Molecular and neuronal mechanisms of complex behaviors

描述（由申请人提供）：拟议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可以微调神经回路的输出，但对于神经系统如何指导神经元组装的顺序激活和抑制以协调行为的理解却令人惊讶地有限。神经递质系统和离子通道的改变长期以来一直与各种神经系统疾病的病因学有关，这强调了开发有效方法的必要性，这些方法可以将特定神经元回路的协调活动与复杂行为直接联系起来。为了阐明神经系统如何在分子和神经水平上协调复杂的行为，我们正在研究C。elegans逃避反应，这是一个高度协调的运动序列，需要感觉处理，决策和独立运动程序的时间协调。我们的分析揭示了突触前电压门控钙离子通道（CaV2）和单胺类物质如何通过突触激活快速作用的离子型受体和突触外激活缓慢作用的代谢型受体来协调不同阶段的反应。我们将使用钙离子成像和光遗传学来定义神经元活动和逃避反应的子运动程序之间的时间和因果关系。为了确定在复合运动序列的执行中独立的运动程序是如何联系在一起的，我们将研究在逃避反应期间逆转是如何与转向行为相耦合的。我们将使用突变体分析来测试，如果符合检测或抑制后反弹机制帐户顺序激活这些子运动程序。由于神经调质通过抑制突触前电压门控Ca2+通道（CaV2）精确调节突触活动，我们将定义新的CaV2信号组件，调节CaV2通道的电路功能。 我们的线人elegans CaV2功能获得性突变体为家族性偏瘫性偏头痛提供了第一个无脊椎动物模型，并为改变逃避反应中的回路性能提供了新的工具。对C.秀丽线虫将阐明在包括人类在内的更复杂的动物中协调复杂行为的类似机制。我们期望我们的研究将对我们理解神经调质和电压门控钙通道如何影响行为和神经系统疾病中的回路功能产生重大影响，并将为治疗这些疾病提供新的分子靶点和策略。

DESCRIPTION (provided by applicant): 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.