Mechanisms underlying axonal plasticity and computational abilities

轴突可塑性和计算能力的机制

• 批准号: RGPIN-2020-05255
• 负责人: Kolta, Arlette
• 金额: $ 4.23万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739865
• 关键词: Mechanisms; underlying; axonal; plasticity; computational

Nervous functions rely on the ability of neurons to communicate, and this communication mode is thought to rely on the capacity of neurons to integrate inputs impinging on their soma and dendritic processes and to transmit this information through their axonal arbors if the changes in membrane potential bring the axon initial segment (AIS) to threshold. Action potentials (APs) generated at the AIS are thought to propagate uniformly across the axonal tree, but growing evidence incite revisions of these "dogmas". Studies have shown that: 1) AIS are plastic: Under or over stimulation of neurons lead to changes in their length, position and ion channel composition. 2) Axons are not "passively" conducting APs: Activation of transmitter receptors located on the axonal trunk can alter AP propagation, and 3) By controlling the ionic extracellular environment, the thickness of the myelin and the size of Ranvier nodes, glial cells affect AP speed of propagation (with consequences on synchrony in an ensemble). Oligodendrocytes forming the myelin interact with (perinodal) astrocytes at Ranvier nodes through gap junctions and coupled astrocytes and oligodendrocytes form what are called panglial networks. Here we propose to use electrophysiology, optogenetic, imaging and immunohistochemistry to examine how glial cells and panglial networks contribute to: 1) plasticity of the AIS and 2) Compartmentalization of the axonal arbor of primary afferent neurons located in the mesenscephalic trigeminal nucleus (NVmes), and 3) Regulation of conduction velocity of APs. NVmes represent a unique opportunity to address these questions because of their large axons that can be maintained and easily targeted for recording in brainstem slices. In Aim 1) we will examine how short term increase of their activity affects the length and position of their AIS using a method to vary focally the extracellular Ca2+ concentration or using Na+ indicators. Live measurements will be confirmed with post-hoc immuno-histochemical labelling with antibodies against Ankyrin G or BetaIV spectrin. AIS changes obtained with these methods will be compared before and after activation or inactivation of astrocytes and/or their coupling with oligodendrocytes. Aims 2 and 3) will examine how astrocytes/oligodendrocytes interactions can affect propagation and conduction velocity of APs in a branch specific manner. There is evidence of GABA dependent decoupling between different compartments of NVmes axons. Here we will examine the effect of astrocytes and/or oligodendrocytes manipulations on propagation of orthodromic and antidromic APs in different axonal branches of NVmes cells and will try to identify the gliotransmitter underlying any observed effect. These experiments raise novel and original questions that may have wide implications on our understanding of factors determining the most basic neuronal functions of computation and communication.

神经功能依赖于神经元的通信能力，并且这种通信模式被认为依赖于神经元整合撞击其索马和树突过程的输入的能力，并且如果膜电位的变化使轴突起始段（AIS）达到阈值，则通过其轴突乔木传递该信息。在AIS产生的动作电位（AP）被认为是均匀地传播整个轴突树，但越来越多的证据煽动这些“教条”的修订。研究表明：1）AIS是塑料的：神经元的刺激不足或过度导致其长度，位置和离子通道组成的变化。2)轴突不是“被动地”传导AP：位于轴突干上的发射器受体的激活可以改变AP传播，以及3）通过控制离子细胞外环境、髓鞘的厚度和朗维尔结的大小，神经胶质细胞影响AP传播速度（对集合中的同步性产生影响）。形成髓磷脂的少突胶质细胞通过间隙连接与朗维尔结处的（结周）星形胶质细胞相互作用，并且偶联的星形胶质细胞和少突胶质细胞形成所谓的神经节网络。在这里，我们建议使用电生理学，光遗传学，成像和免疫组织化学来检查胶质细胞和神经节网络如何有助于：1）AIS的可塑性和2）位于三叉神经系中脑核（NVmes）的初级传入神经元轴突乔木的区室化，以及3）AP传导速度的调节。 NVMes代表了解决这些问题的独特机会，因为它们的大轴突可以被维持并且很容易被定向用于在脑干切片中记录。在目标1）中，我们将使用局部改变细胞外Ca 2+浓度的方法或使用Na+指示剂来检查其活性的短期增加如何影响其AIS的长度和位置。将使用抗锚蛋白G或BetaIV血影蛋白抗体的事后免疫组织化学标记确认活体测量。将在星形胶质细胞活化或失活和/或其与少突胶质细胞偶联之前和之后比较用这些方法获得的AIS变化。 目的2和3）将检查星形胶质细胞/少突胶质细胞相互作用如何以分支特异性方式影响AP的传播和传导速度。存在NVMes轴突的不同隔室之间的GABA依赖性解耦的证据。在这里，我们将研究星形胶质细胞和/或少突胶质细胞的操作对NVMES细胞的不同轴突分支中的顺向和逆向AP的传播的影响，并将尝试识别任何观察到的影响的神经胶质递质。这些实验提出了新颖且原创的问题，这些问题可能对我们理解决定计算和通信最基本神经元功能的因素产生广泛影响。