NEUROSTEROIDS AND ANXIETY RELATED NETWORK FUNCTION

描述（由申请人提供）：我们提出，神经类固醇，GABAAR功能的内源性正调节剂，及其合成类似物，可能有望作为焦虑症的治疗。本研究旨在填补细胞水平的查询和体内效应之间的理解差距。这项工作的一个重要前提是，简单系统中的网络研究可以让我们深入了解临床上有前途的药物的相关作用，包括不容易从受体水平或细胞水平理解的药物作用方面。这个探索性建议的第二个前提是，由于解离培养中的自然WT网络自组织成网络拓扑结构，让人想起体内网络，因此疾病中网络功能障碍的关键方面也可能被重建。最近的研究支持了一个激进的观点，即与压力和焦虑相关的功能障碍可以在分离的文化网络中重演。我们的工作将研究扩展到这个潜在的重要领域。目的1将测试的假设，即细胞积累减少外源性神经类固醇对网络功能的影响，并占类固醇特异性反弹的神经元活动。这些研究使用多电极阵列记录，在探索药代动力学和药效学之间的灰色地带方面是独一无二的，这是药物对网络影响的重要贡献者。目的2将探讨GABAA受体γ 2亚基缺陷模型中网络动力学的性质。将评估神经类固醇纠正网络动力学的能力。这些研究将有助于深入了解由被认为是焦虑症基础的受体变化引起的网络动态变化。这些研究还将提供关于治疗药物效果的新信息，这些信息从以前的分析水平中不容易辨别。

DESCRIPTION (provided by applicant): We propose that neurosteroids, endogenous positive modulators of GABAAR function, and their synthetic analogues, may hold promise as treatments for anxiety disorders. The present study is designed to fill gaps in understanding between cellular-level inquiry and in vivo effects. An important premise of this work is that network studies in simple systems can give us insight into the relevant effects of clinically promising drugs, including aspects of drug actions not easily derived from a receptor-level or cellular-level understanding. A secondary premise of this exploratory proposal is that because natural WT networks in dissociated culture are self-organizing into network topologies reminiscent of in vivo networks, key aspects of network dysfunction in disease may also be reconstituted. Recent work supports the radical idea that dysfunction associated with stress and anxiety can be recapitulated in dissociated culture networks. Our work extends research into this potentially important area. Aim 1 will test the hypothesis that cellular accumulation reduces the effect of exogenous neurosteroids on network function and accounts for steroid-specific rebound of neuronal activity. These studies use multi-electrode array recordings and are unique in probing the gray area between pharmacokinetics and pharmacodynamics as an important contributor to drug effects on networks. Aim 2 will explore the nature of network dynamics in models deficient in the GABAA receptor gamma2 subunit. The ability of neurosteroids to correct network dynamics will be assessed. These studies will lend insight into changes in network dynamics induced by receptor changes believed to underlie anxiety disorder. The studies will also provide new information on the effect of therapeutic drugs not easily discernible from previous levels of analysis.