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基块组成。我们的长期目标是揭开基本微电路的一般原理。在这项研究中，我们将重点关注突触调节对电路功能、感觉加工和动物行为的贡献。GABA是中枢神经系统中主要的抑制性神经递质，在突触调节中起关键作用。GABA通过两种不同的受体系统发挥其调节作用，即快速离子化GABAA受体和慢代谢GABAB受体。人体临床试验和动物实验都有很好的证据表明，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。据报道，GABAB受体的分子克隆缺乏异质性，这表明选择性干扰GABAB受体以避免药物治疗中副作用的可能性有限。对GABAB受体在基本神经回路中介导的突触调节的更深入了解有助于在GABAB系统中选择替代靶点。GABAB受体介导的突触调节是本研究的重点。解剖学上的简单性和遗传学的力量使果蝇成为一个特别适合研究突触调节对电路功能和行为输出的贡献的系统。我们已经获得证据表明果蝇气味受体神经元表达GABAB受体，GABAB受体的激活引起突触前抑制。本研究采用多学科方法，结合分子遗传学、行为学和光学成像，研究GABAB受体介导的嗅觉系统反馈抑制及其对嗅觉行为的影响。对这种嗅觉回路的研究将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目标选择。人类临床试验和动物实验的充分证据表明，GABAB受体激动剂可减少对可卡因、海洛因、酒精和尼古丁等药物的渴望。然而，选择性干扰无副作用的GABAB受体受到缺乏受体异质性的限制。本提案的工作是基础科学，旨在揭示GABAB系统在突触调节和电路功能中的机制，创建一个知识库，从中可以评估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.