Axonal Transport and Long-Term Memory Storage

项目总结 长时记忆(LTM)的存储需要重塑原有的突触并形成新的突触。 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，但它 在很大程度上仍不清楚核和突触过程在LTM存储过程中是如何协调的。 我们之前已经证明了激动素，一种调节细胞核之间通讯的分子马达 而突触通过微管依赖的基因产物的运输，在这一过程中起着关键作用。 我们发现，在海洋生物中，肌动蛋白是诱导长期易化(LTF)的必要条件和充分条件 蜗牛海兔和动蛋白运输了几种与学习相关的蛋白质和信使核糖核酸。我们的 指导性假说是LTM的储存需要调节基因产物的轴突运输。 参与学习的回路中的突触后神经元。在这个提案中，我们测试了我们的中心假设 在学习过程中，激动素介导的运输在双向可塑性中受到不同的调节。我们将表演 我们的研究使用了描述得很好的退出鳃的突触前感觉神经元和突触后运动神经元 海兔反射。感觉神经元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，以研究运输的调节在前和 突触后神经元。具体地说，我们的目标是了解顺行的三个关键组成部分是如何 运输：可以调节马达、货物和微管轨道的运动，以调整货物的运送 LTM期间的突触。这项拟议研究的预期结果是，一旦分子 轴突运输的调节器被识别出来，它们可能受到药理学的操纵，产生 治疗疾病的新的和创新的方法，例如轴突 交通受到影响。

PROJECT SUMMARY 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.