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

神经元与少突胶质前体细胞(OPC)之间的真性突触 导致髓鞘少突胶质细胞(OL)的中枢神经系统在20年前首次被报道。从那以后， 观察到神经活动和经验诱导的成人大脑髓鞘形成的调节 据报道。髓鞘调节的缺陷会导致社交回避行为，运动学习障碍， 和情绪记忆的长期保持的干扰，并且已经假设髓鞘 调节失调会导致神经精神障碍。对支配髓鞘的神经细胞类型的认识 因此，监管可以为神经精神障碍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具有潜在作用。多巴胺相关 神经精神障碍，包括精神分裂症、成瘾和帕金森氏症，与 脑白质束调节失调。白质完整性降低由分数各向异性和 已有报道髓鞘相关基因表达减少，提示OPC功能改变。 以及这些临床人群中的OL。虽然从这些发现中还不清楚白质是否 临床前研究表明，异常是由多巴胺神经传递改变直接引起的 非典型抗精神病药物通过以下方式促进铜酮诱导的脱髓鞘后的髓鞘修复 促进OPC的增殖和分化。我们小组的初步数据表明 前脑来源的OPC和OL的多巴胺受体的表达，与先前的报道一致。然而， CC中的OPC和OL是否接受中脑多巴胺神经元的传入输入 系统地解决了。中脑多巴胺神经元是异质性的，其亚群能够 谷氨酸共同传递。这一点特别相关，因为谷氨酸的神经传递 促进髓鞘形成。初步数据支持中脑多巴胺-谷氨酸神经元在脑内的可能作用 髓鞘调节，其中邻近连接试验(PLA)介导的神经递质特异性检测 释放位点揭示了成人CC中多巴胺-谷氨酸轴突与OPC和OL之间的联系。我们 建议表征多巴胺-谷氨酸神经元轴突和OPC之间的神经胶质细胞相互作用 作为研究这些神经元在髓鞘中的作用的第一步 监管。实验将采用多管齐下的方法，将内含子重组酶结合在一起 启用组合靶向(INTRSECT)，聚乳酸介导多巴胺-谷氨酸神经元的检测 释放部位，广域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对描绘一个 中脑多巴胺神经元功能与髓鞘调节的关系。完成以下工作不可或缺 该项目将是纽约州立大学斯塔滕岛学院的本科生人数不足的学生。

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.