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.

来自父母奖 我们在药理学方面面临的剩下的基本挑战之一是破译 全身麻醉（气）的作用。完整的麻醉状态涉及意识的丧失（催眠） 和运动（固定），以及疼痛感觉的丧失（镇痛）和事件的回忆 （健忘症）。据认为，气体通过多种但特定的蛋白质作用于神经元膜上，并且 不同的配体门控和电压门控离子通道已获得了重大考虑。中的一个 在麻醉机制中研究电压门控钙通道（VGCC）的令人信服的理由 行动是这些渠道对于调节突触传播和兴奋性至关重要 神经元睡眠途径（例如丘脑）和与学习/记忆有关的大脑区域（例如，河马 - 校园组）。重要的是，我们以前的研究已经确定，低压激活的亚型 VGCC或T型钙通道（T通道）在临床上被不同类别的气体抑制 相关浓度范围。在过去的二十年中，我们的工作已经确定了T-家族的角色 在急性和慢性疼痛处理中键入VGCC，包括手术后疼痛。但是，VGCC的角色 在GA诱导的催眠和健忘症的机制中仍然难以捉摸。此外，尽管很大 在过去的二十年中，我们对天然气如何行动的理解取得了进步 分子水平，关于气体如何在完整水平上引起催眠和记忆不足的了解少得多 神经元网络。因此，该提案旨在阐明T通道特定亚型的贡献 在丘脑皮质（研究区域1）和河马校园电路（研究区2）中进行麻醉作用。 我们将利用小鼠遗传学，不同的T通道同工型的选择性敲击，并且 体内电生理学，光学记录以及一系列行为测试，以解决这些键 挑战。我们提出的工作有可能推翻有关麻醉机制的教条 并将重点转移到诸如神经元T通道等靶标不足的目标上。我们认为这种理解 靶向T通道的气体作用的神经生理机制可以用作起点 开发新颖，可能更安全的方法和临床麻醉方法。 Mira机制是 非常适合实现我们既定的目标，因为灵活地追求研究领域的新途径 令人兴趣。我们实验室的一致生产力以及我们与其他领域与他人合作的能力 麻醉药理学强烈表明我们的方法将富有成果。拟议的工作是创新的 在这种有用的全身麻醉剂（例如意识丧失和）有用的临床作用的新机制中 健忘症将被描述。这是很重要的，因为它描述了药物的重要性 目标电压门控钙通道，用于潜在的临床麻醉中更安全实践的发展。