Measuring in Vivo Meth-induced Neurovascular Changes Using Quantitative MRI

描述（由申请人提供）：估计全世界有2600万人滥用甲基苯丙胺（冰毒）。这种高滥用率和随之而来的健康和社会后果需要明确的需要了解长期的神经和血管适应所造成的慢性冰毒，有助于成瘾和复发。接触甲基苯丙胺会干扰神经元和血管的功能，而这些功能是建立相互连接的网络的连接和布线所必需的。血管-神经耦合的组成部分，血脑屏障（BBB），对炎症机制特别敏感，并且BBB健康反映了神经血管串扰的总体健康。急性暴露于高剂量的甲基会导致神经炎症和随后的BBB通透性增加。然而，慢性甲基诱导的神经炎症对神经血管健康的长期后果是甲基成瘾的一个未充分研究的领域。值得注意的是，这些问题还没有得到解决，使用临床相关的啮齿动物模型的冰毒成瘾。我们的中心假设是，慢性自我管理的冰毒导致持久的神经炎症，损害BBB的神经血管耦合。为了验证这一假设，我们将使用最先进的基于磁共振的神经成像技术来确定长期自我给药后炎症的进展。这些炎症反应可能是甲基诱导的神经血管单位损伤和随后的BBB破坏的早期指标。我们将通过测量白色物质完整性和BBB转移率来测量甲基苯丙胺诱导的神经元和血管完整性变化的时间过程，以绘制进行性组织损伤。仅依靠组织学结果无法进行这些评估。因此，终点结果将与内皮和炎症标志物的组织学结局相关。成像实验的目的是获得有关的空间和时间模式的损害神经血管单位提供有价值的信息，对甲基诱导的适应的进展。此外，这项研究将为冰毒成瘾的诊断和治疗计划提供新的信息。

DESCRIPTION (provided by applicant): An estimated 26 million people abuse methamphetamine (meth) worldwide. This high prevalence of abuse and the ensuing health and societal consequences necessitates a clear need to understand the long-term neural and vascular adaptations caused by chronic meth that contribute to addiction and relapse. Meth exposure interferes with the neuronal and vascular function required to establish connectivity and wiring of interconnected networks. An integral part of vascular-neural coupling, the blood brain barrier (BBB), is particularly sensitive to inflammatory mechanisms and BBB health reflects the general health of neurovascular crosstalk. Acute exposure to high doses of meth results in neuroinflammation and subsequent increases in BBB permeability. However, the long-term consequence of chronic meth-induced neuroinflammation on neurovascular health is an understudied area of meth addiction. Notably, these issues have not been addressed using a clinically relevant rodent model of meth addiction. Our central hypothesis is that chronic self-administered meth results in lasting neuroinflammation that compromises neural-vascular coupling of the BBB. To test this hypothesis, we will use cutting edge magnetic resonance based neuroimaging techniques to identify the progression of inflammation following prolonged meth self-administration. These inflammatory responses may be early indicators for meth-induced damage to neurovascular units and subsequent break down of the BBB. We will measure the time course of meth-induced changes in neuronal and vascular integrity during abstinence from meth by measuring white matter integrity and BBB transfer rate to map progressive tissue damage. These assessments are not possible by relying solely on histological outcomes. Therefore, the end point results will be correlated with histological outcomes on endothelial and inflammatory markers. The imaging experiment is designed to acquire information about spatial and temporal patterns of damage to neurovascular unit providing valuable information on the progression of meth-induced adaptations. Further, this study will provide novel information for diagnostic and treatment planning for meth addiction.