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

• 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
• 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' 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

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，学习和记忆的机制研究集中在神经元上，并解释了早期的 神经科学领域的科学进展以及神经病学和 精神病学然而，这种观点使得顽固的认知疾病的潜在疗法尚未开发， 忽视了神经胶质细胞的密切关系，即少突胶质细胞，促进记忆形成的行动 的神经元。最近，髓磷脂和产生髓磷脂的少突胶质细胞已被证明影响运动， 恐惧和社会学习通过一个过程称为髓鞘可塑性。髓磷脂的可塑性是指 对髓鞘网络进行雕刻，以微调介导学习的神经元网络。我们的实验表明， 激肽释放酶6（Klk 6），一种由髓鞘形成少突胶质细胞高度表达的分泌型丝氨酸蛋白酶，具有 控制少突胶质细胞分化以及形成髓鞘形成模式的能力。此外，我们发现全球 Klk 6基因敲除增强恐惧记忆和运动学习。早期的初步数据表明， 在少突胶质细胞前体细胞（OPC），驱动这些变化。这项研究的长期目标是 确定Klk 6在成人CNS稳态和白色物质病理学中的作用，以开发新的治疗药物 目标的这项资助的目的是了解Klk 6在恐惧中的少突胶质细胞特异性机制。 年轻成年小鼠的记忆和运动学习。待检验的中心假设是Klk 6调节 髓磷脂可塑性，例如降低的水平通过释放髓磷脂合成促进学习和记忆。我们 我计划用两个具体目标来检验这一假设。目标1旨在了解OPC Klk 6损失是否足以 在全球Klk 6敲除动物中复制行为发现。我们将描述髓磷脂网络， 关键解剖大脑区域和研究OPC动力学与脉冲标记。目标2审查了机械性 Klk 6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Klk 6敲除小鼠以确定Klk 6信号传导途径。然后我们将测量Klk 6的影响 髓鞘形成少突胶质细胞以及OPC分化区域的丧失。最后，我们将探讨Klk 6是否 与已发现的信号通路协同作用。这项研究是创新的，因为它是第一个 研究Klk 6作为髓鞘可塑性的分子介质，这是神经科学的一个新的令人兴奋的分支 research.拟议的研究是重要的，因为我们希望扩大我们的基本知识， 成人髓鞘的生产，阐明记忆形成的新机制，并揭示了不同的影响， Klk 6在男性和女性中。最终，这项工作将为治疗白色物质病理开辟新的途径 通过提高该领域对髓鞘调节机制的理解， 在成人中枢神经系统的稳态和可塑性。