Axonal Transport and Long-Term Memory Storage

描述（由申请人提供）：长期记忆（LTM）存储需要重塑预先存在的突触和形成新的突触。虽然转录和突触蛋白合成在这些过程中的作用得到了很好的描述，但在LTM储存期间，核和突触过程如何协调仍然是未知的。我们以前已经表明，驱动蛋白，介导细胞核和突触之间的通信，通过微管依赖的基因产物的运输的分子马达，在这一过程中具有关键作用。我们发现驱动蛋白对于诱导海兔长期易化（LTF）是必要且足够的，并且驱动蛋白可以转运多种蛋白质， 与学习相关的mRNA货物。我们的指导性假设是，LTM的存储需要在参与学习的突触前和突触后神经元中调节基因产物的轴突运输。在这个建议中，我们测试我们的中心假设，驱动蛋白介导的运输差异调节学习过程中的双向可塑性。我们将 利用描述良好的Aussia鳃回缩反射的突触前感觉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，并提供实验的灵活性，专门操纵这些神经元，以研究在突触前和突触后神经元的运输调节。具体来说，我们的目标是了解如何顺行运输的三个关键组成部分：驱动蛋白电机，货物和微管轨道可能受到调节，以调整货物的传递到突触在LTM。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剂，它们就可以被操纵，从而产生新的和创新的方法来治疗轴突运输受到影响的疾病，如tau蛋白病。

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.