Exploring the role of de novo myelination in engram formation

学习和记忆的形成是适应外界经验的重要功能。在电路层面，记忆被存储在对应于印迹（或记忆痕迹）的神经元集合中。最近，神经胶质细胞已被证明可以调节记忆功能。特别是少突胶质细胞已经成为研究的焦点，因为最近的研究已经表明，增强或抑制少突胶质细胞前体（OPC）增殖和分化（成年少突胶质细胞发生）影响记忆的形成和巩固。在这个项目中，我首先要阐明成年少突神经元发育对记忆印迹形成的影响，通过调查如何破坏少突神经元发育改变记忆印迹形成的背景恐惧条件反射。使用记忆印记标记和神经元活动的光遗传学操作，我将回答这个问题是否适应性髓鞘形成导致神经元更强的网络分配或是否促进记忆印记的重新激活。我的第二个目标是阐明神经元活动如何诱导OPCs开始分化和髓鞘形成。哪些信号通路是OPCs中神经元活动的下游效应子？由OPCs表达的神经递质受体可能抑制由神经元活动给出的信号，并且可能的下游效应器可能是Ca 2+信号传导。我将研究OPC钙离子动力学诱导的人工刺激的一个特定的远程投影，并在实际的记忆形成过程中使用双光子和单光子在体内钙离子成像，分别。此外，我将损害OPCs中的Ca2+动力学，以确定Ca2+信号传导是否是OPC响应神经元活动的驱动力。总之，我将阐明自适应髓鞘形成对记忆印迹形成的影响，并确定Ca2+信号传导是否是成年少突胶质细胞发生的关键因素。阐明OPCs对记忆印迹形成的贡献将增强我们对学习和记忆形成如何在细胞和回路水平上促进的理解。

Learning and memory formation are crucial functions to adapt to outside experience. At the circuit level, memories are stored in neuronal ensembles that correspond to an engram (or memory trace). Recently glial cells have been shown to modulate memory function. Oligodendrocytes, in particular, have become a focus of research as recent studies have shown that enhancing or inhibiting oligodendrocyte precursors (OPCs) proliferation and differentiation (adult oligodendrogenesis) impacts memory formation and consolidation. In this project, I first want to elucidate the effect of adult oligodendrogenesis on engram formation by investigating how disrupting oligodendrogenesis alters the engram formed by contextual fear conditioning. Using engram tagging and optogenetic manipulation of neuronal activity I will answer the question whether adaptive myelination leads to a stronger allocation of neurons to the network or whether reactivation of the engram is promoted.My second aim is to shed light on how neuronal activity induces OPCs to start differentiating and myelinating. Which signalling pathways are the downstream effectors of neuronal activity in OPCs? Neurotransmitter receptors expressed by OPCs may transduce the signal given by neuronal activity and a possible downstream effector may be Ca2+-signalling. I will examine OPC Ca2+-dynamics induced by artificial stimulation of a specific long-range projection and during actual memory formation using two-photon and one-photon in vivo Ca2+-imaging, respectively. Furthermore, I will impair the Ca2+-dynamics in OPCs to determine whether Ca2+-signalling is the driving force behind OPC response to neuronal activity. In summary, I will shed a light on the influence of adaptive myelination on engram formation and determine whether Ca2+-signalling is a crucial factor in adult oligodendrogenesis. Elucidating the contribution of OPCs to engram formation will enhance our understanding of how learning and memory formation is facilitated at cellular and circuit level.