Glutamate-Mediated Neurotransmission and the Control of Behavior

 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理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遗传多态性表明神经回路的功能改变。我们提出了基于分子的研究，将开始阐明在遗传上易处理的模式生物C中实验可及的神经回路的功能。优雅在初步的实验中，我们已经证明，该电路具有控制导航的C。沿着感觉信息的梯度。这个回路中的许多神经元使用神经递质谷氨酸，其激活在一对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，这些iGluRs突变对出租车行为中的导航有不同的影响。此外，谷氨酸能诱发复合物动作电位和局部细胞内Ca 2+瞬变。我们的研究的目标是提供机制的见解不同的感觉输入到特定的中间神经元是如何转导不同类别的突触后iGluRs修改电活动，从而控制导航。我们将评估突触后电流，电行为和钙瞬变在不同的突变背景，并联系这些参数如何C。优雅线虫能在感觉信息的梯度中导航。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中间神经元，并使用光遗传学策略，确定这些输入如何整合以控制导航。我们的研究将提供一个详细的基于分子的电路功能的理解，可用于生成更复杂的脊椎动物电路可检验的假设。我们预测，我们从我们提出的研究中所学到的将有直接的相关性，正在进行的研究，在脊椎动物的神经元传递和电路功能的控制。因此，我们的研究可能有助于与电路功能改变相关的神经或精神疾病的新的诊断或治疗方式。

 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.