Pericyte function in anesthetic-induced vasodilation and developmental neurotoxicity

项目摘要 越来越多的证据表明，在很小的时候反复接触麻醉药会导致广泛的 脑细胞凋亡和长期的行为和认知障碍。这背后的机制 麻醉引起的发育神经毒性仍不清楚。众所周知，大脑有一个 能量需求异常高，在没有血液流动的情况下，其功能会迅速中断。成年人 在全身麻醉期间，大脑可以通过改变血管直径来维持足够的血流灌注 壁细胞，如周细胞。然而，这种机制在不成熟的大脑中可能还没有完全发展起来。在……里面 支持，我们的初步数据表明，大脑小动脉对吸入麻醉剂的反应是扩张的， 活体成像显示，成年小鼠大脑明显扩张，而幼年小鼠脑内扩张不明显 通过颅窗观察脑血管系统。此外，我们还发现血管周细胞是双重的。 婴儿的大脑比成人的大脑要少。基于这些发现，我们假设收缩的缺乏 婴儿大脑对麻醉的周细胞和血管扩张反应导致脑血流不足， 这可能会导致氧气和营养供应的严重新陈代谢短缺，最终导致脑细胞 当持续时间较长时死亡。在这个应用中，我们将通过在体内结合来检验这一假说 脑血管直径、血流速度和周细胞活动的双光子成像，区域/细胞类型特异性 光遗传调控，细胞凋亡的免疫组织化学分析。具体来说，在目标1中，我们将 婴儿、青少年和青年大脑皮层中挥发性麻醉剂诱发的血管扩张的特征 老鼠。我们将测试对吸入麻醉剂的血管扩张反应是年龄相关的和 发育中的大脑血管扩张不足导致麻醉诱导广泛的细胞凋亡。在……里面 目的2，我们将研究新皮质周细胞在年龄相关的血管扩张反应中的作用。 体内钙成像与光遗传调制相结合的麻醉药。总之，我们提出的研究 将确认周细胞介导的血管扩张的缺陷是麻醉诱导的一种新机制 发育性神经毒性，提示靶向周细胞功能以保护脑血流可能 在接受全身麻醉的婴儿中提供神经保护。

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.