Synaptic Modulation in Neural Circuits

神经回路中的突触调制

• 批准号: 8073601
• 负责人: Jing W Wang
• 金额: $ 28.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-20 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073601
• 关键词: Adopted; Adverse effects; Agonist; Alcohols; Animal Behavior; Animal Experiments; Basic Science; Behavior; Behavioral; Behavioral Paradigm; Biological Assay; Brain; Calcium; Clinical Trials; Cocaine; Detection; Drosophila genus; Feedback; Future; Genetic; Goals; Health; Heroin; Heterogeneity; Human; Individual; Interneurons; Light; Lobe; Locomotion; Measures; Mediating; Molecular Cloning; Molecular Genetics; Neuraxis; Neurons; Neurotransmitters; Nicotine; Odorant Receptors; Odors; Olfactory Nerve; Output; Pharmacotherapy; Play; Presynaptic Terminals; Process; Receptor Activation; Receptor Gene; Regulation; Reporting; Research; Role; Sensory Process; Synapses; System; Testing; Therapeutic Intervention; Work; drug craving; gamma-Aminobutyric Acid; interdisciplinary approach; interest; knowledge base; neural circuit; neurotransmitter release; novel; optical imaging; preference; presynaptic; receptor; response

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.

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。我们的长期目标是揭示基本微电路的一般原理。本研究主要探讨突触调制对神经回路功能、感觉加工和动物行为的影响。GABA是中枢神经系统中主要的抑制性神经递质，在突触调制中起关键作用。GABA通过两种不同的受体系统发挥其调节作用，即快离子型GABAA和慢代谢型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，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。GABAB系统中替代靶点的选择可以通过对基本神经回路中GABAB受体介导的突触调制的更深入理解来帮助。GABAB受体介导的突触调节是本研究的重点。解剖学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制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，果蝇气味受体神经元表达GABAB受体和GABAB受体的激活引起突触前抑制。我们采用多学科的方法，结合分子遗传学，行为学研究，光学成像研究GABAB受体介导的反馈抑制在嗅觉系统中，以及它对嗅觉行为的贡献。对这种明确的嗅觉回路的研究将有助于阐明突触调节和反馈抑制的一般原理。这些一般原则还应指导未来治疗干预的目标选择。公共卫生相关性人体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，选择性干扰GABAB受体而无副作用受到缺乏受体异质性的限制。该提案的工作是基础科学，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，从中可以评估GABAB系统中的替代靶点，用于未来的治疗干预。