The role of spontaneous/sensory-driven activity for migration and integration of adult-born neurons of the mammalian olfactory bulb

哺乳动物嗅球(OB)成体出生的神经干细胞在整合到局部神经元回路之前，在吻端迁移流(RMS)和OB内进行长距离的移动。神经前体在RMS内的迁移有很详细的描述，但直到最近，人们对它们在OB内的迁移知之甚少。我们最近的研究描述了成体出生的细胞在OB内的体内迁移模式，并揭示了目的层内球旁神经元(JGNs)独特的长距离迁移。JGNs在到达目标层后保持至少3周的移动能力(我们称之为整合前阶段)，并经历侧向迁移，同时保留和重塑精心设计的树突树，对具有大的钙瞬变的气味做出反应，并显示细胞内钙浓度的巨大自发波动。在我们先前结果的基础上，利用最近开发的分子工具，在当前的提案中，我们的目标是在体内表征在整合前阶段控制成体出生的JGNs迁移和分化的细胞/分子机制，并了解自发/感觉驱动的活动在这些过程中的作用。为此，我们将解决以下具体目标：(I)表征自发/感觉驱动的活动对神经元迁移和整合的作用，(Ii)了解自发/感觉驱动的活动对成年出生的细胞分化的作用，(Iii)破译成年出生的神经元存活/消除的潜在机制。本提案中概述的实验将提供一个独特的机会，以可视化体内迁移神经元在整合前阶段的活动模式，并了解自发和感觉驱动的活动之间的相互作用如何控制成年干细胞的迁移、分化和存活。以及他们在何时何地融合的决定。

Prior to integration into the local neuronal circuitry adult-born neural stem cells of the mammalian olfactory bulb (OB) travel a long distance within the rostral migratory stream (RMS) and the OB. The migration of neural precursors within the RMS is characterized in much detail, but until recently little was known about their migration within the OB. Our recent study characterized in vivo migration patterns of adult-born cells within the OB and revealed a unique long-range migration of the juxtaglomerular neurons (JGNs) within the destination layer. JGNs retain the ability to move for at least 3 weeks after their arrival at the destination layer (a developmental period which we name a pre-integration phase) and undergo a lateral migration while retaining and remodeling an elaborated dendritic tree, responding to odorants with big calcium transients and exhibiting large spontaneous fluctuations in the intracellular calcium concentration. Building on our previous results and using recently developed molecular tools, in the current proposal we aim to characterize in vivo cellular/molecular mechanisms governing the migration and differentiation of adult-born JGNs during the pre-integration phase and to understand the role of the spontaneous/sensory-driven activity for these processes. To do so we are going to address the following specific goals: (i) characterization of the role of spontaneous/sensory-driven activity for neuronal migration and integration, (ii) understanding the role of spontaneous/sensory-driven activity for differentiation of adult-born cells, (iii) deciphering the mechanisms underlying survival/elimination of adult-born neurons.The experiments outlined in the current proposal will provide a unique opportunity to visualize in vivo activity patterns of migrating neurons during the pre-integration phase and to learn how the interplay between the spontaneous and sensory-driven activities controls migration, differentiation and survival of adult stem cells, as well as their decision when and where to integrate.