The cytoskeleton in neuronal cell biology

细胞骨架是一种进化上保守的结构，由控制细胞结构和功能特征的内部丝状蛋白质支架组成。细胞骨架由微管微丝（MT）、肌动蛋白微丝（MF）、中间丝及其相关蛋白相互连接而成，是细胞内运输的“高速公路”，为细胞提供结构支持并参与细胞信号转导。它在神经元中特别重要，因为它允许这些细胞在形态和功能上对去极化做出反应。我的申请建议 破译“结构 细胞骨架发挥的“->功能”关系 在神经元中，特别关注学习和记忆的过程。“是不是 细胞骨架对学习和记忆很重要？”“细胞骨架是如何 有助于记忆的形成？”维持和平行动的根本动力变化 神经细胞之间的连接（突触）被认为是负责 用于重组神经网络， 包括记忆突触由突触前侧（即轴突）组成 末端）和突触后侧（即从树突突出的棘）。 尽管这两个方面都受到细胞骨架的调节，但细胞骨架在学习和记忆中的作用还不清楚。 我的实验室最近生成了一个 独特的动物模型，使我们能够研究依赖于细胞因子的 空间学习和记忆的出生后机制。我们的新动物 通过基因敲除特定的细胞骨架蛋白而建立的模型， 正常发展。重要的是，突变体表现出深刻的空间学习能力 出生后7周出现缺陷。超微结构研究显示， 海马锥体兴奋性神经元树突的细胞骨架异常 海马体的CA 1区，一个与学习有关的关键大脑区域， 记忆突变体动物大肠杆菌的全基因组转录组分析 揭示了细胞粘附和细胞骨架基因的失调， 神经可塑性 在这里，我建议1）确定放松管制是否 锥体兴奋性神经元细胞骨架的变化影响了 的抑制性中间神经元，以及 两种细胞类型之间的界面，从而改变神经网络，2） 为了验证细胞粘附和细胞间通讯蛋白， 从调节这些细胞之间活性的转录组分析， 类型，并确定它如何与锥体神经元的细胞骨架， 和3）解决细胞骨架的非细胞自主功能 蛋白质，这是目前文献中没有涉及的主题。这些实验将使我们了解 细胞骨架影响细胞间的通讯， 在学习和记忆过程中保护出生后大脑中的神经元网络。

The cytoskeleton is an evolutionarily conserved structure consisting of an internal filamentous protein scaffold that controls the architectural and functional features of cells. Composed by the interconnection of microtubule filaments (MTs), actin microfilaments (MFs), intermediate filaments and their associated proteins, the cytoskeleton serves as a “highway” for intracellular transport, provides architectural support to cells and participates in cell signaling. It is particularly critical in neurons as it allows these cells to respond morphologically and functionally to depolarization. My application proposes to decipher the “structure -> function” relationship played by the cytoskeleton in neurons with a particular focus on the process of learning and memory. “Is the cytoskeleton important for learning and memory?”. “How does the cytoskeleton contribute to memory formation?” Dynamic changes underlying the maintenance of the connections (synapses) between nerve cells are thought to be responsible for the restructuring of neural networks that serve to encode behaviors including memories. Synapses are composed by a presynaptic side (i.e. axon terminal) and a post-synaptic side (i.e. spine protruding from a dendrite). Despite the fact that both sides are regulated by cytoskeleton, the role of the cytoskeleton in learning and memory is not well understood. My lab has recently generated a unique animal model that allows us to study the cytoskeleton-dependent postnatal mechanisms underlying spatial learning and memory. Our new animal model that was created by gene knockout of a particular cytoskeletal protein, develops normally. Importantly, the mutants exhibit profound spatial learning deficits 7 weeks after birth. Ultra-structural studies revealed early cytoskeletal abnormalities in dendrites of pyramidal excitatory neurons in the CA1 region of the hippocampus, a key brain area implicated in learning and memory. Genome-wide transcriptome profiling of hippocampi of the mutant animals revealed deregulation of cell adhesion and cytoskeletal genes involved in neuronal plasticity. Here, I propose 1) to determine whether deregulation of the cytoskeleton in pyramidal excitatory neurons affects the biology of neighbor inhibitory interneurons, as well as the interface between the two cell types, thereby altering the neural network, 2) to validate cell adhesion and cell-cell communications proteins identified from the transcriptome analysis that modulate the activity between these cell types and determine how it relates to the cytoskeleton in pyramidal neurons, and 3) to address the non-cell autonomous functions of cytoskeletal proteins, a topic that is not covered in the current literature. The experiments will allow us to understand how the cytoskeleton impacts cell-cell communication and preserve neuronal networks in the postnatal brain during learning and memory.