Glutamate-Mediated Neurotransmission and the Control of Behavior

谷氨酸介导的神经传递和行为控制

• 批准号: 9754884
• 负责人: Andres Villu Maricq
• 金额: $ 32.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754884
• 关键词: Action Potentials; Animal Model; Behavior; Behavior Control; Behavioral Assay; Bilateral; Caenorhabditis elegans; Calcium; Chemotaxis; Closure by clamp; Complex; Deletion Mutation; Development; Disease; Electrophysiology (science); Exhibits; Genetic; Genetic Polymorphism; Glutamate Receptor; Glutamates; Goals; Imaging Techniques; Injections; Interneurons; Label; Learning; Link; Location; Maps; Measures; Mediating; Medicine; Mental Depression; Mental disorders; Modality; Modeling; Molecular; Mutate; Nervous system structure; Neurobiology; Neurologic; Neurons; Neurophysiology - biologic function; Neurosciences; Neurotransmitters; Organism; Process; Property; Research; Role; Schizophrenia; Sensory; Signal Transduction; Stimulus; Synapses; Techniques; Testing; Time; Vertebrates; Work; autism spectrum disorder; base; experimental study; gene product; glutamatergic signaling; in vivo imaging; insight; kainate; mutant; nervous system disorder; neural circuit; neurotransmission; novel; novel diagnostics; novel therapeutics; optogenetics; postsynaptic; presynaptic; public health relevance; receptor; receptor function; response; selective expression; sensory input; voltage

 DESCRIPTION (provided by applicant): A major goal of neurobiology is to understand the control of behavior by neural circuits at the molecular level. This is also a major goal of clinica medicine as an increasing number of genetic polymorphisms associated with disorders such as autism, schizophrenia and depression suggest altered function of neural circuits. We propose molecular-based studies that will begin to elucidate the function of an experimentally accessible neural circuit in the genetically tractable model organism C. elegans. In preliminary experiments, we have demonstrated that this circuit has a general role in controlling navigation by C. elegans along gradients of sensory information. Many neurons in this circuit use the neurotransmitter glutamate, which activates multiple classes of postsynaptic ionotropic glutamate receptors (iGluRs) expressed in a single pair of interneurons. Interestingly, mutating these iGluRs has different effects on navigation during taxis behaviors. Furthermore, glutamate elicits complex action potentials and regional intracellular Ca2+ transients. The goals of our research are to provide mechanistic insights into how distinct sensory inputs to specific interneurons are transduced by different classes of postsynaptic iGluRs to modify electrical activity and thus control navigation. We will evaluate postsynaptic currents, electrical behavior and calcium transients in different mutant backgrounds, and link these parameters to how C. elegans navigates gradients of sensory information. In these studies, we will precisely map presynaptic sensory inputs to specific downstream interneurons and, using optogenetic strategies, determine how these inputs are integrated to control navigation. Our studies will provide a detailed molecular-based understanding of circuit function that can be used to generate testable hypotheses in more complex vertebrate circuits. We predict that what we learn from our proposed studies will have immediate relevance to ongoing studies of glutamatergic neurotransmission and the control of circuit function in vertebrates. Thus, our studies could contribute to new diagnostic or therapeutic modalities for neurological or psychiatric disorders associated with altered circuit function.

 描述(申请人提供)：神经生物学的一个主要目标是在分子水平上了解神经回路对行为的控制。这也是临床医学的一个主要目标，因为越来越多的与自闭症、精神分裂症和抑郁症等疾病相关的基因多态性表明神经回路的功能发生了变化。我们提出了基于分子的研究，将开始阐明在遗传易驯化的模式生物秀丽线虫中，可通过实验获得的神经回路的功能。在初步实验中，我们已经证明了这个回路在控制线虫沿着感觉信息的梯度导航方面具有普遍的作用。这个回路中的许多神经元使用神经递质谷氨酸，它激活在单个中间神经元中表达的多种突触后离子型谷氨酸受体(IGluRs)。有趣的是，突变这些iGluR会对出租车行为中的导航产生不同的影响。此外，谷氨酸还能引起复杂的动作电位和局部的细胞内钙瞬变。我们研究的目的是提供机械性的见解，了解不同类别的突触后iGluR如何将不同的感觉输入传递到特定的中间神经元，以调节电活动，从而控制导航。我们将评估不同突变背景下的突触后电流、电行为和钙瞬变，并将这些参数与线虫如何导航感觉信息的梯度联系起来。在这些研究中，我们将准确地将突触前感觉输入映射到特定的下游中间神经元，并使用光遗传策略来确定这些输入是如何整合起来控制导航的。我们的研究将提供对电路功能的详细分子理解，可用于在更复杂的脊椎动物电路中产生可测试的假说。我们预测，我们从拟议的研究中所学到的将与正在进行的谷氨酸能神经传递和脊椎动物回路功能控制的研究直接相关。因此，我们的研究可能有助于为与电路功能改变相关的神经或精神疾病提供新的诊断或治疗方法。