NEUROSTEROIDS AND ANXIETY RELATED NETWORK FUNCTION

描述(由申请人提供)：我们建议神经类固醇，GABAAR功能的内源性正向调节剂，及其合成类似物，可能作为焦虑症的治疗药物。本研究旨在填补细胞水平研究和体内效应之间的理解空白。这项工作的一个重要前提是，在简单系统中的网络研究可以让我们深入了解具有临床前景的药物的相关作用，包括不易从受体水平或细胞水平了解的药物作用的各个方面。这一探索性建议的第二个前提是，由于分离文化中的自然WT网络自组织成使人想起活体网络的网络拓扑，因此疾病中网络功能障碍的关键方面也可能被重组。最近的工作支持这样一个激进的观点，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现。我们的工作将研究扩展到这一潜在的重要领域。目的1将验证一个假设，即细胞积累减少了外源性神经类固醇对网络功能的影响，并解释了类固醇特异性神经元活动的反弹。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区域作为网络药物效应的重要贡献者方面是独一无二的。目的2将探索GABAA受体Gamma2亚单位缺陷模型中网络动力学的本质。将评估神经类固醇纠正网络动态的能力。这些研究将有助于深入了解由受体变化引起的网络动态变化，这些变化被认为是焦虑症的基础。这些研究还将提供有关治疗药物效果的新信息，这些药物不容易从以前的分析水平上区分出来。

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.