Investigating the role of oxytocin signaling in the social regulation of eating

项目总结/摘要 催产素是一种进化上保守的神经肽，主要由垂体产生和分泌。 下丘脑室旁核和视上核。催产素受体的广泛表达 在不同的大脑区域，催产素（OXTR）可以介导对行为的广泛影响。虽然 传统上以其在调解社会和母性行为中的功能而闻名，越来越多的证据表明， 动物模型和人体研究都表明，神经肽催产素是一种有效的促神经元凋亡信号， 并且是肥胖药物治疗开发的有前景的靶点[1-4]。事实上，鼻内催产素对体重 目前正在进行一项积极的临床试验[5]。将催产素系统作为目标的兴趣 用于肥胖治疗的研究部分是基于发现鼻内催产素减少了可口的 [6]而这些影响在肥胖症患者中更有效[7]。更深 了解介导催产素对食物摄入影响的神经通路和行为过程 考虑到这个系统的临床潜力，食物驱动的行为是必要的。 催产素因其对社会行为的影响而被广泛研究。食物摄入调节是 在人类和啮齿类动物中，催产素都受到社会因素的严重影响，但催产素对 这两个相关的基本行为是相互关联的，以前没有研究过。此外，本发明还 催产素调节的许多行为表现出性二态性，包括社会行为和 食物摄入量控制[8，9]。在这里，我们专注于背海马（HPCd）作为一个候选的大脑区域， 这些功能重叠，因为HPCd催产素信号以性二态的方式促进社会记忆[10] 这一区域最近与食物摄入控制有关[11]。我们的初步结果表明，HPCd 当雄性大鼠被隔离在笼子里时，催产素的递送减少了摄入量，但增加了雄性大鼠的食物摄入量。 一个熟悉的存在，但不是一个陌生的同种。Aim 1实验使用一种 新的社会饮食模式和药理学和病毒发生学方法在男性和女性， 研究HPCd OXTR信号如何以社会背景和性别特异性方式调节食物摄入。我们 额外的初步数据显示，中央催产素增强了食物偏好的社会传播， （STFP）学习在同种熟悉依赖的方式。最近的一篇论文确定了HPCd在以下方面的作用： 通过多巴胺信号传导介导STFP学习[12]。Aim 2实验将在这些发现的基础上， 研究HPCd是否是介导催产素对STFP作用的作用部位（目的2），并将利用 药理学、神经解剖学和体内成像策略，以评估催产素和 多巴胺系统相互作用，以社会背景和性别依赖的方式调节进食（目标3）。 总的来说，这些实验将揭示新的神经，生理和行为机制介导 催产素对食物摄入控制的影响

Project Summary/Abstract Oxytocin is an evolutionarily conserved neuropeptide primarily produced and secreted from the paraventricular and supraoptic nuclei of the hypothalamus. Widespread expression of the oxytocin receptor (OXTR) across various brain regions allows oxytocin to mediate a wide range of effects on behavior. Though classically known for its functions in mediating social and maternal behavior, a growing body of evidence from both animal models and human studies indicates that the neuropeptide oxytocin is a potent anorexigenic signal and a promising target for obesity pharmacotherapy development [1-4]. Indeed, intranasal oxytocin for weight loss is currently under investigation in an active clinical trial [5]. The interest in the oxytocin system as a target for obesity treatment is based, in part, on findings showing that intranasal oxytocin reduces intake of palatable foods in humans [6], and that these effects are more potent in participants with obesity [7]. A deeper understanding of the neural pathways and behavioral processes mediating oxytocin's effects on food intake and food-motivated behavior is imperative given the clinical potential for this system. Oxytocin has been most widely studied for its influence on social behavior. Food intake regulation is heavily influenced by social factors in both humans and rodents, yet the extent that oxytocin's influence on these two related fundamental behaviors is interconnected has not been previously investigated. Further, many of the behaviors modulated by oxytocin show sexual dimorphism, including both social behaviors and food intake control [8, 9]. Here we focus on the dorsal hippocampus (HPCd) as a candidate brain region where these functions overlap as HPCd oxytocin signaling facilitates social memory in sexually dimorphic ways [10] and this region has been recently linked to food intake control [11]. Our preliminary results show that HPCd oxytocin delivery in male rats reduces intake when isolated in the home cage, yet increases food intake in the presence of a familiar, but not an unfamiliar conspecific. Aim 1 experiments build off these findings using a novel social eating paradigm and both pharmacological and virogenetic approaches in males and females to investigate how HPCd OXTR signaling modulates food intake in social context- and sex-specific ways. Our additional preliminary data reveal that central oxytocin enhances social transmission of food preference (STFP) learning in a conspecific familiarity-dependent manner. A recent paper identified a role for the HPCd in mediating STFP learning through dopamine signaling [12]. Aim 2 experiments will build off these findings to investigate whether the HPCd is a site of action mediating oxytocin's effects on STFP (Aim 2), and will utilize pharmacological, neuroanatomical, and in vivo imaging strategy to assess the extent to which oxytocin and dopamine systems interact to regulate eating in a social context- and sex-dependent manner (Aim 3). Collectively, these experiments will reveal novel neural, physiological, and behavioral mechanisms mediating oxytocin's effects on food intake control.