Novel SCN-OVLT portal system: Dissecting Anatomical and Functional Properties

新型 SCN-OVLT 门户系统：剖析解剖和功能特性

• 批准号: 10754088
• 负责人: Javier E Stern
• 金额: $ 45.36万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754088
• 关键词: Acute; Address; Anatomy; Anterior Pituitary Gland; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Cell Nucleus; Cephalic; Computer Assisted; Data; Distant; Equilibrium; Female; Gland; Hypothalamic structure; Image; Immunohistochemistry; Knowledge; Lamina Terminalis; Light; Mediating; Microscopy; Modality; Modeling; Mus; Names; Neurons; Operative Surgical Procedures; Osmosis; Output; Pathway interactions; Periodicity; Photic Stimulation; Physiological; Pituitary Gland; Play; Portal System; Posterior Pituitary Gland; Property; Rat Transgene; Rattus; Regulation; Research Personnel; Resolution; Retina; Role; Route; Signal Transduction; Sodium Chloride; Source; Stimulus; Structure; System; Techniques; Testing; Time; Travel; Vasopressins; Work; cell type; circadian; circadian pacemaker; designer receptors exclusively activated by designer drugs; genetic approach; in vivo; innovation; interdisciplinary approach; male; neural tract; novel; organum vasculosum of the lamina terminalis; pharmacologic; response; suprachiasmatic nucleus; two-photon

PROJECT SUMMARY The suprachiasmatic nucleus (SCN), the locus of the brain’s circadian clock, plays a critical role in mediating circadian rhythmicity of numerous important functions. A growing body of work supports that these actions are not only mediated via hard-wired efferent projections from the SCN, but also via diffusible signals. Still, the routes by which diffusible signals from the SCN act, and whether and how this signaling modality is regulated, remains to be determined. Almost 90 years after the discovery of thehypothalamic-pituitary portal system, considered the sole brain portal system in the brain, we identified a new portal system connecting the SCN and a cirumventricular organum, the organum vascullosum of the lamina terminalis (OVLT) in mouse. This novel portal system, named hereSCN-OVLTP, stands as a likely candidate vascular route by which small amounts of biologically significant secretions generated in the SCN could reach specialized local targets in the OVLT. Because the OVLT provides the portal system with direct access to the CSF, this system can orchestrate rhythms throughout the body. For this to be proven however, fundamental properties of the SCN-OVLTP, including directionality of blood flow and underlying regulatory mechanisms must be determined. To address this critical gap in our knowledge, we first asked whether the SCN-OVLTp pathway occurs in rats as we showed for mice. Using iDisco clearing and high resolution light sheet microcopy our exciting preliminary data indicates that the SCN-OVLTP is in fact present in the rat. The OVLT, like the SCN is a heterogeneous structure, and it will be critical to assess which OVLT compartments are target of signals carried in the portal pathway. Importantly, we developed a novel surgical/imaging experimental approach that enables, for the first time, the in vivo assessment of blood flow and its regulation in the SCN-OVLTp. We determined that blood flows unidirectionally from the SCN towards the OVLT and notably, it varies according to the day-night cycle. In addition, we show that systemic vasopressin (VP) can access and travel within this portal system. Collectively, these data lead us to propose the overarching novel hypothesis that the SCN-OVLTP is a functionally relevant route by which low amounts of signals generated within the SCN can act in a diffusible manner to efficiently regulate distant targets via de CSF The proposed work will delineate (1) where the portal vessels originate within the SCN, and the targets reached by SCN-OVLTp within this CVO and its fenestrated blood veesels, and thence to the CSF; and (2) whether blood flow within the SCN-OVLTP is regulated in an activity-dependent manner, by photic stimulation and/or by systemic homeostatic challenges. Using a multidisciplinary approach and state-of-the-art techniques in Aim 1 we will characterize the SCN-OVLTP in the rat to determine the origin of the portal vessels within the SCN and their targets in the OVLT. In Aim 2, we will define whether blood flow directionality and velocity within SCN- OVLTP is amenable to regulation. We expect results from this work to contribute to a better understanding of fundamental mechanisms by which the SCN orchestrates circadian rhythmicity throughout the body. 1

项目概要 视交叉上核 (SCN) 是大脑生物钟的所在地，在调节生物钟方面发挥着关键作用 越来越多的研究表明，这些行为具有昼夜节律性。 不仅通过来自 SCN 的硬连线传出投射进行调节，而且还通过可扩散信号进行调节。 SCN 的扩散信号通过何种方式发挥作用，以及这种信号传导方式是否以及如何受到调节，仍然是 下丘脑-垂体门脉系统发现近 90 年后才确定。 大脑中唯一的大脑门户系统，我们确定了一个新的门户系统，连接 SCN 和 脑室器，即小鼠终板血管器（OVLT）​​。 门静脉系统，此处命名为 SCN-OVLTP，是一种可能的候选血管途径，少量的 SCN 中产生的具有生物学意义的分泌物可以到达 OVLT 中的特定局部目标。 由于 OVLT 为门户系统提供了直接访问 CSF 的机会，因此该系统可以协调节奏 然而，为了证明这一点，SCN-OVLTP 的基本特性包括： 为了解决这个关键问题，必须确定血流的方向性和潜在的调节机制。 由于我们的知识差距，我们首先询问 SCN-OVLTp 通路是否像我们在小鼠中显示的那样发生在大鼠中。 使用 iDisco 清除和高分辨率光片显微复制，我们令人兴奋的初步数据表明 SCN-OVLTP 实际上存在于大鼠体内，就像 SCN 一样，它也是一种异质结构。 评估哪些 OVLT 区室是门脉通路中信号的目标至关重要。 开发了一种新颖的手术/成像实验方法，首次实现了体内评估 我们确定 SCN-OVLTp 中的血流是单向流动的。 OVLT，值得注意的是，它根据昼夜周期而变化。此外，我们表明系统性的。 加压素 (VP) 可以访问该门户系统并在该系统内移动，这些数据促使我们提出以下建议。 总体新颖的假设，即 SCN-OVLTP 是一种功能相关的途径，通过该途径，少量的 SCN 内产生的信号可以以扩散的方式起作用，通过 de CSF 有效调节远处的目标 拟议的工作将描述 (1) 门脉血管在 SCN 内的起源以及达到的目标 通过该 CVO 及其有孔血管内的 SCN-OVLTp，并从那里到达 CSF；以及 (2) 是否有血液； SCN-OVLTP 内的流动以活性依赖性方式通过光刺激和/或 在目标 1 中使用多学科方法和最先进的技术。 我们将表征大鼠的 SCN-OVLTP 以确定 SCN 内门脉血管的起源， 在目标 2 中，我们将定义 SCN 内的血流方向和速度。 OVLTP 服从监管。我们期望这项工作的结果有助于更好地理解。 SCN 协调整个身体昼夜节律的基本机制。 1