Brainstem Arousal Network in Human Consciousness: Healthy development vs SIDS

人类意识中的脑干唤醒网络：健康发展与 SIDS

• 批准号: 10209378
• 负责人: Lilla Zollei
• 金额: $ 72.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209378
• 关键词: 1 year old; 3-Dimensional; Adult; Age; Age-Months; Anatomy; Arousal; Asphyxia; Autopsy; Awareness; Axon; Beds; Birth; Brain; Brain Stem; Cardiovascular system; Cause of Death; Cell Density; Cell Nucleus; Cells; Cessation of life; Complex; Conscious; Cytology; Defect; Deformity; Developed Countries; Development; Diffusion; Early Intervention; Elements; Environmental Risk Factor; Failure; Fiber; Foundations; Future; Graph; Growth; Homeostasis; Human; Hypercapnia; Hypotension; Hypothalamic structure; Hypoxia; Image; Infant; Intervention; Investigation; Laboratories; Lesion; Life; Link; Location; Magnetic Resonance Imaging; Maintenance; Maps; Measures; Mediating; Microscopic; Microscopy; Neuroanatomy; Neurons; Optical Coherence Tomography; Optics; Pathogenesis; Pathway interactions; Pattern; Positioning Attribute; Prevention strategy; Process; Resolution; Reticular Formation; Risk; Serotonin; Site; Sleep; Source; Structure; Structure of nucleus infundibularis hypothalami; Sudden infant death syndrome; Surface; Techniques; Testing; Time; Tissues; United States; Work; algorithm development; basal forebrain; brain research; critical developmental period; density; heavy nuclei; human disease; immunocytochemistry; in vivo; mind control; multidisciplinary; neural network; neuroimaging; neuropathology; novel; postneonatal mortality; relating to nervous system; respiratory; response; restoration; sleep position; statistics; stressor; tool; tractography; ultra high resolution

Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality in industrialized nations today. Typically it occurs during a sleep period – unwitnessed, it is presumed to occur during sleep itself, or during one of the many transitions between sleep and waking that occur during normal infant sleep. A leading hypothesis today is the arousal deficit hypothesis: SIDS, or a subset of SIDS, is due to a failure in the ascending arousal network (AAN) to a life-threatening stressor during sleep in a critical developmental period. Arousal is considered an essential element of consciousness, as well as essential for restoration of homeostasis during respiratory and cardiovascular challenges by providing excitatory drive to vital processes from sleep. The AAN is interconnected with cortical and subcortical networks that regulate the integration of homeostatic responses, comprised of connectivity with brainstem and limbic nodes. Our laboratory has provided evidence over the last two decades that serotonin (5-HT) defects are concentrated mainly in a cytologically defined region of the rostral medullary reticular formation in the AAN of the brainstem which we call the putative "core lesions of SIDS" (CLS). In this R01 application, we propose to test the two-fold hypothesis that the core nuclei in the CLS have fiber interconnections with each other and with one or more known nuclei of the AAN within and above the brainstem, thereby demonstrating they are anatomically part of the AAN; and that there are structural anatomic abnormalities in the serotonergic CLS in the SIDS cases compared to the age-matched autopsy controls. We will perform ex vivo MRI with diffusion tractography and optical coherence tomography at unprecedented spatial resolution along with 5-HT immunocytochemistry in postmortem infant brains from birth to the end of the first year of life, the period of risk for SIDS. This work is expected to have a significant positive impact. By establishing the putative core CLS as an integral part of the AAN involving medullary 5-HT neurons, it will provide the foundation for targeted future brain research in SIDS, bringing us closer to the ultimate cause(s) of SIDS and specific preventive strategies.

婴儿猝死综合征(SIDS)是工业化国家新生儿后死亡的主要原因 今天的国家。通常情况下，它发生在睡眠期间--没有目击，它被推定为发生在睡眠期间 或者在正常婴儿睡眠期间发生的许多睡眠和清醒转换中的一种。一个 今天的主要假说是唤醒缺陷假说：小岛屿发展中国家，或小岛屿发展中国家的子集，是由于 在关键发育时期的睡眠中，提升唤醒网络(AAN)成为威胁生命的压力源。 觉醒被认为是意识的基本要素，也是恢复 通过为生命过程提供兴奋性驱动，实现呼吸和心血管挑战期间的动态平衡 从睡梦中醒来。AAN与大脑皮层和皮质下网络相互连接，调节 动态平衡反应，包括与脑干和边缘结节的连接。我们的实验室有 在过去的二十年里提供了证据表明5-羟色胺(5-羟色胺)缺陷主要集中在 脑干顶端延髓网状结构的细胞学定义区 我们将其称为“小岛屿发展中国家核心病变”(CLS)。在这个R01应用程序中，我们建议测试两个 假设CLS中的核心核彼此有纤维互连，并与一个或多个 AAN在脑干内和脑干上方的已知核团，从而证明它们在解剖学上是 AAN；小儿麻痹症5-羟色胺能CLS存在结构解剖异常 与年龄匹配的尸检对照组相比。我们将在体外进行磁共振弥散成像和 以前所未有的空间分辨率进行光学相干断层扫描和5-羟色胺免疫细胞化学 婴儿死后大脑从出生到生命的第一年结束，是小岛屿发展中国家的风险期。这项工作是 预计将产生重大的积极影响。通过建立假定的核心CLS作为 AAN涉及延髓5-羟色胺神经元，它将为小岛屿发展中国家未来的有针对性的脑研究提供基础， 使我们更接近小岛屿发展中国家的根本原因(S)和具体的预防策略。