Cellular and circuit mechanisms of the therapeutic action of inhaled nitrous oxide in rodent models of chronic stress

吸入一氧化二氮对慢性应激啮齿动物模型治疗作用的细胞和回路机制

• 批准号: 10712012
• 负责人: JOSEPH CICHON
• 金额: $ 40.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712012
• 关键词: Acute; Aftercare; Anesthetics; Animal Model; Animals; Antidepressive Agents; Automobile Driving; Behavioral; Brain region; Calcium; Chronic stress; Clinical Research; Dissociative Anesthetics; Dose; Electrophysiology (science); Foundations; Goals; Hour; Image; Imaging Techniques; Individual; Inhalation; Intervention; Intravenous; Involutional Depression; Ketamine; Link; Mediating; Mental Depression; Mission; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Institute of General Medical Sciences; Neocortex; Neuronal Plasticity; Neurons; Nitrous Oxide; Patients; Refractory; Resistance; Rodent Model; Structure; Synapses; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Work; antagonist; clinical effect; clinical practice; depressive symptoms; disability; hippocampal pyramidal neuron; improved; in vivo imaging; innovation; neocortical; neuropsychiatric disorder; novel; pharmacologic; stem

Project Summary/Abstract Depression is the leading cause of disability worldwide and new treatments are needed. This therapeutic challenge stems from the fact that depression involves deficits distributed among neuronal subtypes and multiple brain regions. A growing body of clinical research demonstrates that a single dose of N-methyl-D-aspartate receptor , induce rapid and durable improvements in depressive symptoms persisting for days to weeks in patients refractory to conventional antidepressant therapies. Despite nitrous oxide being the oldest and one of the safest anesthetics in current (NMDA-R) antagonists, inhaled nitrous oxide or intravenous ketamine clinical practice, our understanding of how nitrous oxide modulates neuronal activity and circuit function to produce its clinical effects is extraordinarily limited. While it has been hypothesized that the therapeutic effect of NMDA-R antagonists is related to their ability to induce plasticity, the mechanisms that initiate and sustain this plasticity remain unclear. By combining in vivo imaging of synaptic structure, functional calcium imaging, electrophysiology, and behavioral recordings, this proposal will test an innovative hypothesis that changes in neuronal activity imposed by nitrous oxide acutely, automatically give rise to sustained plasticity through activity-dependent mechanisms. This hypothesis is based on extensive work on activity- dependent plasticity in the neocortex and on our own novel preliminary results showing that nitrous oxide specifically and directly activates layer 5 pyramidal neurons, which mediate cortico-cortical and cortico- subcortical connectivity, through a novel mechanism. All animal models and techniques have been established in the studies that generated the preliminary results, making the proposal highly achievable. In line with the mission of the NIGMS, the immediate goal of this proposal is to lay the foundation for advances in the treatment of depression by understanding the mechanisms of action of nitrous oxide in cortical circuits. Such an understanding may explain how acute pharmacologic interventions can lead to sustained therapeutic benefits in the setting of depression and potentially other neuropsychiatric diseases.

项目摘要/摘要 抑郁症是全球残疾的主要原因，需要新的治疗方法。这是一种治疗 挑战来自于这样一个事实，即抑郁症涉及分布在神经元亚型和多个 大脑区域。越来越多的临床研究表明，单剂N-甲基-D-天冬氨酸 受体，诱导快速持久 常规治疗无效患者持续数天至数周的抑郁症状的改善 抗抑郁疗法。尽管一氧化二氮是目前最古老和最安全的麻醉剂之一 (NMDA-R)拮抗剂、吸入一氧化二氮或静脉注射氯胺酮 临床实践中，我们对一氧化二氮如何调节神经元活动和电路功能的理解 产生其临床效果是非常有限的。虽然有假说认为阿司匹林的治疗效果 NMDA-R拮抗剂与其诱导可塑性的能力有关，即启动和维持可塑性的机制 可塑性仍不清楚。通过结合突触结构的活体成像，功能钙成像， 电生理学和行为记录，这项提议将检验一个创新的假设 一氧化二氮引起的神经元活动的急剧变化，自动引起持续性 通过活动依赖机制的可塑性。这一假设是基于对活动的广泛研究-- 大脑皮层中的依赖可塑性和我们自己的新的初步结果表明，一氧化二氮 特异性地和直接地激活第5层锥体神经元，这些神经元介导皮质和皮质- 皮层下的连接，通过一种新的机制。所有的动物模型和技术都已建立 在产生初步结果的研究中，使该提议高度可实现。符合 NIGMS的使命，这项提议的直接目标是为在 通过了解一氧化二氮在大脑皮层回路中的作用机制来治疗抑郁症。 这样的理解可以解释急性药物干预如何导致持续治疗。 在设置抑郁症和潜在的其他神经精神疾病方面有好处。