Noninvasive disruption of the blood-brain barrier in the marmoset monkey.
Noninvasive disruption of the blood-brain barrier in the marmoset monkey.
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DOI：
10.1038/s42003-023-05185-3
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发表时间：
2023-08-02
影响因子：
5.9
通讯作者：
Schaeffer, David J. J.
中科院分区：
文献类型：
--
作者：
Parks, T. Vincenza;Szuzupak, Diego;Choi, Sang-Ho;Alikaya, Aydin;Mou, Yongshan;Silva, Afonso C. C.;Schaeffer, David J. J.
普通绒猴（Callithrix jacchus）是一种在神经科学中日益突出的物种，由于其体型小，易于处理，繁殖快，以及与旧世界灵长类动物共享的功能和结构特征。随着越来越多的关注在绒猴中模拟人类脑疾病，了解如何将治疗剂或神经营养剂非侵入性地递送到绒猴脑中具有重要的临床前重要性。在包括人类在内的其他物种中，经颅聚焦超声（tFUS）在静脉注射微泡的辅助下已被证明是一种短暂、可靠和安全的方法，可破坏血脑屏障（BBB），使治疗药物能够局灶性通过，否则这些药物不会轻易穿过BBB的紧密内皮连接。我们在这里解决的关键差距是使用tFUS在绒猴中记录可靠和安全地破坏BBB的参数。通过整合我们的绒猴脑图谱和使用绒猴特异性立体定向靶向系统，我们在9只绒猴中进行了一系列系统的经颅超声实验。我们证明了中心频率，声压，爆破周期和持续时间的影响，建立一个最小的微泡剂量，估计微泡清除时间，并估计持续时间，血脑屏障保持开放通道。成功的血脑屏障破坏报告在体内与MRI为基础的造影剂，以及伊文思蓝染色离体评估。组织学（苏木精和伊红染色）和免疫组织化学表明，BBB可以安全可靠地打开这些实验中获得的参数。本文提出的一系列实验建立了在普通绒猴中使用tFUS安全地、可重复地和局灶性地扰乱BBB的方法，该方法可以作为治疗剂或神经营养剂的非侵入性递送的基础。MRI、组织学和免疫组织化学的组合用于建立参数以暂时且安全地破坏绒猴的血脑屏障。
The common marmoset monkey (Callithrix jacchus) is a species of rising prominence in the neurosciences due to its small size, ease of handling, fast breeding, and its shared functional and structural brain characteristics with Old World primates. With increasing attention on modeling human brain diseases in marmosets, understanding how to deliver therapeutic or neurotropic agents to the marmoset brain noninvasively is of great preclinical importance. In other species, including humans, transcranial focused ultrasound (tFUS) aided by intravenously injected microbubbles has proven to be a transient, reliable, and safe method for disrupting the blood-brain barrier (BBB), allowing the focal passage of therapeutic agents that do not otherwise readily traverse the tight endothelial junctions of the BBB. The critical gap that we address here is to document parameters to disrupt the BBB reliably and safely in marmosets using tFUS. By integrating our marmoset brain atlases and the use of a marmoset-specific stereotactic targeting system, we conduct a series of systematic transcranial sonication experiments in nine marmosets. We demonstrate the effects of center frequency, acoustic pressure, burst period, and duration, establish a minimum microbubble dose, estimate microbubble clearance time, and estimate the duration that the BBB remains open to passage. Successful BBB disruption is reported in vivo with MRI-based contrast agents, as well as Evans blue staining assessed ex vivo. Histology (Hematoxylin and Eosin staining) and immunohistochemistry indicate that the BBB can be safely and reliably opened with the parameters derived from these experiments. The series of experiments presented here establish methods for safely, reproducibly, and focally perturbing the BBB using tFUS in the common marmoset monkey that can serve as a basis for noninvasive delivery of therapeutic or neurotropic agents. A combination of MRI, histology, and immunohistochemistry is used to establish parameters to transiently and safely disrupt the blood-brain barrier in marmoset monkeys.
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