Ratner Marcia H, Farb David H
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States.
Center for Systems Neuroscience, Boston University, Boston, MA, United States.
Front Toxicol. 2022 Apr 25;4:836427. doi: 10.3389/ftox.2022.836427. eCollection 2022.
Adverse effects of drugs on the human nervous system are rarely possible to anticipate based on preclinical neurotoxicity data, thus propagating the centuries long single most important obstacle to drug discovery and development for disorders of the nervous system. An emerging body of evidence indicates that electrophysiology using chronically implanted high-density electrodes (ciHDE) in freely moving animals is a rigorous method with enhanced potential for use in translational research. In particular, the structure and function of the hippocampal trisynaptic circuit (HTC) is conserved from rodents to primates, including , suggesting that the effects of therapeutic agents and other potential neurologically active agents, whether beneficial or adverse, are likely to translate across species when interrogated using a conserved neural circuitry platform. This review explores science advances in the rapidly moving field of ciHDE in animal models of learning and memory. For this reason we focus on the HTC, where substantial research has investigated neural circuitry level responses and specific behaviors that reflect memory permitting a test of the ground truth validity of the findings. Examples of changes in neural network activity induced by endogenous neurotoxicants associated with neurodegenerative diseases, as well as exogenous therapeutics, drugs, and neurotoxicants are presented. Several illustrative examples of relevant findings that involve longer range neural circuitry outside of the HTC are discussed. Lastly, the limitations of ciHDE as applied to preclinical neurotoxicology are discussed with a view toward leveraging circuitry level actions to enhance our ability to project the specificity of target engagement with the desired psychopharmacological or neurological outcome. At the same time, the goal of reducing or eliminating significant neurotoxic adverse events in human is the desired endpoint. We believe that this approach will lead to enhanced discovery of high value neuroactive therapeutics that target neural circuitry domains as their primary mechanism of action, thus enhancing their ultimate contribution toward discovery of precision therapeutics.
基于临床前神经毒性数据，很难预测药物对人类神经系统的不良反应，因此这延续了几个世纪以来药物研发针对神经系统疾病所面临的最重要的单一障碍。越来越多的证据表明，在自由活动的动物中使用慢性植入式高密度电极（ciHDE）进行电生理研究是一种严谨的方法，在转化研究中具有更大的应用潜力。特别是，海马三突触回路（HTC）的结构和功能从啮齿动物到灵长类动物都是保守的，这表明当使用保守的神经回路平台进行研究时，治疗药物和其他潜在的神经活性药物的作用，无论是有益的还是有害的，都可能在不同物种间得到转化。本综述探讨了在学习和记忆动物模型中ciHDE这一快速发展领域的科学进展。因此，我们聚焦于HTC，在那里大量研究调查了反映记忆的神经回路水平反应和特定行为，从而可以检验研究结果的基本真实性。文中展示了与神经退行性疾病相关的内源性神经毒素以及外源性治疗药物、毒品和神经毒素所诱导的神经网络活动变化的实例。还讨论了一些涉及HTC以外更长范围神经回路的相关研究结果的实例。最后，探讨了ciHDE应用于临床前神经毒理学的局限性，旨在利用回路水平的作用来提高我们预测靶点参与与预期心理药理学或神经学结果特异性的能力。同时，减少或消除人类中重大神经毒性不良事件是期望的终点。我们相信，这种方法将有助于加强对以神经回路域为主要作用机制的高价值神经活性治疗药物的发现，从而增强它们对精准治疗药物发现的最终贡献。
