Molecular and neuronal mechanisms of complex behaviors

项目摘要 这项拟议中的研究的目标是了解神经系统如何协调复杂的 行为。复杂的行为需要独立神经回路的时间协调。尽管 人们普遍认识到，神经递质和离子通道的作用微调 神经回路，人们对神经系统如何指挥的了解令人惊讶地有限 神经元组装的顺序激活和抑制，以协调行为。建筑的改动 神经递质系统和离子通道长期以来一直被认为与各种 神经障碍，强调需要开发有效的方法，可以直接联系 特定神经元回路对复杂行为的协调活动。为了解释为什么 神经系统在分子和神经水平上协调复杂的行为，我们正在研究 线虫的逃避反应，这是一种高度协调的运动序列，需要感官 独立运动程序的处理、决策和时间协调。我们的 分析揭示了突触前电压门控钙通道(CaV2)和单胺类物质是如何 通过快速反应的突触激活在时间上协调反应的不同阶段 离子亲和性受体，以及慢作用代谢性受体的突触外激活。我们将使用 CA2成像和光遗传学确定神经元活动之间的时间和因果关系 以及逃逸反应的次级运动程序。确定独立的运动程序如何 在执行复合马达序列时是相连的，我们将研究反转是如何耦合到 在逃逸反应中改变行为。我们将使用突变分析来测试是否符合 检测或抑制后反弹机制解释了这些亚马达的顺序激活 程序。由于神经调节剂通过抑制突触活性来精确地调节突触活动 突触前电压门控钙通道(CaV2)，我们将定义新的CaV2信号成分 调节CaV2通道在电路功能中的作用。我们的线虫CaV2功能增益突变体提供了 首个家族性偏瘫的无脊椎动物模型，并提供了修改电路的新工具 在逃逸反应中的表现。在逃逸回路组织活动的机制。 优雅的人将阐明在更复杂的环境中协调复杂行为的类似机制 包括人类在内的动物。我们希望我们的学习将对我们的理解产生重大影响 神经调节剂和电压门控钙通道如何影响行为和 神经功能障碍，并将为治疗这些疾病提供新的分子靶点和策略 疾病。

Project Summary The goal of the proposed research is to understand how the nervous system orchestrates complex behavior. Complex behaviors require the temporal coordination of independent neural circuits. Despite widespread recognition that the action of neurotransmitters and ion channels fine tune the output of neural circuits, there is a surprisingly limited understanding of how the nervous system directs sequential activation and inhibition of assemblies of neurons to orchestrate behavior. Alterations in the neurotransmitter systems and ion channels have long been implicated in the etiology of a variety of neurological disorders, underlining the need to develop effective approaches that can directly relate the coordinated activity of specific neuronal circuits to complex behaviors. To elucidate how the nervous system orchestrates complex behaviors at the molecular and neural level we are studying the C. elegans escape response, which is a highly orchestrated motor sequence that requires sensory processing, decision-making and the temporal coordination of independent motor programs. Our analysis has unraveled how presynaptic voltage-gated Ca2+ channels (CaV2) and monoamines temporally coordinate different phases of the response through synaptic activation of fast-acting ionotropic receptors, and extra-synaptic activation of slow-acting metabotropic receptors. We will use Ca2+ imaging and optogenetics to define temporal and causal relationship between neuronal activity and the sub-motor programs of the escape response. To determine how independent motor programs are linked in the execution of a compound motor sequence we will study how reversals are coupled to turning behavior during the escape response. We will use mutant analysis to test if coincidence detection or post-inhibitory rebound mechanisms account for sequential activation of these sub-motor programs. Since neuromodulators precisely regulate synaptic activity through the inhibition of presynaptic voltage-gated Ca2+ channels (CaV2), we will define novel CaV2 signaling components that regulate CaV2 channels in circuit function. Our C.elegans CaV2 gain-of-function mutant provides the first invertebrate model for familial hemiplegic migraine and provides novel tool to modify circuit performance in the escape response. The mechanisms that organize activity in the escape circuit of C. elegans will illuminate similar mechanisms that orchestrate complex behaviors in more complex animals including humans. We expect that our studies will have a major impact on our understanding of how neuromodulators and voltage-gated-calcium channels affect circuit function in behavior and neurological disorders, and will provide new molecular targets and strategies for the treatment of these diseases.