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

项目摘要 大脑昼夜钟的轨迹上的核（SCN）在介导中起着至关重要的作用 许多重要功能的昼夜节律。越来越多的工作支持这些行动是 不仅是通过SCN的硬连线有效项目介导的，而且还通过可扩散的信号进行了介导。仍然，路线 从SCN ACT中的可扩散信号以及该信号传导方式的调节方式以及如何保留 要确定。在发现下丘脑 - 垂体门户系统后将近90年， 大脑中唯一的大脑门户网站系统，我们确定了一个连接SCN和A的新门户系统 小鼠椎板末端（OVLT）​​的细胞腔细胞器。这本小说 名为HERESCN-OVLTP的门户系统是一条候选血管路线 SCN中产生的具有生物学意义的分泌物可以达到OVLT中的专门局部靶标。 因为OVLT为门户网站系统提供了直接访问CSF的访问，因此该系统可以协调节奏 整个身体。但是，要证明这一点，SCN-OVLTP的基本属性，包括 必须确定血流的方向性和潜在的调节机制。解决这个关键 根据我们的知识，我们首先询问SCN-OVLTP途径是否像小鼠所显示的大鼠发生在大鼠中。 使用IDISCO清算和高分辨率轻纸微拷贝我们令人兴奋的初步数据表明 实际上，scn-ovltp存在于大鼠中。 OVLT，就像SCN一样是一个异质结构，它将是 对于评估哪些OVLT隔室是门户途径中携带的信号的目标。重要的是，我们 开发了一种新型的外科/成像实验方法，该方法首次实现了体内评估 血流及其在SCN-OVLTP中的调节。我们确定血液从SCN上单向流动 朝向OVLT，值得注意的是，它根据昼夜周期而变化。此外，我们证明了系统 加压素（VP）可以在此门户系统中访问和旅行。总的来说，这些数据使我们提出了 总体新的假设SCN-OVLTP是一条与功能相关的途径 SCN中产生的信号可以以扩散的方式作用，以通过DE CSF有效调节遥远的目标 拟议的工作将描绘（1）门户船只起源于SCN，目标到达 通过SCN-OVLTP在此CVO及其散言的血液中，然后到CSF； （2）是否鲜血 SCN-OVLTP内部的流量是通过光刺激和/或通过活性依赖性方式调节的 系统性稳态挑战。使用AIM 1中的多学科方法和最先进的技术 我们将在大鼠中表征SCN-OVLTP，以确定SCN内的门户容器的起源 它们在OVLT中的目标。在AIM 2中，我们将定义SCN中的血流方向性和速度是否 OVLTP适合调节。我们希望这项工作的结果有助于更好地理解 SCN通过其在整个身体上精心策划的昼夜节律的基本机制。 1