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：
9009657
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/9009657
关键词：
Action Potentials Animal Model Autistic Disorder Behavior Behavior Control Behavioral Assay Bilateral Caenorhabditis elegans Calcium Chemotaxis Complex Deletion Mutation Development Disease Exhibits Genetic Genetic Polymorphism Glutamate Receptor Glutamates Goals 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 Proteins Research Role Schizophrenia Sensory Signal Transduction Stimulus Synapses Techniques Testing Time Vertebrates Work base 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 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，因为越来越多的遗传多态性与自闭症等疾病相关。精神分裂症并表明抑郁症会改变神经回路的功能，我们提出基于分子的研究，该研究将开始阐明遗传易处理的模型生物线虫中可通过实验获得的神经回路的功能。在初步实验中，我们已经证明该回路在控制线虫沿感觉信息梯度的导航方面具有一般作用，该回路中的许多神经元使用神经递质谷氨酸，它激活表达的多种突触后离子型谷氨酸受体（iGluR）。在一对中间神经元中，突变这些 iGluR 对滑行行为的导航有不同的影响。此外，谷氨酸会引发复杂的动作电位和区域。我们研究的目标是提供关于不同类别的突触后 iGluR 如何转导特定中间神经元的不同感觉输入以改变电活动从而控制导航的机制见解。在不同的突变背景中，并将这些参数与秀丽隐杆线虫如何导航感觉信息梯度联系起来。在这些研究中，我们将精确地将突触前感觉输入映射到特定的下游。我们的研究将提供对神经元间神经元的详细的基于分子的理解，并使用光遗传学策略确定如何整合这些输入来控制导航，该理解可用于在更复杂的脊椎动物回路中生成可测试的假设。我们提出的研究中的结果将与正在进行的脊椎动物谷氨酸神经传递和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回路功能相关的神经或精神疾病提供新的诊断或治疗方式。