Regulation of structural plasticity and actin cytoskeleton by plasma membrane cholesterol turnover in dendritic spines

所有的细胞都被控制细胞与环境相互作用的脂质和蛋白质膜所包围。这种膜通过改变其组成和形状，迅速适应环境和细胞的需要。胆固醇是所有动物细胞膜的基本成分，调节着它们的弹性、通透性和其他特性。我们的研究项目侧重于神经细胞膜中的胆固醇。我们研究了膜上的胆固醇水平是如何调节的，以及膜上胆固醇水平的变化如何影响神经细胞的通讯。神经细胞有着非常复杂的形状，它被优化为与许多其他神经细胞连接，在大脑中形成一个巨大的通信网络。为了能够接受许多其他细胞的输入，神经有被称为树突的长而分支的突起，这些突起还有被称为树突的额外的小膜突起。在这些脊椎的顶端，神经细胞与另一个神经细胞相连，以接收信号。一个神经元有许多树突，每个树突都有许多刺，所以每个神经元可以接受来自许多其他神经细胞的输入。脊椎的数量和大小会影响传入信号的强度。神经细胞可以根据传入的信号快速调整脊椎的形状。这个过程被称为突触可塑性，是学习和记忆的基础。其他研究表明，神经细胞在接收到来自其他细胞的强烈信号时，会从细胞膜释放胆固醇，然后再恢复胆固醇。然而，尚不清楚最初的释放如何影响脊椎的形状和功能，也不知道神经细胞在释放胆固醇后如何迅速恢复；它们可以从周围的支持细胞中吸收胆固醇，也可以自己制造胆固醇。我们的目标是通过在神经细胞正常支持细胞存在的情况下培养神经细胞来解决这些问题，并通过实验诱导神经细胞内胆固醇释放或胆固醇产生的缺陷。然后，我们将描述这些变化对树突棘的大小和数量的影响，并确定它们是否仍能适应传入的信号。我们还打算确定在神经细胞活动期间脊椎中的胆固醇含量是如何变化的。初步实验表明，当胆固醇产生中断时，脊柱对信号的反应受到损害，即使神经细胞仍然可以从外部获得胆固醇。我们的目标是阐明胆固醇如何影响脊柱的机制，以及为什么外部胆固醇可能不能完全取代来自其他细胞的外部胆固醇。我们的工作解决了神经细胞功能的一个基本方面。此外，鉴于神经细胞并不是唯一对信号做出反应而迅速改变形状的细胞，其中一些机制可能对其他类型的细胞也很重要。

All cells are surrounded by a membrane of lipids and proteins that controls the cell's interaction with the environment. The membrane rapidly adjusts to the environment and the cell's needs by changing its composition and shape. Cholesterol is an essential component of all animal membranes and regulates their flexibility, permeability and other characteristics. Our research program focuses on cholesterol in nerve cell membranes. We investigate how cholesterol levels in the membrane are regulated and how changes in membrane cholesterol levels influence nerve cell communication. Nerve cells have a very intricate shape which is optimized to connect with many other nerve cells to form a large communication network in the brain. To be able to receive input from many other cells, nerve have long, branched processes called dendrites, which have additional small membrane protrusions called dendritic spines. At the tip of these spines, the nerve cell connects with another nerve cell to receive a signal. One neuron has many dendrites, each with many spines, so each neuron can receive input from with many other nerve cells. The number of spines and their size influence the strength of the incoming signal. Nerve cells can rapidly adjust the shape of the spines according to an incoming signal. This process is called synaptic plasticity and is the basis for learning and memory. Other studies have shown that nerve cells release cholesterol from the membrane when they receive strong signals from other cells, and later recover that cholesterol. However, it is not known how the initial release affects the shape and function of the spines, and it is not known how nerve cells quickly regain cholesterol after having released it; they could take it up from surrounding support cells or make it themselves. We aim to address these questions by culturing nerve cells in the presence of their normal support cells, and experimentally induce defects in cholesterol release or in the production of cholesterol inside nerve cells. We will then characterize the effects of these changes on the size and number of dendritic spines, and determine whether they can still adjust to incoming signals. We also aim to determine how cholesterol content in the spines changes during nerve cell activity. Preliminary experiments suggest that spine growth in response to signals is impaired when cholesterol production is disrupted, even though the nerve cells can still get cholesterol from outside. We aim to elucidate the mechanisms through which how cholesterol influences the spine, and why external cholesterol may not be able to fully replace external cholesterol coming from the other cells. Our work addresses a fundamental aspect of nerve cell function. Moreover, given that nerve cells are not the only cells that change their shape rapidly in response to signals, some of these mechanisms may also be important in other cell types.