Axonal Transport and Long-Term Memory Storage

描述(由申请人提供)：长期记忆(LTM)存储需要对先前存在的突触进行重塑并形成新的突触。虽然转录和突触蛋白合成在这些过程中的作用已经被很好地描述，但在很大程度上仍然不清楚核和突触过程在LTM储存过程中是如何协调的。我们之前已经证明，Kinesin是一种分子马达，通过依赖微管的基因产物运输来调节细胞核和突触之间的通讯，在这一过程中发挥着关键作用。我们已经发现，在海洋蜗牛海兔中，动蛋白是诱导长期促进(LTF)的必要条件和充分条件，并且动蛋白转运几种蛋白质和 与学习相关的信使核糖核酸。我们的指导性假设是，LTM的存储需要调节参与学习的回路中突触前和突触后神经元中基因产物的轴突运输。在这个提议中，我们检验了我们的中心假设，即在学习过程中，Kinesin介导的运输在双向可塑性中受到不同的调节。我们会 使用海兔缩鳃反射的突触前感觉神经元和突触后运动神经元进行我们的研究。感觉和运动神经元突触可以在体外重建，并提供实验灵活性，专门操纵这些神经元来研究突触前和突触后神经元的运输调节。具体地说，我们的目标是了解在LTM过程中如何调节顺行运输的三个关键组成部分：运动蛋白、货物和微管轨道来调节货物向突触的输送。这项拟议研究的预期结果是，一旦确定了轴突运输的分子调节器，它们可能会被药理学操纵，产生新的创新方法来治疗疾病，如影响轴突运输的肌萎缩侧索硬化症。

DESCRIPTION (provided by applicant): Long-term memory (LTM) storage requires remodeling of pre-existing synapses and formation of new ones. While the roles of transcription and synaptic protein synthesis in these processes are well described, it remains largely unknown how nuclear and synaptic processes are coordinated during LTM storage. We have previously shown that kinesin, the molecular motor that mediates communication between nucleus and synapses through the microtubule-dependent transport of gene products, has a key role in this process. We have discovered that kinesins are necessary and sufficient to induce long-term facilitation (LTF) in marine snail Aplysia and that kinesin transport several protein and mRNA cargos that are relevant for learning. Our guiding hypothesis is that storage of LTM requires regulation of axonal transport of gene products in pre- and post-synaptic neurons of circuits involved in learning. In this proposal, we test our central hypothesis that kinesin mediated transport is differentially regulated in bidirectional plasticity during learning. We will perform our studies using the well-described pre-synaptic sensory and post-synaptic motor neurons of gill withdrawal reflex of Aplysia. The sensory and motor neuron synapses can be re-constituted in vitro and provide experimental flexibility to specifically manipulate these neurons to study regulation of transport in pre- and post-synaptic neurons. Specifically, we aim to understand how the three critical components of anterograde transport: the kinesin motor, cargo and microtubule tracks may be regulated to adjust delivery of cargo to synapses during LTM. An anticipated outcome of this proposed research is that once the molecular regulators of axonal transport are identified, they may be manipulated pharmacologically, producing new and innovative approaches to the treatment of disorders such as tauopathies in which axonal transport is affected.