Measuring in Vivo Meth-induced Neurovascular Changes Using Quantitative MRI

描述（由申请人提供）：全世界估计有2600万人滥用甲基苯丙胺。这种滥用的高流行率以及随之而来的健康和社会后果，明确需要了解慢性冰毒导致成瘾和复发的长期神经和血管适应。甲基安非他明会干扰神经元和血管功能，而这些功能是建立互联网络的连接性和布线所必需的。血脑屏障（BBB）是血管-神经耦合的一个组成部分，对炎症机制特别敏感，血脑屏障的健康反映了神经血管串扰的总体健康状况。急性暴露于高剂量冰毒会导致神经炎症和随后的血脑屏障通透性增加。然而，慢性冰毒诱导的神经炎症对神经血管健康的长期影响是冰毒成瘾的一个未充分研究的领域。值得注意的是，这些问题还没有解决使用临床相关的冰毒成瘾啮齿动物模型。我们的中心假设是，慢性自我服用冰毒会导致持久的神经炎症，损害血脑屏障的神经血管耦合。为了验证这一假设，我们将使用尖端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苯丙胺诱导的神经血管单位损伤和随后血脑屏障分解的早期指标。我们将通过测量白质完整性和血脑屏障转移率来测量冰毒戒断期间冰毒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。这些评估不可能仅仅依靠组织学结果。因此，终点结果将与内皮和炎症标志物的组织学结果相关。成像实验旨在获得有关神经血管单元损伤的时空模式的信息，为冰毒诱导适应的进展提供有价值的信息。此外，本研究将为甲基苯丙胺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.