Pericyte function in anesthetic-induced vasodilation and developmental neurotoxicity

麻醉诱导的血管舒张和发育神经毒性中的周细胞功能

基本信息

批准号：
10811278
负责人：
Ansgar M Brambrink
金额：
$ 45.24万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10811278
关键词：
Adolescent Adult Age Anesthesia procedures Anesthetics Animal Model Apoptosis Blood Vessels Blood flow Brain Cell Death Cells Cephalic Cerebral cortex Cerebrovascular Circulation Cerebrovascular system Cerebrum Child Chronic Collaborations Data Diameter Exposure to General Anesthesia Image Immunohistochemistry Impaired cognition Infant Inhalation Anesthetics Knowledge Mediating Metabolic Monitor Mus Neocortex Nutrient Oxygen Perfusion Pericytes Pharmaceutical Preparations Play Pre-Clinical Model Process Relaxation Research Role Sedation procedure Techniques Testing Time Vasodilation Volatilization age related arteriole awake behavioral impairment brain cell cell type cerebral microvasculature developmental neurotoxicity improved in vivo in vivo calcium imaging in vivo imaging in vivo two-photon imaging innovation innovative technologies insight neocortical neuroprotection novel optogenetics pediatric patients preservation response young adult

Adolescent Adult Age Anesthesia procedures Anesthetics Animal Model Apoptosis Blood Vessels Blood flow Brain Cell Death Cells Cephalic Cerebral cortex Cerebrovascular Circulation Cerebrovascular system Cerebrum Child Chronic Collaborations Data Diameter Exposure to General Anesthesia Image Immunohistochemistry Impaired cognition Infant Inhalation Anesthetics Knowledge Mediating Metabolic Monitor Mus Neocortex Nutrient Oxygen Perfusion Pericytes Pharmaceutical Preparations Play Pre-Clinical Model Process Relaxation Research Role Sedation procedure Techniques Testing Time Vasodilation Volatilization age related arteriole awake behavioral impairment brain cell cell type cerebral microvasculature developmental neurotoxicity improved in vivo in vivo calcium imaging in vivo imaging in vivo two-photon imaging innovation innovative technologies insight neocortical neuroprotection novel optogenetics pediatric patients preservation response young adult

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项目摘要

Project Summary Mounting evidence suggests that repeated exposure to anesthetic drugs at a very young age causes widespread brain cell apoptosis and long-lasting behavioral and cognitive impairments. The mechanisms underlying this anesthesia-induced developmental neurotoxicity remain unclear. It is well known that the brain has an exceptionally high energy demand, and its function is rapidly disrupted in the absence of blood flow. The adult brain can maintain adequate perfusion during general anesthesia by altering vessel diameter through vascular mural cells, such as pericytes. However, this mechanism may not be fully developed in the immature brain. In support, our preliminary data suggest that cerebral arterioles dilate in response to inhaled anesthetics, with the magnitude of dilation pronounced in adult brains but insignificant in the brains of infant mice, using in vivo imaging of cerebral vasculature through a cranial window. Moreover, we have found that vascular pericytes are two-fold less abundant in infant than adult brains. Based on these findings, we hypothesize that the lack of contractile pericytes and vasodilatory responses to anesthesia in the infant brain causes a deficiency in cerebral blood flow, which may lead to a critical metabolic shortage of oxygen and nutrient supply that ultimately causes brain cell death when lasting for a prolonged duration. In this application, we will test this hypothesis by combining in vivo two-photon imaging of cerebral vessel diameter, flow velocity, and pericyte activity, region/cell-type-specific optogenetic modulation, and immunohistochemical analysis of cell apoptosis. Specifically, in Aim 1, we will characterize volatile anesthetic-evoked vasodilation in the cerebral cortex of infant, juvenile, and young adult mice. We will test the hypothesis that the vasodilatory response to inhaled anesthetics is age-dependent and inadequate vasodilation in the developing brain contributes to anesthesia-induced extensive cell apoptosis. In Aim 2, we will investigate the roles of neocortical pericytes in age-related vasodilatory responses to volatile anesthetics by combining in vivo calcium imaging with optogenetic modulation. Together, our proposed research will identify the deficiency of pericyte-mediated vasodilation as a novel mechanism of anesthesia-induced developmental neurotoxicity and suggest that targeting pericyte function to preserve cerebral blood flow may confer neuroprotection in infants undergoing general anesthesia.

项目摘要越来越多的证据表明，在很小的时候反复暴露于麻醉药会导致广泛脑细胞凋亡以及持久的行为和认知障碍。这是基础的机制麻醉引起的发育神经毒性尚不清楚。众所周知，大脑有一个在没有血流的情况下，能量需求异常高，其功能迅速中断。成人大脑可以通过血管改变血管直径在全身麻醉期间保持足够的灌注壁细胞，例如周细胞。但是，这种机制可能无法在未成熟的大脑中充分发展。在支持，我们的初步数据表明，脑小动物会随着吸入麻醉的响应而扩张，并与在成年大脑中发音的扩张幅度，但使用体内成像在婴儿小鼠的大脑中微不足道脑血管通过颅窗。此外，我们发现血管周细胞是两倍婴儿比成人大脑少。基于这些发现，我们假设缺乏收缩对婴儿大脑麻醉的周细胞和血管舒张反应会导致脑血流不足，这可能导致氧气和养分供应的严重代谢短缺，最终导致脑细胞长时间持续时间死亡。在此应用中，我们将通过在体内结合来检验该假设大脑容器直径，流速和周细胞活性的两光子成像，区域/细胞类型特异性光遗传学调节和细胞凋亡的免疫组织化学分析。具体来说，在AIM 1中，我们将表征婴儿，少年和年轻人的大脑皮层中挥发性麻醉的诱发血管舒张老鼠。我们将检验以下假设：吸入麻醉的血管舒张反应是年龄依赖性的，并且发育中的大脑血管舒张不足会导致麻醉引起的广泛细胞凋亡。在 AIM 2，我们将研究新皮质周细胞在与年龄相关的血管舒张反应中的作用通过将体内钙成像与光遗传学调节相结合，麻醉药。一起，我们提出的研究将确定周细胞介导的血管舒张的缺乏是麻醉诱导的一种新机制发育性神经毒性，建议靶向周围的功能保存脑血流在接受全身麻醉的婴儿中提供神经保护作用。