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

激肽释放酶 6 在髓鞘可塑性、运动学习和恐惧记忆中的机制

基本信息

批准号：
10677390
负责人：
Lincoln I Wurtz
金额：
$ 4.77万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2025-05-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677390
关键词：
Acceleration Adult Alzheimer&apos s Disease Amygdaloid structure Anabolism Anatomy Behavioral Brain Brain region Cell Differentiation process Cell Maturation Central Nervous System Central Nervous System Diseases Cognition Disorders Communication Complex Cre-LoxP Cues Data Demyelinating Diseases Development Disease Female Freezing Fright Functional disorder Goals Grant Health Hippocampus Homeostasis Hormones Kininogenase Knock-out Knockout Mice Knowledge Label Learning Libraries LoxP-flanked allele Maps Measures Mediating Mediator Memory Mental disorders Modeling Molecular Motor Motor Cortex Multiple Sclerosis Mus Myelin Myelin Proteins Names Neurobiology Neuroglia Neurologic Neurology Neurons Neurosciences Neurosciences Research Oligodendroglia Pathology Pathway Analysis Pattern Phenotype Physiologic pulse Post-Traumatic Stress Disorders Prefrontal Cortex Process Production Proteinase-Activated Receptors Proteins Proto-Oncogene Proteins c-akt Psychiatry Reporter Research Role Running Scientific Advances and Accomplishments Series Serine Protease Shapes Signal Pathway Slice Social Behavior Spinal Cord Spinal cord injury Testing Therapeutic Work autocrine conditional knockout conditioned fear fear memory gray matter improved innovation knock-down knockout animal knockout gene long term memory male motor learning myelination neglect neural network neuroinflammation new therapeutic target novel oligodendrocyte precursor oligodendrocyte progenitor paracrine precursor cell preservation progenitor protein expression response single-cell RNA sequencing social learning stem cells white matter young adult

项目摘要

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.

项目摘要传统上，学习和记忆的机械研究一直集中在神经元上，并提早解释神经科学领域的科学进步以及神经病学目前的治疗方法和精神病学。但是，这种观点使潜在的疗法尚未针对固执的认知疾病尚未开发忽略神经胶质的亲密关系，即少突胶质细胞，从而有助于记忆形成动作神经元。最近，髓磷脂和产生少突胶质细胞的髓鞘会影响运动，恐惧和通过称为髓鞘可塑性的过程的社会学习。髓鞘可塑性恰当地命名为雕刻髓鞘网络以微调介导学习的神经元网络。我们的实验室表明 Kallikrein 6（KLK6）是一种由髓鞘少突胶质细胞高表达的分泌的丝氨酸蛋白酶，具有控制少突胶质细胞分化和形状髓鞘形态的能力。此外，我们发现全球 KLK6敲除可以增强恐惧记忆和运动学习。早期初步数据表明这是KLK6的损失在驱动这些变化的少突胶质细胞前体细胞（OPC）中。这项研究的长期目标是确定KLK6在成人CNS稳态和白质病理学中的作用目标。这笔赠款的目的是了解KLK6在恐惧中的少突胶细胞特定机制年轻小鼠的记忆和运动学习。要测试的中心假设是KLK6调节髓鞘可塑性使降低的水平通过释放髓磷脂合成来促进学习和记忆。我们计划以两个具体目标检验这一假设。 AIM 1试图了解OPC KLK6损失是否足以复制全球KLK6基因敲除动物中的行为发现。我们将在关键的解剖学大脑区域和使用脉冲标记研究OPC动力学。 AIM 2考试机械 KLK6在髓磷脂合成和可塑性中的作用。首先，我们将在OPC-中生成单细胞RNA测序数据特定的KLK6敲除小鼠以确定KLK6信号通路。然后，我们将衡量KLK6的影响骨髓少突胶质细胞和OPC分化的领土上的损失。最后，如果KLK6，我们将探测与发现的信号通路同时起作用。这项拟议的研究具有创新性，因为它是第一个检查KLK6作为髓磷脂可塑性的分子介质，这是神经科学的新分支研究。拟议的研究很重要，因为我们希望扩大我们对成人髓磷脂的产生，阐明了记忆形成的新机制，并发现了不同的影响男性和女性的KLK6。最终，这项工作将为治疗白质病理的新途径开放通过改善领域对调节髓磷脂的机制的理解，在神经和精神病学上成人中枢神经系统中的稳态和可塑性。