Synaptic Modulation in Neural Circuits

描述(由申请人提供)：中枢神经系统由有限数量的微电路图案组成。我们的长期目标是解开基本微电路的一般原理。在这项研究中，我们着重于突触调节对回路功能、感觉加工和动物行为的贡献。GABA是中枢神经系统中的主要抑制性神经递质，在突触调节中起着关键作用。GABA通过两个不同的受体系统发挥其调节作用，快离子亲和性GABAA受体和慢代谢性GABAB受体。人类临床试验和动物实验有很好的证据表明，GABAB受体激动剂可以减少对可卡因、海洛因、酒精和尼古丁等药物的渴望。GABAB受体的分子克隆报告缺乏异质性，这表明选择性干扰GABAB受体以避免药物治疗副作用的可能性有限。更深入地了解GABAB受体在基础神经回路中介导的突触调节，可以帮助选择GABAB系统中的替代靶点。GABAB受体介导的突触调节是本研究的重点。解剖的简单性和遗传学的力量使果蝇成为一个特别容易研究突触调节对电路功能和行为输出的贡献的系统。我们已经获得的证据表明，果蝇气味感受器神经元表达GABAB受体，而GABAB受体的激活会导致突触前抑制。我们采用分子遗传学、行为学和光学成像相结合的多学科方法来研究嗅觉系统中GABAB受体介导的反馈抑制及其对嗅觉行为的贡献。对这种明确的嗅觉回路的研究应该有助于揭示突触调节和反馈抑制的一般原理。这些一般原则也应该指导未来治疗干预的靶点选择。公共卫生相关性人类临床试验和动物实验有很好的证据表明，GABAB受体激动剂可以减少对可卡因、海洛因、酒精和尼古丁等药物的渴望。然而，对GABAB受体的选择性干扰而没有副作用的限制是缺乏受体的异质性。该提案的工作是一门基础科学，旨在揭示GABAB系统在突触调制和电路功能中的机制，创建一个知识库，根据该知识库可以评估GABAB系统中的替代靶点，以用于未来的治疗干预。

DESCRIPTION (provided by applicant): The central nervous system is made from a limited number of microcircuit motifs. Our long-term goal is to unravel the general principles of the elementary microcircuits. In this study, we focus on the contribution of synaptic modulation to circuit function, sensory processing and animal behavior. GABA is the major inhibitory neurotransmitter in the central nervous system and plays a key role in synaptic modulation. GABA exerts its modulatory role via two distinct receptor systems, the fast ionotropic GABAA and the slow metabotropic GABAB receptors. There is good evidence from human clinical trials and animal experiments to suggest that GABAB receptor agonists reduce the craving for drugs such as cocaine, heroin, alcohol, and nicotine. The molecular cloning of GABAB receptors report a lack of heterogeneity, suggesting limited possibilities for selective interference with the GABAB receptors to avoid side effects in pharmacotherapy. Selection of alternative targets in the GABAB system could be aided by a deeper understanding of the GABAB receptor mediated synaptic modulation in basic neural circuits. GABAB receptor mediated synaptic modulation is the focus of this study. The anatomical simplicity and the power of genetics make Drosophila a particularly amenable system to investigate the contribution of synaptic modulation to circuit function as well as behavioral output. We have obtained evidence showing that Drosophila odorant receptor neurons express GABAB receptors and the activation of GABAB receptors causes presynaptic inhibition. We adopt a multidisciplinary approach that combines molecular genetics, behavioral studies, and optical imaging to study GABAB receptor mediated feedback inhibition in the olfactory system, and also its contribution to olfactory behaviors. Studies of such defined olfactory circuit should shed light on the general principles of synaptic modulation and feedback inhibition. These general principles should also guide target selection for future therapeutic interventions. PUBLIC HEALTH RELEVANCE There is good evidence from human clinical trials and animal experiments to suggest that GABAB receptor agonists reduce the craving for drugs such as cocaine, heroin, alcohol, and nicotine. However, a selective interference with the GABAB receptors without side effect is limited by the lack of receptor heterogeneity. The work of this proposal is basic science that seeks to reveal the mechanisms of the GABAB system in synaptic modulation and circuit function, creating a knowledge base from which alternative targets in the GABAB system can be evaluated for future therapeutic interventions.