Mechanisms of Kallikrein 6 in Myelin Plasticity, Motor Learning, and Fear Memory

项目摘要 学习和记忆的机制研究传统上集中在神经元上，并解释了早期 神经科学领域的科学进展以及目前神经病学和 精神病学。然而，这种观点留下了对顽固性认知疾病的潜在治疗方法 忽略了促进记忆形成行为的神经胶质细胞的亲密关系，即少突胶质细胞 神经细胞的。最近，髓鞘和产生髓鞘的少突胶质细胞被证明影响运动， 恐惧，以及通过一种称为髓鞘可塑性的过程进行的社会学习。顾名思义，髓鞘可塑性指的是 塑造髓鞘网络，以微调参与学习的神经元网络。我们的实验室已经证明 激肽释放酶6(KLK6)是一种分泌型丝氨酸蛋白酶，由髓鞘少突胶质细胞高度表达。 控制少突胶质细胞分化以及形成髓鞘模式的能力。此外，我们发现全球 KLK6基因敲除可增强恐惧记忆和运动学习。早期的初步数据表明这是KLK6的丢失 在驱动这些变化的少突胶质前体细胞(OPC)中。这项研究的长期目标是 确定KLK6在成人中枢神经系统稳态和白质病理中的作用(S)以开发新的治疗方法 目标。这项资助的目的是了解KLK6在恐惧中的少突胶质细胞特异性机制 幼年成年小鼠的记忆和运动学习。需要检验的中心假设是KLK6调节 髓鞘的可塑性降低通过释放髓鞘合成来促进学习和记忆。我们 计划用两个具体的目标来检验这一假设。目标1试图了解OPC KLK6的损失是否足以 在全球KLK6基因敲除动物中复制行为发现。我们将在下面描述髓鞘网络 关键解剖脑区，用脉搏标记法研究OPC动力学。目标2考查机械原理 KLK6在髓鞘合成和可塑性中的作用首先，我们将在OPC中生成单细胞RNA测序数据- 特异性KLK6基因敲除小鼠确定KLK6信号通路。然后我们将衡量KLK6的影响 髓鞘少突胶质细胞区域的丢失以及OPC的分化。最后，我们将调查KLK6是否 与已发现的信号通路协同作用。这项拟议的研究具有创新性，因为它是第一次 研究KLK6作为神经科学一个新的令人兴奋的分支--髓鞘可塑性的分子介体 研究。这项拟议的研究具有重要意义，因为我们希望扩大我们对 成人髓鞘的产生，阐明了记忆形成的新机制，并揭示了 KLK6在男性和女性。最终，这项工作将为白质病理学的治疗开辟新的途径。 通过提高该领域对髓鞘调节机制的理解，在神经学和精神病学方面取得了进展 成人中枢神经系统的动态平衡和可塑性。

PROJECT ABSTRACT Mechanistic studies of learning and memory have traditionally focused on the neuron and account for early scientific advances in the field of neuroscience as well as the current therapeutic approach in neurology and psychiatry. However, this perspective leaves potential therapies untapped for stubborn cognitive diseases by neglecting the intimate relationship of glia, namely oligodendrocytes, that facilitate the memory forming actions of neurons. Recently, myelin and the myelin producing oligodendrocyte have been shown to influence motor, fear, and social learning through a process termed myelin plasticity. Aptly named, myelin plasticity refers to the sculpting of myelin networks to fine tune the neuronal networks that mediate learning. Our lab has shown that kallikrein 6 (Klk6), a secreted serine protease highly expressed by myelinating oligodendrocytes, has the power to control oligodendrocyte differentiation as well as shape myelination patterns. Further, we find global Klk6 knockout enhances fear memory and motor learning. Early preliminary data suggests it is the loss of Klk6 in oligodendrocyte precursor cells (OPC) that drives these changes. The long-term goal of this research is to determine the role(s) of Klk6 in adult CNS homeostasis and white matter pathology to develop new therapeutic targets. The objective of this grant is to understand oligodendrocyte-specific mechanisms of Klk6 in fear memory and motor learning in young adult mice. The central hypothesis to be tested is that Klk6 regulates myelin plasticity such that reduced levels promote learning and memory by unleashing myelin synthesis. We plan to test this hypothesis with two specific aims. Aim 1 seeks to understand if OPC Klk6 loss is sufficient to replicate the behavioral findings in the global Klk6 knockout animals. We will characterize myelin networks in key anatomical brain regions and study OPC dynamics with pulse labeling. Aim 2 examines the mechanistic role of Klk6 in myelin synthesis and plasticity. First, we will generate single cell RNA sequencing data in OPC- specific Klk6 knockout mice to determine Klk6 signaling pathways. Then we will measure the impact of Klk6 loss on the territory of myelinating oligodendrocytes as well as OPC differentiation. Finally, we will probe if Klk6 acts in tandem with discovered signaling pathways. This proposed research is innovative because it is the first to examine Klk6 as a molecular mediator of myelin plasticity, a new and exciting branch of neuroscience research. The proposed research is significant because we expect to expand on our fundamental knowledge of adult myelin production, elucidate new mechanisms of memory formation, and uncover a differential impact of Klk6 in males and females. Ultimately, this work will open new avenues for treatment of white matter pathology in neurology and psychiatry by improving the field’s understanding of mechanisms regulating myelin homeostasis and plasticity in the adult central nervous system.