Role of adenosinergic inhibition of serotonin neurons in seizure induced respiratory arrest

腺苷能抑制血清素神经元在癫痫发作引起的呼吸骤停中的作用

• 批准号: 10349842
• 负责人: Benton Scott Purnell
• 金额: $ 6.64万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-23 至 2023-05-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349842
• 关键词: Adenosine; Affect; Arousal; Back; Brain; Brain Stem; Breathing; Carbon Dioxide; Cause of Death; Cell Nucleus; Cessation of life; Disease; Epilepsy; Etiology; Functional disorder; Goals; Knowledge; Lead; Life; Link; Mentorship; Mus; Neurologic; Neurons; Patients; Persons; Pharmacology; Prevention; Regulation; Respiration Disorders; Respiratory Failure; Respiratory physiology; Role; Science; Seizures; Serotonergic System; Serotonin; Signal Transduction; Stroke; System; Testing; Therapeutic; Tissues; Training; Transgenic Organisms; Travel; Writing; brain tissue; career; cohesion; expectation; experimental study; extracellular; insight; neurotransmission; premature; prevent; raphe nuclei; relating to nervous system; respiratory; sudden unexpected death in epilepsy

Project Summary Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature death in persons with epilepsy who do not have satisfactory seizure control. SUDEP results in more years of potential life lost than any other neurological condition with the exception of stroke. There are no known ways of reliably preventing SUDEP. Convergent lines of evidence suggest that respiratory dysfunction is a critical component of SUDEP pathophysiology. There are several potential mechanistic explanations for the respiratory arrest seen in SUDEP. (1) Serotonin signaling is important for stable breathing and increasing serotonergic tone may be protective against seizure-induced respiratory arrest. Unfortunately, seizures disrupt serotonergic neurotransmission. There is a gap in knowledge as to the mechanism responsible for seizure-induced disruption of serotonergic neurotransmission. (2) Seizures also cause a surge in extracellular adenosine throughout the brain. Increases in adenosine levels suppress breathing and inhibit neural activity. Excessive adenosine signaling has been implicated in the respiratory dysfunction seen in SUDEP; however, the mechanism by which adenosine affects breathing after seizures is unknown. (3) Slow moving (2-5 mm/min) waves of spreading depolarization are sometimes triggered by seizures. Spreading depolarization transiently inactivates the brain tissue. Under certain circumstances spreading depolarization can travel into the brainstem where it halts neural activity in nuclei necessary for cardiorespiratory function and causes death. Brainstem spreading depolarization is a potential cause of SUDEP. Spreading depolarization also causes an increase in extracellular adenosine. It is not known whether the increase in adenosine due to spreading depolarization contributes to seizure-induced death. The goal of this proposal is to integrate the serotonergic, adenosinergic, and spreading depolarization explanations of SUDEP etiology by testing the central hypothesis that adenosine surging as the result of seizure activity and spreading depolarization disrupts serotonergic neurotransmission thereby potentiating respiratory failure. In the first aim, adenosine signaling will be augmented in the serotonergic raphe nuclei during seizures to determine if this alters respiratory responsiveness to CO2 and the likelihood of respiratory failure. In the second aim, brainstem spreading depolarization will be induced in mice in which adenosine signaling has been pharmacologically or genetically altered in the raphe nuclei. The proposed experiments will generate compelling evidence for or against the hypothesized interaction between serotonin and adenosine while providing the training in writing, mentorship, and quantitatively rigorous hypothesis-testing necessary for a career in science.

项目摘要 癫痫（SUDEP）突然意外死亡是癫痫患者过早死亡的主要原因 谁没有令人满意的癫痫发作控制。 SUDEP导致潜在的生命比其他任何人都多 神经系统状况，但中风除外。没有已知的方法可靠地防止Sudep。 收敛的证据线表明呼吸障碍是SUDEP的关键组成部分 病理生理学。在SUDEP中看到了几种潜在的机械解释。 （1）5-羟色胺信号对于稳定的呼吸很重要，而血清素能的音调可能是保护性的 反对癫痫发作引起的呼吸停滞。不幸的是，癫痫发作破坏了血清素能神经传递。 关于导致癫痫发作诱导的血清素能破坏的机制的知识差距存在差距 神经传递。 （2）癫痫发作还会导致整个大脑的细胞外腺苷激增。增加 在腺苷水平中，抑制呼吸并抑制神经活性。腺苷信号过多 与SUDEP中看到的呼吸障碍有关；但是，腺苷影响的机制 癫痫发作后的呼吸是未知的。 （3）移动缓慢（2-5 mm/min）的扩散去极化波是 有时是由癫痫发作触发的。扩散去极化会瞬时失活。在一定程度上 扩散去极化的情况可以进入脑干，在该脑干中停止神经活动 心肺功能所必需的，并导致死亡。脑干扩散去极化是一种潜力 Sudep的原因。扩散去极化还会导致细胞外腺苷的增加。这是不知道的 由于扩散去极化而引起的腺苷的增加是否导致癫痫发作诱发的死亡。这 该建议的目标是整合血清素能，腺苷能和扩散的去极化解释 通过测试腺苷发生癫痫发作和 扩散去极化会破坏血清素能神经传递，从而增强呼吸衰竭。在 首先，在癫痫发作期间，腺苷信号传导将在5-羟色源性raphe核中增强，以确定是否是否确定是否是否 这改变了对CO2的呼吸反应性和呼吸衰竭的可能性。在第二个目标中 在腺苷信号传导的小鼠中，将诱导脑干扩散去极化 在raphe核中有药理学或遗传改变。提出的实验将产生引人注目的 在提供羟色胺和腺苷之间假设相互作用的证据时 在科学职业中所需的写作，指导和定量严格的假设检验培训。