Axo-glial interactions between midbrain dopamine neuron axons and oligodendrocyte lineage cells in the corpus callosum.

中脑多巴胺神经元轴突与胼胝体中少突胶质细胞系细胞之间的轴胶质细胞相互作用。

• 批准号: 10673849
• 负责人: Leora Yetnikoff
• 金额: $ 13.23万
• 依托单位: COLLEGE OF STATEN ISLAND
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673849
• 关键词: Address; Adopted; Adult; Anatomy; Anisotropy; Axon; Biological Assay; Brain; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cell Separation; Clinical; Complex; Confocal Microscopy; Corpus Callosum; Cuprizone; Data; Demyelinations; Detection; Dopamine; Dopamine Receptor; Emotional; Female; Fluorescence-Activated Cell Sorting; Foundations; Functional disorder; Genes; Glutamate Receptor; Glutamates; Impairment; Island; Knowledge; Label; Letters; Ligation; Light; Maps; Measures; Mediating; Memory; Mentors; Midbrain structure; Mus; Myelin; Neuroglia; Neurons; Neurotransmitters; Oligodendroglia; Parkinson Disease; Pathogenesis; Phenotype; Population; Positioning Attribute; Process; Proliferating; Prosencephalon; Regulation; Reporter; Reporting; Research; Resources; Role; Schizophrenia; Science; Site; Synapses; Techniques; Testing; Therapeutic Intervention; Western Blotting; Work; addiction; atypical antipsychotic; avoidance behavior; behavioral plasticity; career; cell type; college; combinatorial; density; design; dopaminergic neuron; experience; experimental study; insight; laboratory experience; male; motor learning; myelination; neural; neuropsychiatric disorder; neurotransmission; oligodendrocyte lineage; oligodendrocyte precursor; preclinical study; precursor cell; progenitor; promoter; receptor expression; recombinase; repaired; social; transmission process; undergraduate student; white matter

Bona fide synapses between neurons and oligodendrocyte precursor cells (OPCs), a class of progenitors in the CNS that gives rise to myelinating oligodendrocytes (OLs), were first reported two decades ago. Since then, observations of neural activity- and experience- induced regulation of myelination in the adult brain have been reported. Impairments in myelin regulation contribute to social avoidance behaviors, motor learning deficits, and perturbations in the long-term retention of emotional memories, and it has been posited that myelin dysregulation contributes to neuropsychiatric disorders. Knowledge of the neuronal cell types governing myelin regulation could therefore provide new possibilities for therapeutic intervention in neuropsychiatric disorders. Evidence suggests a potential role for midbrain dopamine neurons in myelin regulation. Dopamine-related neuropsychiatric disorders, including schizophrenia, addiction, and Parkinson's disease, are associated with dysregulation of white matter tracts. Reduced white matter integrity as measured by fractional anisotropy and decreased expression of myelin-associated genes have been reported, suggesting altered function of OPCs and OLs in these clinical populations. While it is not clear from these findings whether white matter abnormalities are directly caused by altered dopamine neurotransmission, preclinical studies have demonstrated that atypical antipsychotics enhance myelin repair following cuprizone-induced demyelination by increasing the proliferation and differentiation of OPCs. Preliminary data from our group demonstrate dopamine receptor expression by forebrain-derived OPCs and OLs, consistent with previous reports. However, whether OPCs and OLs in the CC receive afferent input from midbrain dopamine neurons has never been systematically addressed. Midbrain dopamine neurons are heterogeneous, with subpopulations capable of glutamate co-transmission. This is particularly relevant in light of the fact that glutamate neurotransmission promotes myelination. Preliminary data supports a possible role for midbrain dopamine-glutamate neurons in myelin regulation, wherein proximity ligation assay (PLA)-mediated detection of neurotransmitter-specific release sites reveals contacts between dopamine-glutamate axons and OPCs and OLs in the adult CC. We propose to characterize neuro-glia interactions between dopamine-glutamate neuron axons and OPCs and OLs in the adult corpus callosum (CC) as a first step in examining the role of these neurons in myelin regulation. Experiments will adopt a multi-pronged approach that incorporates `intronic recombinase sites enabling combinatorial targeting' (INTRSECT), PLA-mediated detection of `dopamine-glutamate' neuron release sites, wide field and computational confocal microscopy, fluorescence-activated cell sorting (FACS), and complex motor learning. A promising aspect of this work is its potential contribution to the delineation of a relationship between midbrain dopamine neuron function and myelin regulation. Integral to completion of the project will be underrepresented undergraduate students at the College of Staten Island, CUNY.

神经元和少突胶质细胞前体细胞（OPCs）之间的真正突触，OPCs是神经元中的一类祖细胞。 20年前首次报道了产生髓鞘化少突胶质细胞（OL）的CNS。从那时起， 对成年人大脑中神经活动和经验诱导的髓鞘形成调节的观察， 报道髓鞘调节的损伤导致社交回避行为，运动学习缺陷， 以及长期保持情感记忆的干扰，并且已经假设髓磷脂 调节异常导致神经精神障碍。对控制髓鞘的神经元细胞类型的认识 因此，监管可以为神经精神疾病的治疗干预提供新的可能性。 有证据表明中脑多巴胺神经元在髓鞘调节中的潜在作用。多巴胺相关 神经精神障碍，包括精神分裂症，成瘾和帕金森病，与 白色物质束的失调。通过分数各向异性测量的白色物质完整性降低， 已经报道了髓鞘相关基因表达的减少，表明OPCs的功能改变 和OLs在这些临床人群中。虽然从这些发现中还不清楚白色是否重要 异常是由多巴胺神经传递的改变直接引起的，临床前研究 证明非典型抗精神病药物通过以下方式增强铜腙诱导的脱髓鞘后的髓鞘修复： 增加OPCs的增殖和分化。我们小组的初步数据表明 多巴胺受体表达的前脑衍生的OPC和OL，与以前的报告一致。然而，在这方面， CC中的OPCs和OLs是否接受来自中脑多巴胺神经元的传入输入， 系统地处理。中脑多巴胺神经元是异质的，具有能够 谷氨酸共传递。这一点特别重要，因为谷氨酸神经传递 促进髓鞘形成。初步的数据支持中脑多巴胺-谷氨酸神经元在 髓鞘调节，其中邻位连接测定（PLA）介导的神经递质特异性的检测 释放位点揭示了成年CC中多巴胺-谷氨酸轴突与OPC和OL之间的接触。我们 建议描述多巴胺-谷氨酸神经元轴突和OPC之间的神经胶质相互作用， 成年人胼胝体（CC）中的OL作为检查这些神经元在髓鞘中作用的第一步 调控实验将采用多管齐下的方法，将“内含子重组酶位点 能够组合靶向“（INTRSECT），PLA介导的”多巴胺-谷氨酸“神经元检测 释放位点，宽视野和计算共聚焦显微镜，荧光激活细胞分选（FACS）， 和复杂的运动学习。这项工作的一个有希望的方面是，它可能有助于划定一个 中脑多巴胺神经元功能与髓鞘调节的关系。是完成 该项目将在纽约市立大学斯塔顿岛学院的本科生人数不足。