Molecular and neuronal mechanisms of complex behaviors

项目摘要 这项研究的目的是了解神经系统是如何协调复杂的 行为复杂的行为需要独立神经回路的时间协调。尽管 广泛的认识是，神经递质和离子通道的作用可以微调神经递质的输出， 神经回路，有一个令人惊讶的有限的了解如何神经系统指挥 连续的激活和抑制神经元的组装以协调行为。的改变 神经递质系统和离子通道长期以来与多种神经系统疾病的病因学有关。 神经系统疾病，强调需要制定有效的方法，可以直接关系到 特定神经元回路的协调活动以实现复杂行为。为了阐明 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 C.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 一项分析揭示了突触前电压门控钙通道（CaV2）和单胺 通过快速作用的突触激活在时间上协调反应的不同阶段 离子型受体和慢作用代谢型受体的突触外激活。我们将使用 Ca2+成像和光遗传学用于确定神经元活动之间的时间和因果关系 和逃避反应的子运动程序。为了确定独立的运动程序 在复合运动序列的执行中是联系在一起的，我们将研究逆转是如何与 逃避反应时的转向行为我们将使用突变分析来检验 检测或抑制后反弹机制解释了这些子运动的顺序激活 程序.由于神经调质通过抑制突触活性来精确调节突触活性， 突触前电压门控Ca2+通道（CaV2），我们将定义新的CaV2信号传导组件， 在电路功能中调节CaV2通道。我们的秀丽隐杆线虫CaV2功能获得性突变体提供了 家族性偏瘫性偏头痛的第一个无脊椎动物模型，并提供了新的工具来修改电路 逃避反应的表现。对C. elegans将阐明类似的机制，协调复杂的行为，在更复杂的 包括人类在内的动物。我们期望我们的研究将对我们的理解产生重大影响 神经调质和电压门控钙通道如何影响行为中的电路功能， 神经系统疾病，并将提供新的分子靶点和治疗这些战略 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.