Glutamate-Mediated Neurotransmission and the Control of Behavior

谷氨酸介导的神经传递和行为控制

基本信息

批准号：
9128053
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
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9128053
关键词：
Action Potentials Animal Model Autistic Disorder Behavior Behavior Control Behavioral Assay Bilateral Caenorhabditis elegans Calcium Chemotaxis Complex Deletion Mutation Development Disease Electrophysiology (science)Exhibits Genetic Genetic Polymorphism Glutamate Receptor Glutamates Goals Health Imaging Techniques Injection of therapeutic agent Interneurons Label Learning Link Location Maps Measures Mediating Medicine Mental Depression Mental disorders Modality Modeling Molecular Mutate Nervous system structure Neurobiology Neurologic Neurons Neurosciences Neurotransmitters Organism Process Property Research Role Schizophrenia Sensory Signal Transduction Stimulus Synapses Techniques Testing Time Vertebrates Work base gene product glutamatergic signaling in vivo imaging insight kainate mutant nervous system disorder neural circuit neurotransmission novel novel diagnostics novel therapeutics optogenetics postsynaptic presynaptic receptor receptor function research study response selective expression sensory input voltage

项目摘要

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（由适用提供）：神经生物学的主要目标是了解分子水平上神经电路对行为的控制。这也是临床医学的主要目标，因为与自闭症，精神分裂症和抑郁症等疾病相关的遗传多态性越来越多，这表明神经信号的功能改变了。我们提出了基于分子的研究，该研究将开始阐明在一般可牵引的模型有机体秀丽隐杆线虫中实验可访问的神经元回路的功能。在初步实验中，我们已经证明，该电路在控制秀丽隐杆线虫在感觉信息梯度上的导航中具有一般作用。该电路中的许多神经元使用神经递质谷氨酸，该神经递质激活了在一对中神经元中表达的多种突触后离子谷氨酸受体（iGlurs）。在出租车行为期间，伊吉尔人对导航有不同的影响。此外，谷氨酸会引起复杂的作用电位和区域内Ca2+瞬变。我们研究的目标是提供机械洞察，以了解如何通过不同类别的突触后iglurs转导特定的中间神经元的感觉输入，以修改电活动并控制导航。我们将评估不同突变背景中的突触后电流，电行为和钙瞬变，并将这些参数与秀丽隐杆线虫导航的感觉信息的导航梯度联系起来。在这些研究中，我们将准确地将突触前的感觉输入映射到特定的下游中间神经元，并使用光学遗传策略来确定如何整合这些输入以控制导航。我们的研究将提供对电路功能的详细基于分子的理解，可用于在更复杂的脊椎动物电路中产生可检验的假设。我们预测，我们从拟议的研究中学到的知识将与正在进行的谷氨酸能神经传递和脊椎动物中电路功能的控制立即相关。这，我们的研究可能有助于与电路功能改变有关的神经或精神疾病的新诊断或治疗方式。