SoSexOT - Deciphering Oxytocin Circuitries Orchestrating Socio-Sexual Behavior

生殖是生物体的基本特征，在脊椎动物中主要由下丘脑神经肽催产素（OT）及其同质物调节。哺乳动物的生殖功能是通过复杂的社会性行为（SS）来实现的，这些行为可以机械地分为预交配行为和交配行为，两者都由OT调节。然而，隐藏在OT效应背后的精确OT电路还远不清楚。虽然毫无疑问，外行促进了性行为，但通过前脑区域协调交配前行为的外行回路在很大程度上是未知的。为了解决这些问题，我们将采用一种最新开发的遗传技术（称为“基于病毒的遗传活性诱导标记”，简称为vGAIT）来标记在大鼠交配前和交配行为中激活的OT神经元。利用这种技术，我们将阐明下丘脑中这些OT神经元的空间分布、它们的表型和它们的投射，以及识别前脑、脑干和脊髓中接受标记OT神经元输入的结构。同时，在自由运动的大鼠中，我们将记录这些OT神经元的活动，以阐明它们在SS行为中的性质和兴奋性。根据解剖数据，我们将刺激与SS行为相关的前脑结构的轴突OT释放。最后，利用光遗传学和药物遗传学技术，我们将激活或抑制整个标记的OT神经元群体来监测SS行为的变化。预期的数据将是全新的，并将在SS行为的背景下为OT系统的生理学提供机制见解。我们的建议与人类健康高度相关，因为它将为遇到性唤起和生殖功能问题的患者的发病机制和可能的药理干预提供基础。

Reproduction is an essential feature of living organisms and is largely modulated in vertebrates by hypothalamic neuropeptide oxytocin (OT) and its homologs. In mammals, reproductive function is realized by complex socio-sexual (SS) behaviors, which can be mechanistically divided into precopulatory and copulatory behaviors, both modulated by OT. However, precise OT circuits underlying OT effects are far from clear. Although there are no doubts that OT promotes sexual behavior, the OT circuits orchestrating precopulatory behavior via forebrain regions are largely unknown. To address these questions, we will employ a recently developed genetic technique (called 'virus-based Genetic Activity-Induced Tagging' and abbreviated as vGAIT) to tag only those OT neurons which were activated during precopulatory and copulatory behaviors of rats. Using this technique, we will elucidate spatial distribution of such OT neurons in the hypothalamus, their phenotype and their projections as well as identify structures receiving input from tagged OT neurons in the forebrain, brainstem, and spinal cord. In parallel, in freely moving rats, we will record the activity of these OT neurons to elucidate their properties and excitability during SS behavior. Based on anatomical data, we will stimulate axonal OT release in those forebrain structures which are functionally related with SS behavior. At the end, using optogenetic and pharmacogenetic techniques, we will activate or inhibit entire populations of tagged OT neurons to monitor changes in SS behavior. The expected data will be entirely novel and will provide mechanistic insights into the physiology of the OT system in the context of SS behavior. Our proposal is highly relevant to human health as it will provide a basis for pathogenesis and possible pharmacological intervention in patients experiencing problems with sexual arousal and reproductive function.