In vivo dual color imaging of neuronal networks during anesthesia

麻醉期间神经元网络的体内双色成像

• 批准号: 10582000
• 负责人: Slobodan M. Todorovic
• 金额: $ 16.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582000
• 关键词: Absence of pain sensation; Acute Pain; Address; Amnesia; Anesthesia procedures; Anesthetics; Area; Award; Brain region; Calcium; Calcium Channel; Categories; Clinical; Color; Development; Drug Targeting; Electrophysiology (science); Event; Face; Family; General anesthetic drugs; Goals; Hippocampal Formation; Hippocampus (Brain); Hypnosis; Image; Immobilization; Ion Channel Gating; Learning; Ligands; Medical; Membrane; Memory; Memory impairment; Molecular; Movement; National Institute of General Medical Sciences; Neurons; Optics; Parents; Pathway interactions; Pharmacology; Postoperative Pain; Productivity; Protein Isoforms; Proteins; Regulation; Research; Role; Sleep; Synaptic Transmission; T-Type Calcium Channels; Thalamic structure; Unconscious State; Work; behavior test; chronic pain; clinical effect; clinically relevant; flexibility; in vivo; innovation; interest; knock-down; mouse genetics; neurophysiology; novel; pain processing; pain sensation; voltage

From Parent Award One of the remaining fundamental challenges we face in pharmacology is deciphering the mechanisms of action of general anesthetics (GAs). A complete anesthetic state involves loss of consciousness (hypnosis) and movement (immobilization), as well as loss of pain sensation (analgesia) and recollection of the event (amnesia). It is believed that GAs act through the multiple but specific proteins on neuronal membrane and different ligand-gated and voltage-gated ion channels have received a significant consideration. One of the compelling reasons to study voltage-gated calcium channels (VGCCs) in the mechanisms of anesthetic actions is that these channels are essential in regulation of synaptic transmission and excitability in the neuronal sleep pathway (e.g. thalamus) and in the brain regions involved in learning/memory (e.g. hippo- campal formation). Importantly, our previous studies have established that low-voltage-activated subtype of VGCCs or T-type calcium channels (T-channels) are inhibited by different classes of GAs within the clinically relevant concentration range. For the past two decades our work has established the role of the family of T- type VGCCs in acute and chronic pain processing, including post-surgical pain. However the role of VGCCs in the mechanisms of GA-induced hypnosis and amnesia remains elusive. Furthermore, despite substantial progress that has been made in the last two decades towards our understanding of how GAs act at the molecular level, much less is known about how GAs cause hypnosis and memory deficit at the level of intact neuronal networks. Hence, this proposal aims to elucidate the contribution of specific subtypes of T-channels to anesthetic effects in the thalamocortical (Research area 1) and hippo- campal circuitry (Research area 2). We will take advantage of mouse genetics, selective knock-down of different T-channel isoforms ex vivo and in vivo electrophysiology, optical recordings, as well as a battery of behavioral tests to address these key challenges. Our proposed work has the potential to overturn ex- isting dogma about anesthetic mechanisms and to shift the focus to underappreciated targets, such as neuronal T-channels. We posit that understanding the neurophysiological mechanisms of action of GAs that target T-channels may be used as a starting point to develop novel and potentially safer approaches and practices in clinical anesthesia. MIRA mechanism is well suited to achieve our stated goals because of flexibility to pursue new avenues within the research area of interest to NIGMS. Consistent productivity of our lab and our ability to collaborate with others in the field of anesthetic pharmacology strongly suggest that our approach will be fruitful. The proposed work is innovative in that new mechanisms of useful clinical effects of general anesthetics such as loss of consciousness and amnesia will be characterized. It is med- ically significant because it describes the importance of drugs that target voltage-gated calcium channels for potential development of safer practices in clinical anesthesia.

来自家长奖 我们在药理学中面临的剩余基本挑战之一是破译其机制 全身麻醉药 (GA) 的作用。完全麻醉状态会导致意识丧失（催眠） 和运动（固定），以及痛觉丧失（镇痛）和事件回忆 （健忘症）。据信 GA 通过神经元膜上的多种但特定的蛋白质起作用 不同的配体门控和电压门控离子通道已受到重要考虑。中的一个 研究麻醉机制中电压门控钙通道（VGCC）的令人信服的理由 作用在于这些通道对于调节突触传递和兴奋性至关重要 神经元睡眠通路（例如丘脑）和参与学习/记忆的大脑区域（例如河马） 营的形成）。重要的是，我们之前的研究已经证实，低电压激活的亚型 VGCC 或 T 型钙通道（T 通道）在临床上被不同类别的 GA 抑制 相关浓度范围。在过去的二十年里，我们的工作确立了 T 家族的作用—— VGCC 型在急性和慢性疼痛处理中的作用，包括术后疼痛。然而 VGCC 的作用 GA 引起的催眠和遗忘的机制仍然难以捉摸。此外，尽管大量 过去二十年来，我们在理解 GA 如何在全球范围内发挥作用方面取得了进展 在分子水平上，人们对于 GA 如何在完整的水平上导致催眠和记忆缺陷知之甚少。 神经元网络。因此，该提案旨在阐明 T 通道特定亚型的贡献 丘脑皮质（研究领域 1）和海马回路（研究领域 2）的麻醉作用。 我们将利用小鼠遗传学，体外选择性敲低不同的 T 通道亚型，并 体内电生理学、光学记录以及一系列行为测试来解决这些关键问题 挑战。我们提出的工作有可能推翻有关麻醉机制的现有教条 并将焦点转移到未被充分认识的目标，例如神经元 T 通道。我们假定这种理解 GA 靶向 T 通道的神经生理学作用机制可作为起点 开发新颖且可能更安全的临床麻醉方法和实践。 MIRA机制是 由于能够在研究领域内灵活地寻求新途径，因此非常适合实现我们既定的目标 NIGMS 感兴趣。我们实验室始终如一的生产力以及与该领域其他人合作的能力 麻醉药理学强烈表明我们的方法将会卓有成效。拟议的工作具有创新性 全身麻醉的有用临床效果的新机制，例如意识丧失和 健忘症将被表征。它具有医学意义，因为它描述了药物的重要性 靶向电压门控钙通道，以开发临床麻醉中更安全的实践。