Ultrahigh-resolution optical tomography of cocaine-induced neurovascular toxicity

描述（由申请人提供）：越来越多的临床证据表明，许多滥用药物（包括可卡因）具有血管活性作用，可能导致脑血管病理和脑血流（CBF）功能障碍，如动脉瘤样出血、出血性和缺血性中风。可卡因神经血管毒性的潜在机制仍然不明确，因此，由于难以评估可卡因血管活性作用的性质和严重程度，有效治疗可能受到阻碍。这一关键的知识差距部分是由于目前用于研究动物模型中可卡因诱导的血管效应的神经成像技术的局限性（即缺乏高时空分辨率或成像毛细血管脑血流网络的足够视野）。在这项R21 CEBRA资助中，我们建议通过开发一种基于超分辨率光学相干多普勒断层扫描的新型神经成像技术来弥补这一差距，该技术能够对毛细血管脑血流网络进行定量3D成像，并允许人们评估体内的实时功能变化。我们的初步动物研究结果表明，该成像技术能够准确检测激光诱导的微血管破裂和随之而来的CBF中断，以及量化高碳酸血症时3D CBF网络变化（包括毛细血管CBF），所有这些都为拟议的技术开发和动物验证研究奠定了坚实的基础。我们在此应用中的新策略是结合超高分辨率3D光学血管造影和多普勒断层扫描来研究可卡因诱导的神经血管病理（微出血）和血流动力学功能障碍（包括毛细血管血流变化）。提出了以下具体目标：(1)开发和优化超分辨率激光多普勒断层扫描技术，以实现毛细血管血流网络的体内定量3D成像；(2)通过建立的强迫性可卡因使用大鼠模型，验证这种新技术用于可卡因诱导的神经血管毒性的实时成像评估。这项新技术的成功开发和验证将允许在高空间和时间分辨率（<35m, ~30s）下对毛细血管血流网络及其对可卡因的实时反应进行无标记、定量3D成像，这将允许在体内评估可卡因对微血管的潜在毒性作用和伴随的微循环损伤，这是其他技术无法检测到的。这种技术，除了为可卡因的脑血管毒性机制提供新的见解外，还将对评估药物以帮助从可卡因的脑血管毒性和其他脑血管疾病中恢复有价值。

DESCRIPTION (provided by applicant): Accumulating clinical evidence shows that many of the drugs of abuse (including cocaine) have vasoactive effects that may result in cerebrovascular pathology and cerebral blood flow (CBF) dysfunction such as aneurysm-like bleeds, hemorrhagic and ischemic strokes. The mechanisms underlying cocaine's neurovascular toxicity remain ambiguous, and as a result effective treatment may be hindered by difficulties in assessing the nature and severity of vasoactive effects of cocaine. This key knowledge gap is due in part to the limitations of current neuroimaging techniques (i.e., lack of either high spatiotemporal resolution or sufficient field of view for imaging capillary CBF networks) used to investigate cocaine-induced vascular effects in animal models. In this R21 CEBRA grant, we propose to bridge the gap by developing a novel neuroimaging technique based on ultrahigh-resolution optical coherence Doppler tomography, which enables quantitative 3D imaging of capillary CBF networks and allows one to assess real-time functional changes in vivo. Results from our preliminary animal studies have shown the capabilities of this imaging technique to accurately detect laser-induced micro-vessel rupture and the consequent CBF disruption, as well as to quantify 3D CBF network changes (including capillary CBF) in response to hypercapnia, all of which have laid a solid foundation for the proposed technological development and animal validation study. Our new strategy in this application is to combine ultrahigh-resolution 3D optical angiography and Doppler tomography to investigate cocaine- induced neurovascular pathology (micro hemorrhage) and hemodynamic dysfunction (including capillary CBF changes). The following Specific Aims are proposed: (1) develop and optimize ultrahigh-resolution laser Doppler tomography to enable in vivo quantitative 3D imaging of capillary CBF networks, (2) validate this new technique for real-time imaging assessment of cocaine-induced neurovascular toxicity using a well-established rat model of compulsive cocaine use. Successful development and validation of this new technique will permit label-free, quantitative 3D imaging of capillary CBF networks and their real-time responses to cocaine at high spatial and temporal resolution (<35m, ~30s), which will permit an in vivo assessment of potential toxic effects of cocaine to micro vessels and concomitant impairment to the microcirculation that would be undetected by other technologies. Such a technology, in addition to providing new insights into the mechanisms underlying cocaine's cerebrovascular toxicity, will also be valuable to evaluate medications to help recover from cerebrovascular toxicity of cocaine and other cerebrovascular pathologies.