Trust, but verify: A cautionary tale of translating chemogenetic methods (A commentray on Galvan et al).
Trust, but verify: A cautionary tale of translating chemogenetic methods (A commentray on Galvan et al).
复制标题
信任，但要验证：转化化学遗传学方法的警示故事（Galvan 等人的评论）。
DOI：
10.1111/ejn.14496
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Rudebeck,PeterH
中科院分区：
文献类型：
--
作者：
Fredericks,JMegan;Fujimoto,Atsushi;Rudebeck,PeterH
化学遗传学的出现使大脑研究发生了革命性的变化。离散和可逆控制神经活动的能力使神经科学家能够以20年前似乎不可想象的方式探索区域、回路和基因定义的神经元群的功能。在啮齿类动物中，这些技术揭示了对喂养、防御威胁反应、决策和视觉处理的令人眼花缭乱的见解，仅举几例（Sternson & Roth, 2014）。将化学遗传学完整而有力地翻译到非人类灵长类动物身上，同样具有革命性。这将增强基础科学研究，我们在非人类灵长类动物身上学到的东西可以更容易地转化为人类，化学遗传学可以为基因治疗提供“生物”神经调节替代方案（Axelsen & Woldbye, 2018）。化学发生方法通过病毒转导非内源性神经调节受体进入大脑，这些受体被惰性药物配体激活，从而改变神经活动（Sternson & Roth, 2014）。人们对非人类灵长类动物的化学遗传学有很大的关注，部分原因是大面积的组织（大约10平方毫米）可以被远程定位和操纵，这是光遗传学不可能做到的。最广泛使用的化学发生系统之一是由Brain Roth及其同事（Armbruster, Li, Pausch, Herlitze, & Roth, 2007）开发的突变胆碱能G蛋白偶联受体家族的设计药物（DREADDs）专门激活的设计受体。这些受体可以抑制、增加或促进神经活动的短暂爆发。尽管最近发现氯氮平-一氧化氮（CNO）激活DREADD的机制可能是通过酶促CNO转化为氯氮平
The advent of chemogenetics has revolutionized brain research. The ability to discretely and reversibly control neural activity has allowed neuroscientists to probe the function of areas, circuits, and genetically defined populations of neurons in ways that would have seemed unimaginable two decades ago. In rodents, these techniques have revealed dazzling insights into feeding, defensive threat responses, decision‐making, and visual processing to name just a few (Sternson & Roth, 2014). The full and robust translation of chemogenetics to non‐human primates would be no less revolutionary. It would augment basic science research and what we learn in non‐human primates can be more readily translated to humans where chemogenetics could provide “biological” neuromodulation alternatives to gene therapy (Axelsen & Woldbye, 2018).Chemogenetic methods alter neural activity by virally transducing non‐endogenous neuromodulatory receptors into the brain that are activated by an inert pharmacological ligand (Sternson & Roth, 2014). There has been a great deal of focus on chemogenetics in non‐human primates in part because large areas of tissue (> 10 mm2) can be targeted and manipulated remotely, something not possible with optogenetics. One of the most widely used chemogenetic systems is the designer receptors exclusively activated by designer drugs (DREADDs) family of mutated cholinergic G protein‐coupled receptors developed by Brain Roth and colleagues (Armbruster, Li, Pausch, Herlitze, & Roth, 2007). These receptors can either inhibit, increase, or promote short bursts of neural activity. The recent discovery that the mechanism of DREADD activation by clozapine‐N‐oxide (CNO) may be via enzymatic conversion of CNO to clozapine notwithstanding