Axonal myelination of interneurons in cortex: functional significance and plasticity

皮质中间神经元的轴突髓鞘形成：功能意义和可塑性

• 批准号: 9315233
• 负责人: Vernon Daniel MADISON
• 金额: $ 34.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315233
• 关键词: 4-Aminobutyrate aminotransferase; Action Potentials; Affect; Anatomy; Animals; Area; Array tomography; Autistic Disorder; Axon; Brain; Cerebral cortex; Cerebrum; Characteristics; Cognitive; Data; Demyelinating Diseases; Developmental Course; Disease; Electrophysiology (science); Equilibrium; Experimental Autoimmune Encephalomyelitis; Fiber; Generations; Human; Individual; Interneurons; Investigation; Ion Channel; Knowledge; Learning; Length; Measurement; Mental disorders; Modeling; Modification; Molecular; Multiple Sclerosis; Mus; Myelin; Myoepithelial cell; Nervous system structure; Neuronal Plasticity; Neurons; Parvalbumins; Pathologic; Pathology; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Play; Process; Property; Proteins; Published Comment; Role; Schizophrenia; Sensory Deprivation; Source; Speed; Stimulus; Synapses; Synaptic Transmission; Thick; Vigabatrin; barrel cortex; base; cell type; density; excitatory neuron; experience; gamma-Aminobutyric Acid; gray matter; hippocampal pyramidal neuron; information processing; inhibitor/antagonist; mouse model; myelination; nervous system disorder; neural circuit; neuronal circuitry; neurotransmission; novel; physical property; postsynaptic neurons; relating to nervous system; response; somatosensory; synaptic inhibition; white matter

Axonal myelination of interneurons in cortex: functional significance and plasticity The speed and efficiency of impulse conduction in myelinated fibers is clearly fundamental to component density and functional powers of the human nervous system. There is also growing evidence that changes in myelination can have profound effects on the function of local brain circuits, including synchrony of neuronal activity and the interaction of neural oscillators. Myelin is most often thought of in association with the processes of long-axon projection neurons. But recently, we have discovered that the locally-projecting, relatively short-axon inhibitory interneurons are a major source of myelinated axons within cortical gray matter, in contrast to the myelin in white matter that forms almost exclusively on the axons of long-distance projecting excitatory neurons. In particular, interneuronal myelin appears to be confined to interneurons containing the protein parvalbumin. Synaptic inhibition is a central feature of neuronal networks. In cortex, numerous types of inhibitory interneurons participate in regulating the excitatory/inhibitory balance, in neuronal synchronization and cortical rhythms generation, and in plasticity associated with experience and learning. Even though axonal myelination defines crucial properties of neuronal transmission, it has not been specifically studied in cortical interneurons. Furthermore, pathologies of both the cortical inhibitory circuitry and of myelin are associated with many neurological and mental disorders, including multiple sclerosis, schizophrenia, and autism. Our present knowledge of myelination in the cortical gray matter, and in particular the myelination of inhibitory axons, is limited and certainly must be augmented if we are to conquer such devastating disorders. This proposal is based on a novel combination of electrophysiology and array tomography that delivers functional, structural and molecular data on individual neurons or pairs of synaptically connected neurons. The project will begin by investigating myelinated axons of parvalbumin positive basket cells and correlating their structural organization and molecular composition with the electrophysiological properties of their action potential discharge and resulting synaptic transmission onto target pyramidal neurons. Once such a baseline has been established, the contribution of axonal myelination of parvalbumin interneurons to the plasticity of neuronal circuits will be assessed using barrel cortex sensory deprivation as a model. The project will conclude with a study of the pathological changes of interneuronal myelination in a mouse model of multiple sclerosis. This proposal will provide much needed data regarding the organization of myelin of cortical interneurons, the functional consequences and the plasticity of this organization, and its potential role in multiple sclerosis.

皮质中间神经元的轴突髓鞘形成：功能意义和可塑性 有髓纤维中脉冲传导的速度和效率显然是组件的基础 人类神经系统的密度和功能。也有越来越多的证据表明， 髓鞘形成会对局部脑回路的功能产生深远的影响，包括神经元的同步性 神经振荡器的活动和相互作用。髓磷脂通常被认为与 长轴突投射神经元的过程。但最近，我们发现局部投影， 相对较短的轴突抑制性中间神经元是皮质灰质内有髓轴突的主要来源， 与白质中的髓磷脂相反，髓磷脂几乎完全形成于长距离投射的轴突上 兴奋性神经元。特别是，神经元间髓磷脂似乎仅限于含有 蛋白质小清蛋白。 突触抑制是神经元网络的核心特征。在皮质中，有多种类型的抑制 中间神经元参与调节兴奋/抑制平衡、神经元同步和皮质 节奏的产生，以及与经验和学习相关的可塑性。尽管轴突髓鞘化 定义了神经元传递的关键特性，但尚未在皮质中间神经元中进行专门研究。 此外，皮质抑制回路和髓磷脂的病理学与许多疾病有关。 神经和精神疾病，包括多发性硬化症、精神分裂症和自闭症。我们的现在 关于皮质灰质髓鞘形成，特别是抑制性轴突髓鞘形成的知识， 如果我们要克服这种毁灭性的疾病，那么这种能力是有限的，而且肯定必须得到加强。 该提案基于电生理学和阵列断层扫描的新颖组合，可提供 单个神经元或突触连接神经元对的功能、结构和分子数据。这 项目将首先研究小清蛋白阳性篮状细胞的有髓轴突并将其关联起来 结构组织和分子组成及其作用的电生理特性 潜在的放电和由此产生的突触传递到目标锥体神经元。一旦有了这样的基线 已经确定，小白蛋白中间神经元的轴突髓鞘化对可塑性的贡献 将使用桶状皮层感觉剥夺作为模型来评估神经元回路。该项目将结束 研究多发性硬化症小鼠模型中神经元间髓鞘形成的病理变化。 该提案将提供有关皮质中间神经元髓磷脂组织的急需数据， 该组织的功能后果和可塑性及其在多发性硬化症中的潜在作用。