The Roles of Genetically Distinct Cortical Neuron Types in General-Anesthesia- and Sleep-Induced Slow Waves

遗传上不同的皮质神经元类型在全身麻醉和睡眠引起的慢波中的作用

• 批准号: 10449437
• 负责人: Eric D Melonakos
• 金额: $ 10万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-11 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449437
• 关键词: Adrenergic Agonists; Adrenergic Receptor; Affect; Agonist; Anesthesia procedures; Anesthetics; Area; Arousal; Awareness; Bilateral; Biomimetics; Boston; Brain Stem; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; California; Cerebral cortex; Community Hospitals; Conscious; Data; Dexmedetomidine; Educational process of instructing; Electroencephalogram; Exhibits; Faculty; Frequencies; Future; General Anesthesia; General Hospitals; General anesthetic drugs; Generations; Goals; Grant; Head; Health; Image; Individual; Institutes; Interneurons; Intracellular Membranes; Ketamine; Lead; Learning; Los Angeles; Massachusetts; Measures; Medical; Membrane Potentials; Mentors; Methods; Microscope; Molecular; Molecular Target; Monitor; N-Methylaspartate; Narcolepsy; Neurons; Occupations; Parvalbumins; Pattern; Peer Review; Persons; Phase; Prefrontal Cortex; Preoptic Areas; Propofol; Protocols documentation; Rattus; Research; Rodent; Role; Sleep; Sleep Disorders; Sleeplessness; Slow-Wave Sleep; Somatostatin; Statistical Data Interpretation; Techniques; Technology; Testing; Training; Unconscious State; Universities; Vasoactive Intestinal Peptide; Writing; antagonist; base; calcium indicator; computational neuroscience; cortex mapping; experimental study; hippocampal pyramidal neuron; improved; information processing; inhibitory neuron; medical schools; member; neural circuit; neural stimulation; non rapid eye movement; optogenetics; parabrachial nucleus; patient safety; prevent; programs; relating to nervous system; side effect

Project Summary/Abstract. Reversible loss of consciousness is a crucial part of two major medical fields: general anesthesia and sleep. General anesthetics and non-rapid-eye-movement (NREM) sleep both induce slow waves (0.1-4 Hz) in the cortical electroencephalogram (EEG). It is unknown whether slow waves generated with different anesthetic agents and during NREM sleep are generated with the same neural circuit activity. Dr. Melonakos’ preliminary data suggests that anesthetic agents with different molecular targets have distinct slow wave mechanisms (Aim 1 Hypothesis). In addition, although dexmedetomidine anesthesia shares neural circuits with NREM sleep, it may also have distinct direct cortical effects, possibly leading to different slow wave activity (Aim 2 Hypothesis). The purpose of this research is to test these hypotheses by mapping cortical neural activity with respect to the EEG slow waves of both anesthesia and NREM sleep. In order to do this, Dr. Melonakos will learn how to perform calcium imaging experiments in freely behaving rodents. He will then record calcium images from Ca2+/calmodulin-dependent protein kinase IIa-positive (CaMKIIa+), parvalbumin-positive (PV+), somatostatin-positive (SST+), and vasoactive intestinal peptide-positive (VIP+) cortical neurons during anesthesia- and sleep-induced slow waves. Propofol, ketamine, and dexmedetomidine anesthesia will be tested. Dr. Melonakos will then compare the neural activity between the anesthetics and between general anesthesia and sleep. Finally, he will identify the role of SST+ neurons in slow waves (Aim 3 Hypothesis) by (1) looking at the activity of cortical neurons following disruption of slow waves by stimulation of the parabrachial nucleus, an arousal area in the brainstem, and (2) inhibiting SST+ neurons during anesthesia- and sleep-induced slow waves. During the K99 phase of this project, Dr. Melonakos will be mentored by Drs. Christa Nehs and Emery Brown, experts in anesthesia and sleep neurocircuitry and faculty at Harvard Medical School, Massachusetts General Hospital (MGH), and Massachusetts Institute of Technology (MIT). Dr. Melonakos will also collaborate with Drs. Michael Hasselmo (Boston University), Nancy Kopell (Boston University), and Daniel Aharoni (University of California, Los Angeles). He will be trained in calcium imaging by Drs. Hasselmo and Aharoni, and statistical analysis by Dr. Brown. Dr. Kopell will guide Dr. Melonakos as he orients his findings within hypothesized slow wave mechanisms from the field of computational neuroscience. Dr. Melonakos will also learn optogenetics stimulation techniques from Dr. Nehs and in a course at MIT. The mentors, collaborators, and other members of the MGH community will also provide him with professional guidance as he nears independence, including training in grant writing, peer review, teaching, and the faculty job search. The scientific and professional training Dr. Melonakos receives will enable him to develop an independent research program to study anesthetics’ direct vs. indirect effects. The resulting understanding of slow wave mechanisms has potential to improve the protocols used to monitor general anesthesia and treat sleep disorders, thus benefiting patient safety and health.

项目摘要/摘要。可逆的意识丧失是两个主要医疗领域的关键部分： 全身麻醉和睡眠。全身麻醉和非依质 - 动作（NREM）睡眠两者都有影响 皮质脑电图（EEG）中的慢波（0.1-4 Hz）。尚不清楚慢波是否产生 具有不同的麻醉剂和在NREM睡眠期间，具有相同的神经回路活性。博士 Melonakos的初步数据表明，具有不同分子靶标的麻醉剂的慢速 波机制（AIM 1假设）。此外，尽管右美度胺麻醉有神经回路 使用NREM睡眠，它也可能具有不同的直接皮质作用，可能导致不同的慢波活动 （AIM 2假设）。这项研究的目的是通过绘制皮质神经元活性来检验这些假设 关于麻醉和NREM睡眠的脑电图慢波。为此，Melonakos博士将 了解如何在自由表现啮齿动物中执行钙成像实验。然后，他将记录钙图像 从Ca2+/钙调蛋白依赖性蛋白激酶IIA阳性（CAMKIIA+），白蛋白阳性（PV+）， 生长抑素阳性（SST+）和血管活性肠道肽阳性（VIP+）皮质神经元期间 麻醉和睡眠引起的慢波。丙泊酚，氯胺酮和右美托咪定麻醉将进行测试。 然后，Melonakos博士将比较麻醉药之间的神经活动和全身麻醉之间 和睡觉。最后，他将通过（1）看SST+神经元在慢波（AIM 3假设）中的作用 通过刺激止痛核破坏慢波后皮质神经元的活性， 脑干中的唤醒区域，（2）在麻醉和睡眠引起的慢波中抑制SST+神经元。 在该项目的K99阶段，Melonakos博士将由Christa Nehs博士和Emery Brown博士考虑， 马萨诸塞州哈佛医学院的麻醉和睡眠神经记录和教师的专家 医院（MGH）和马萨诸塞州理工学院（MIT）。 Melonakos博士还将与Drs合作。 迈克尔·哈塞尔莫（Michael Hasselmo）（波士顿大学），南希·科佩尔（波士顿大学）和丹尼尔·阿哈罗尼（Daniel Aharoni）（大学 加利福尼亚，洛杉矶）。 DRS将对他进行钙成像的培训。 Hasselmo和Aharoni以及统计 布朗博士的分析。 Kopell博士将指导Melonakos博士在假设的慢速中提出他的发现 来自计算神经科学领域的波浪机制。 Melonakos博士还将学习光遗传学 NEHS博士和麻省理工学院的课程中的刺激技术。导师，合作者和其他成员 MGH社区还将在他近乎独立时为他提供专业指导，包括 赠款写作，同行评审，教学和教师求职培训。科学和专业培训 Melonakos博士收到的将使他能够制定一个独立的研究计划来研究麻醉药的直接 与间接影响。对慢波机制的理解有可能改善协议 用于监测全身麻醉和治疗睡眠障碍，从而使患者的安全和健康受益。