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）的成体神经干细胞在整合到局部神经元回路之前，在吻侧迁移流（RMS）和OB内行进很长的距离。RMS内的神经前体细胞迁移的特征非常详细，但直到最近，对它们在OB内的迁移知之甚少。我们最近的研究特点在体内迁移模式的成人出生的细胞内的OB，并揭示了一个独特的远程迁移的肾小球神经元（JGN）内的目的层。JGN在其到达目的层后保留移动至少3周的能力（我们称之为预整合阶段的发育期），并在保留和重塑精心制作的树突树的同时进行侧向迁移，对具有大钙瞬变的气味剂做出响应，并在细胞内钙浓度中表现出大的自发波动。基于我们以前的研究结果，并使用最近开发的分子工具，在目前的建议，我们的目标是在体内的细胞/分子机制，在整合前阶段的成人出生的JGN的迁移和分化的特点，并了解这些过程中的自发/感觉驱动的活动的作用。为此，我们将致力于实现以下具体目标：（i）表征自发/感觉驱动的活动对于神经元迁移和整合的作用，（ii）理解自发/感觉驱动的活动对于成体细胞分化的作用，（iii）破译成年人生存/消除的机制-本提案中概述的实验将提供一个独特的机会，以可视化在整合前阶段迁移神经元的体内活动模式，并了解自发和感觉神经元之间的相互作用。驱动活动控制成体干细胞的迁移、分化和存活，以及它们决定何时和何处整合。

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.