Visualization of oxytocin receptor for translational social neuroscience

转化社会神经科学中催产素受体的可视化

基本信息

  • 批准号:
    10226503
  • 负责人:
  • 金额:
    $ 9.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-20 至 2022-06-30
  • 项目状态:
    已结题

项目摘要

Decades of research have shown that the peptide oxytocin (OT) can act as a potent neuromodulator in a variety of species to influence complex social behaviors, including social bonding, affiliation, and social reward. Administering intranasal OT to humans affects a suite of social behaviors, such as trust, eye contact, emotion recognition, and pair-bonding-related behaviors. Due to the ability of OT to modulate social function in animals as well as humans, the OT system has been highly implicated in the biology and treatment of several psychiatric conditions that are characterized by deficits in sociality, including autism spectrum disorder, schizophrenia, and social anxiety disorder. Because of this high translational potential for OT to benefit human health, it is crucial that research efforts focus on the fundamental neuroanatomy and physiology of the oxytocin system in the brains of both animals and humans. Thanks to the suite of transgenic tools available, research in mice has contributed considerably to our understanding of the function of OT in the regulation of social behavior. But non-mouse models are increasingly being used, including monogamous rodents as well as nonhuman primates. To complement the elegant behavioral pharmacology being done in these species, rigorous neuroanatomical work is required to characterize the underlying neural circuits. Currently, the most reliable and widely available technique for the visualization of OXTR in brain tissue sections is receptor autoradiography, but this method has some limitations. It only resolves receptors at the gross anatomical level; it is not possible to analyze receptor expression on the cellular scale. The most common technique to visualize receptors on the cellular level is with a method called immunohistochemistry. But because there are no reliable, commercially-available antibodies for OXTR, the field of OXTR research has been left without a widely available and tractable technique to investigate these receptors on the cellular level. Thus, the first aim of our proposal is to advance the field of OT research by developing a novel method for the cellular staining of OXTR in brain tissue. This technique will use a novel biotinylated OXTR ligand provided by our chemist collaborator and will be optimized from prairie voles, titi monkeys, and humans. The second limitation of receptor autoradiography is that it uses an indirect visualization method (radiosensitive film) that doesn’t label the tissue directly. Thus, it is impossible to perform co-localization studies with targets of other neurotransmitter systems known to interact with OT/OXTR to modulate social function. Aim 2 seeks to resolve this issue by applying the novel OXTR staining method to the localization of OXTR on dopaminergic neurons in prairie voles. Our decision to start with the dopaminergic system in prairie voles is based on extensive experimental evidence for the interaction between these two systems in the regulation of pair bond formation in this monogamous rodent. By developing a cellular stain for OXTR that is tractable across laboratories and species, a massive opportunity will be created for future studies of OXTR-expressing neurons.
数十年的研究表明,肽催产素(OT)可以作为一种有效的神经调节剂 各种物种影响复杂的社会行为,包括社会联系、归属和社会奖励。 对人类进行鼻内 OT 会影响一系列社会行为,例如信任、目光接触、情绪 识别和配对相关行为。由于 OT 能够调节动物的社会功能 与人类一样,OT 系统与多种疾病的生物学和治疗密切相关 以社交缺陷为特征的精神疾病,包括自闭症谱系障碍, 精神分裂症和社交焦虑症。由于 OT 造福人类的巨大转化潜力 为了健康,研究工作重点关注催产素的基本神经解剖学和生理学至关重要 动物和人类大脑中的系统。由于现有的转基因工具套件,研究 小鼠对我们理解 OT 在社交调节中的功能做出了很大贡献 行为。但非小鼠模型的使用越来越多,包括一夫一妻制的啮齿动物以及 非人类灵长类动物。为了补充在这些物种中进行的优雅的行为药理学, 需要进行严格的神经解剖学工作来表征潜在的神经回路。目前,最 在脑组织切片中可视化 OXTR 的可靠且广泛使用的技术是受体 放射自显影,但该方法有一定的局限性。它仅在总体解剖水平上解析受体; 不可能在细胞规模上分析受体表达。最常用的可视化技术 细胞水平上的受体是通过一种称为免疫组织化学的方法进行的。但因为没有 尽管 OXTR 的可靠、市售抗体尚未得到广泛应用,但 OXTR 研究领域尚未得到广泛应用。 可用且易于处理的技术来在细胞水平上研究这些受体。因此,我们的首要目标是 提案旨在通过开发一种新的细胞染色方法来推进 OT 研究领域 脑组织中的OXTR。该技术将使用我们的化学家提供的新型生物素化 OXTR 配体 合作者,并将根据草原田鼠、蒂蒂猴和人类进行优化。第二个限制 受体放射自显影术的特点是它使用不标记的间接可视化方法(放射敏感胶片) 直接组织。因此,不可能与其他神经递质的靶标进行共定位研究 已知与 OT/OXTR 相互作用以调节社会功能的系统。目标 2 旨在通过以下方式解决此问题 将新型 OXTR 染色方法应用于 OXTR 在多巴胺能神经元上的定位 草原田鼠。我们决定从草原田鼠的多巴胺能系统开始研究是基于广泛的研究 这两个系统之间相互作用调节成对键形成的实验证据 这种一夫一妻制的啮齿动物。通过开发一种可在实验室和实验室中处理的 OXTR 细胞染色剂 物种,将为未来表达 OXTR 的神经元的研究创造巨大的机会。

项目成果

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