Coordinated regulation of feeding and social preferences by oxytocin in the rat and human

下丘脑神经肽催产素(OT)在调节社会交往和进食方面起着重要作用。然而，一个分子--OT--如何有区别地协调这种不同形式的行为，在很大程度上是未知的。基于岛叶皮质(IC)作为控制摄食和社会行为的中枢的累积报道，在我们的项目中，我们的目标是研究IC中的OT信号如何形成对食物的偏好而不是同种的。为了实现这一目标，我们在DFG-中东计划的框架内建立了一个国际团队，由以下领域的专家组成：OT系统的功能解剖(Valery Grneich，Mannheim)、社会行为和活体电生理学(Shlomo Wagner，Haifa)以及IC的细胞/分子生物学(Kobi Rosenblum，Haifa)。利用最近产生的OT受体(OTR)敲入大鼠，我们将实施一种跨学科的方法来解剖(I)IC内特定的OTR电路，(Ii)研究OT如何调节IC中的局部网络，以及(Iii)研究IC内诱发的内源性OT释放如何有助于目标导向行为，例如，在两种奖励刺激-食物和同种刺激之间做出选择。同时，我们将分别使用纤维光度法和细胞外记录技术，研究清醒行为大鼠下丘脑内OT系统和OTR神经元的活动。接下来，应用尖端的细胞和分子技术，包括新开发的活性依赖的激活细胞标签(称为CRAM)，我们将剖析OTR下游的细胞内通路，当动物遇到先天或后天的食欲或厌恶的食物来源或社会经历时，这些通路在IC神经元内被激活。最后，我们将研究从健康成年男性多能干细胞分化而来的皮质神经元中OTR的表达及其细胞内信号转导。因此，除了获得关于OT系统内功能多样性的新信息，明确或同时调节社会和摄食行为，我们的结果将高度可翻译到人类病理，如Prader-Willi综合征，其特征是社交能力、摄食和OT合成的联合变化。

The hypothalamic neuropeptide oxytocin (OT) is a crucial actor in the regulation of both social communication and feeding. However, it is largely unknown how one molecule – OT – can discriminately coordinate such distinct forms of behaviors. Based on accumulated reports that the insular cortex (IC) serves as the hub controlling both feeding and social behaviors, in our project we aim to investigate how OT signaling in the IC may form a preference towards food vs. conspecifics. To achieve this aim, we have built an international team in the framework of the DFG-Middle East program by experts in the functional anatomy of the OT system (Valery Grinevich, Mannheim), social behavior and in vivo electrophysiology (Shlomo Wagner, Haifa), and cellular/molecular biology of the IC (Kobi Rosenblum, Haifa). Using recently generated OT receptor (OTR) knock-in rats, we will implement an interdisciplinary approach to dissect (i) specific OTR circuits within the IC, (ii) investigate how OT modulates local networks in the IC, and (iii) study how evoked endogenous OT release within the IC contributes to goal-directed behavior, e.g., making a choice between two rewarding stimuli – food vs. conspecifics. In parallel, we will study the activity of the OT system and OTR neurons in the IC, using fiber photometry and extracellular recording in awake behaving rats, respectively. Next, applying cutting edge cellular and molecular techniques, including newly developed activity-dependent tagging of activated cells (termed CRAM), we will dissect intracellular pathways downstream of OTR, which are activate within IC neurons when the animal encounters innate or learned appetitive or aversive food sources or social experiences. Finally, we will study OTR expression and OTR intracellular signaling in cortical neurons differentiated from pluripotent stem cells from healthy adult male humans. Thus, in addition to gaining a novel information on functional diversity within the OT system, distinctly or concomitantly modulating social and feeding behaviors, our results will be highly translatable to human pathologies, such as Prader-Willi syndrome, characterized by joint alterations in social competence, feeding, and OT synthesis.