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，但令人惊讶的是，人们对神经系统如何指导神经元集合的顺序激活和抑制来协调行为的理解有限。神经递质系统和离子通道的改变长期以来被认为与各种神经系统疾病的病因有关，这强调了开发有效方法的必要性，这些方法可以直接将特定神经元回路的协调活动与复杂行为联系起来。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，我们正在研究秀丽隐杆线虫的逃逸反应，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Ca2+通道（CaV2）和单胺如何通过快速作用的嗜离子受体的突触激活和缓慢作用的代谢受体的突触外激活在时间上协调反应的不同阶段。我们将使用Ca2+成像和光遗传学来定义神经元活动和逃避反应的亚运动程序之间的时间和因果关系。为了确定独立的运动程序在复合运动序列的执行中是如何联系在一起的，我们将研究在逃逸响应期间反转是如何与转向行为耦合的。我们将使用突变体分析来测试是否巧合检测或抑制后反弹机制解释了这些亚运动程序的顺序激活。由于神经调节剂通过抑制突触前电压门控Ca2+通道（CaV2）来精确调节突触活动，我们将定义新的CaV2信号传导成分来调节电路功能中的CaV2通道。我们的秀丽隐杆线虫CaV2功能获得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，并提供了在逃逸反应中修改电路性能的新工具。秀丽隐杆线虫逃逸回路中组织活动的机制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节剂和电压门控钙通道如何影响行为和神经系统疾病的电路功能产生重大影响，并将为这些疾病的治疗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.