Visualization of oxytocin receptor for translational social neuroscience

几十年的研究表明，缩宫素（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，从属关系和社会奖励。 给人鼻内注射OT会影响一系列社会行为，如信任、眼神接触、情感 识别和配对相关行为。由于OT能够调节动物的社会功能， 以及人类，OT系统已高度牵连在生物学和治疗的几个 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的这种高转化潜力使人类受益 因此，研究工作必须集中在催产素的基本神经解剖学和生理学上， 在动物和人类的大脑中。多亏了一套可用的转基因工具， 小鼠对我们理解OT在社会调节中的功能做出了很大贡献。 行为但非小鼠模型越来越多地被使用，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 在脑组织切片中观察OXTR的可靠和广泛可用的技术是受体 放射自显影，但这种方法有一定的局限性。它只在大体解剖水平上分辨受体; 不可能在细胞水平上分析受体表达。最常见的可视化技术 细胞水平上的受体是用一种叫做免疫组织化学的方法。但是因为没有 由于OXTR缺乏可靠的、可商购的抗体，OXTR研究领域还没有广泛的研究。 可用的和易于处理的技术来研究这些受体的细胞水平。因此，我们的第一个目标是 建议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，并将从草原田鼠，titi猴子和人类优化。第二个限制 受体放射自显影的另一个优点是它使用间接可视化方法（放射敏感胶片）， 组织直接。因此，不可能与其他神经递质的靶点进行共定位研究 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这一问题： 将新的OXTR染色方法应用于多巴胺能神经元上的OXTR定位， 草原田鼠我们决定从草原田鼠的多巴胺能系统开始，是基于广泛的 这两个系统之间的相互作用的实验证据，在对键形成的调节， 一夫一妻制的啮齿动物通过开发一种在实验室间易于处理的OXTR细胞染色剂， 物种，一个巨大的机会将创造未来的研究OXTR表达神经元。

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.