketamine; Light; Link; Measures; Molecular; Parietal; Pattern; Property; Propofol; Rattus; Recovery; Reflex action; Research; Rest; Signal Transduction; Site; System; Testing; Thalamic structure; Unconscious State; Wakefulness; awake; behavior test; experimental study; flexibility; imaging approach; neural circuit; neural network; neuromechanism; relating to nervous system; segregation; study characteristics; tool

Project Summary Despite fairly clear understanding on the molecular basis of various anesthetic agents, the systems-level neural mechanism by which anesthetics induce unconsciousness remains elusive. Substantial evidence suggests that anesthetic-induced unconsciousness (AIU) is a brain network phenomenon. Anesthetics appear to suppress consciousness by disrupting information exchange across large-scale brain networks. Therefore, to understand the systems-level mechanism underlying AIU, a critical step is to comprehensively characterize how whole-brain networks dynamically reorganize to support different patterns of information exchange during AIU. This issue can be studied using resting-state functional magnetic resonance imaging (rsfMRI), as it measures between-region functional connectivity (FC) with a whole-brain field of view. In particular, applying rsfMRI to animal models offers several advantages for studying AIU: 1) Intracranial electrophysiology can be concurrently measured with rsfMRI in animals to reveal characteristic neural activity/connectivity patterns and the corresponding global brain network dynamics during AIU; 2) distinct anesthetic agents can be applied to the same group of animals so that common brain network changes during AIU shared by different anesthetics, if any, can be identified; and 3) anesthetic depths can be easily manipulated. However, a major obstacle to fully realize these potentials is that animal fMRI experiments typically use anesthesia to immobilize animals first. Consequently, it is very difficult to reveal how brain networks change from the awake state into an unconscious state. To bridge this gap, our group has established the approach of conducting rsfMRI experiments in fully awake animals. In addition, we have integrated our awake rat rsfMRI approach with multi-laminar electrophysiology recording and animal behavior, which allows us to directly link brain network reorganization to concurrent neural activity patterns and animal’s consciousness states. By using rsfMRI, electrophysiology and behavioral tests, the primary objective of this grant is to comprehensively elucidate the dynamic reorganization of the whole-brain functional network to support different patterns of information exchange from the awake state into an unconscious state. Four anesthetics, including isoflurane, propofol, ketamine and dexmedetomidine will be tested. In Aim 1, we will identify characteristic neural activity and brain connectivity patterns at different steady consciousness levels. In Aim 2, we will systematically characterize topological changes of brain networks during AIU. In Aim 3, we will elucidate layer-specific cortical activity and connectivity patterns, as well as brain network dynamics during the loss and recovery of consciousness. Successful completion of the proposed research will provide a comprehensive framework of how whole-brain networks dynamically reconfigure during AIU. Given the tight link between FC and conscious states, it will broadly shed light onto the neural basis of consciousness, and help reveal biomarkers to indicate levels of consciousness.

项目摘要 尽管对各种麻醉剂的分子基础有相当清楚的了解，但系统水平的 麻醉剂诱导无意识的神经机制仍然是不清楚的。大量证据 麻醉诱导的无意识（AIU）是一种脑网络现象。麻醉剂出现 通过破坏大规模大脑网络的信息交换来抑制意识。因此 了解AIU的系统级机制，关键一步是全面表征 全脑网络如何动态重组以支持不同的信息交换模式 在AIU期间。这个问题可以使用静息态功能磁共振成像（rsfMRI）进行研究， 它测量具有全脑视野的区域间功能连接（FC）。特别是， 将rsfMRI应用于动物模型为研究AIU提供了几个优点：1）颅内电生理学 可以在动物中用rsfMRI同时测量，以揭示特征性神经活动/连接 AIU期间的模式和相应的全球脑网络动力学; 2）不同的麻醉剂可以 应用于同一组动物，以便在AIU期间由不同的 如果有的话，可以识别麻醉剂;和3）可以容易地操纵麻醉深度。然而一个主要 充分实现这些潜力的障碍是动物fMRI实验通常使用麻醉， 动物第一。因此，很难揭示大脑网络在清醒状态下的变化 进入无意识状态。为了弥合这一差距，我们的小组建立了进行 rsfMRI实验在完全清醒的动物。此外，我们还整合了清醒大鼠rsfMRI方法， 通过多层电生理记录和动物行为，这使我们能够直接将大脑 网络重组到并发的神经活动模式和动物的意识状态。通过使用 rsfMRI，电生理学和行为测试，这项资助的主要目标是全面 阐明全脑功能网络的动态重组，以支持不同的模式， 从清醒状态到无意识状态的信息交换。四种麻醉剂，包括异氟烷， 将测试丙泊酚、氯胺酮和右美托咪定。在目标1中，我们将识别特征神经元 活动和大脑连接模式在不同的稳定意识水平。在目标2中，我们将 系统地描述AIU期间脑网络拓扑结构的变化。在目标3中，我们将阐明 层特异性皮层活动和连接模式，以及在损失和 恢复意识。成功完成拟议的研究将提供全面的 全脑网络在AIU期间如何动态重新配置的框架。鉴于FC与 和意识状态，它将广泛地揭示意识的神经基础，并有助于揭示 生物标志物来指示意识水平。