Interactions of the Noradrenergic and Serotonergic Systems in Autoresuscitation

去甲肾上腺素能系统和血清素能系统在自动复苏中的相互作用

• 批准号: 10537397
• 负责人: Savannah J Lusk
• 金额: $ 7.23万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-09-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537397
• 关键词: Anoxia; Autopsy; Biological Assay; Brain Stem; Breathing; Cause of Death; Cells; Cessation of life; Clozapine; Data; Development; Diagnostic; Disease; Educational workshop; Electrolytes; Environment; Equipment; Failure; Foundations; Functional disorder; Future; Genetic; Health; Homeostasis; Immunohistochemistry; Infant; Investigation; Joints; Knowledge; Lesion; Life; Link; Medical History; Methodology; Methods; Mus; Outcome; Oxides; Pharmacology; Phenotype; Population; Reflex action; Regulation; Research; Resolution; Respiration Disorders; Respiratory Center; Respiratory System; Resuscitation; Role; Serotonergic System; Serotonin; Solid; Stains; Sudden infant death syndrome; Symptoms; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxin; Training; United States; Work; combinatorial; congenital respiratory disorder; course development; disease diagnosis; genetic manipulation; infant death; loss of function; mortality; neonate; neural network; neuroregulation; noradrenergic; novel; protective effect; recombinase; respiratory; respiratory challenge; respiratory reflex; response; tool

Project Summary/ Abstract The noradrenergic (NA) and serotonergic (5-HT) networks of the brainstem are highly regulated and necessary components of the respiratory homeostatic network. Dysfunction of these systems has been linked to many congenital respiratory disorders including Sudden Infant Death Syndrome (SIDS). SIDS is a leading cause of neonate death and is thought to occur, in part, by the failure of the neonate autoresuscitation reflex. Previous data have informed our understanding of how these systems modulate protective respiratory responses to life threatening challenges independently, but limited information is available on the potential interplay between these two key systems while previous studies lack a more finessed manipulation provided by our methodology. In the following aims, I will test the hypothesis that the 5-HT and NA systems are integrally linked in regulating the autoresuscitation reflex and that different combinations of 5-HT and NA perturbation and stimulation will result in additive positive and negative outcomes in autoresuscitation. Aim 1. Determine the separate and combined functional and cellular effects of serotonergic activation and noradrenergic inhibition on the autoresuscitation reflex and respiratory network dynamics in response to hypercapnic anoxia. Aim 2. Determine the effect of serotonergic inhibition and noradrenergic activation on the autoresuscitation reflex. Aim 3. Determine the effect of serotonergic inhibition and noradrenergic inhibition or serotonergic activation and noradrenergic activation on the autoresuscitation reflex. To test these aims, I will utilize compounded recombinase and effector lines to access and manipulate the activity of the 5-HT and NA systems. For example, the Pet1::Cre; F_hM4D line bred to a DBH_FLPo; P_hM3D line will produce mice that, upon clozapine-N-oxide (CNO) application, will concurrently excite the 5-HT system (Pet1::Cre + P_hM3D) while inhibiting the NA system (DBH_FLPo + F_hM4D). For functional characterizations, the mice will be challenged with repeated bouts of hypercapnic anoxia to test their autoresuscitation reflex. For network activity characterization, cFos staining will be carried out on brainstem tissue in mice that have been challenged with sublethal hypercapnic anoxic exposures after excitation or inhibition of the 5-HT or NA systems. Understanding if these systems are independently regulating autoresuscitation will provide valuable information for future therapeutic investigations. This study will progress the field by expanding our understanding of interplay between the 5-HT and NA systems in health and disease as well as informing on the use of intricate genetic manipulations in the study of these two key respiratory systems. This work will significantly advance our understanding of the neural networks involved in respiratory regulation and disease. The training plan and environment that accompany this proposal will provide a solid foundation for a transition to research independence. Training includes scientific and professional development courses, workshops, and seminars while the environment includes cutting edge technology and equipment with training offered in house at BCM.

项目摘要/摘要 脑干的去甲肾上腺素能（NA）和血清素能（5-HT）网络受到高度调节和必要的 呼吸稳态网络的组成部分。这些系统的功能障碍已与许多 先天性呼吸系统疾病，包括猝死综合症（SIDS）。 SIDS是主要原因 新生儿死亡，被认为部分是由于新生儿自动震动反射的失败而发生的。以前的 数据已经了解了我们对这些系统如何调节对生活的保护性呼吸反应的理解 独立威胁挑战，但有关潜在相互作用的信息有限 这两个关键系统虽然先前的研究缺乏我们的方法论提供的更精细的操纵。 在以下目的中，我将检验以下假设：5-HT和NA系统在调节中始终链接 自动引起反射以及5-HT和Na扰动和刺激的不同组合将 导致自动震荡的添加阳性和负结果。目标1。确定单独的 血清素能激活和去甲肾上腺素能抑制对综合功能和细胞的效应对 响应高碳水化合物的反射反射和呼吸网络动力学。目标2。确定 血清素能抑制和去甲肾上腺素激活对自身引起反射的影响。目标3。 确定血清素能抑制作用和去甲肾上腺素能抑制或血清素能激活以及 自动引起反射的去肾上腺素能激活。为了测试这些目标，我将利用复合 重组酶和效应线，以访问和操纵5-HT和NA系统的活性。例如， Pet1 :: Cre; f_hm4d线繁殖到dbh_flpo； P_HM3D线将产生氯氮平-N-氧化物的鼠标 （CNO）应用，同时激发5-HT系统（PET1 :: CRE + P_HM3D），同时抑制NA系统 （dbh_flpo + f_hm4d）。对于功能性特征，将挑战小鼠的反复回合 高含量缺氧，以测试其自动震动反射。对于网络活动表征，CFOS染色将 在脑干组织上进行的小鼠，这些小鼠受到挑战的挑战 激发或抑制5-HT或NA系统后暴露。了解这些系统是否是 独立调节自动示威将为未来的治疗调查提供有价值的信息。 这项研究将通过扩展我们对5-HT和NA系统之间相互作用的理解来进步该领域 在健康和疾病方面，并在这两个研究中通知使用复杂的遗传操作 关键呼吸系统。这项工作将大大提高我们对所涉及的神经网络的理解 在呼吸道调节和疾病中。该提议随附的培训计划和环境将 为过渡到研究独立性提供了坚实的基础。培训包括科学和专业 开发课程，研讨会和研讨会，而环境包括尖端技术和 在BCM提供的培训设备。