Effects of acute and chronic activation of oxytocin receptor on intraneuronal signaling cascades: implications for anxiety-like behaviour

催产素受体的急性和慢性激活对神经元内信号级联的影响：对焦虑样行为的影响

• 批准号: 338314427
• 负责人: Dr. Benjamin Jurek
• 金额: --
• 依托单位: Abteilung für Stress Neurobiologie und Neurogenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/338314427?language=en
• 关键词: Effects; acute; chronic; activation; oxytocin

The growing interest in the behavioral effects of the neuropeptide oxytocin (OXT) as treatment option for various psychopathologies including anxiety disorders creates the need for a deeper understanding of the molecular processes following acute, but especially chronic OXT receptor (OXTR) activation. Surprisingly, compared to the high number of behavioural studies in animals and humans, neuronal and molecular mechanisms underlying the OXT effects are rarely reported, especially in the context of chronically activated intracellular signaling cascades and their downstream target proteins and genes.Therefore, the present project aims to reveal OXTR-mediated intraneuronal effects in hypothalamic neurons after acute treatment, and to compare these effects with cytoplasmic or genetic alterations after chronic application of OXT in vivo and in vitro. We aim to identify signalling cascades and transcription factors that are essentially involved in the anxiolytic effect of OXT, i.e. we will study alterations in anxiety-related behavior following specific pharmacogenetic manipulation of selected factors using siRNA, CRISPR/cas9, and antagonists in male and female rats. Although some candidate signaling cascades and transcription factors have already been associated with the OXTR in myometrial or neuronal cells, the involvement of those cascades in the regulation of any behavior is unknown. This allowed us to narrow the focus of this application down to a selected set of 7 neuronal factors that are likely to be involved in the regulation of anxiety-like behavior (TRPV2, MEK1/2, ERK5, CaMKII, PKC, CREB, MEF-2). After identifying intraneuronal target factors regulated by acute (Aim 1) or chronic (Aim 2) OXT in vivo, we will assess the molecular details and prove causal links between cascades, transcription factors, and gene transcription in vitro. We hypothesize that the unique combination of signaling cascades causes OXT-specific effects, which are dependent on the dose and duration of treatment, sex, and tissue (brain or periphery, Aim 3). Overall, we aim to reveal detailed neuronal mechanisms of action of OXT essential for the design of an effective and specific therapeutic treatment, e.g. of patients suffering from anxiety disorders.

对神经肽催产素（OXT）作为各种心理病理学（包括焦虑症）的治疗选择的行为影响的兴趣日益增长，这使人们需要更深入地了解急性后的分子过程，尤其是慢性OXT受体（OXTR）激活。令人惊讶的是，与动物和人类的行为研究大量相比，很少报道OXT效应的神经元和分子机制，尤其是在长期激活的细胞内信号级联级联及其下游靶蛋白和基因的情况下，因此，本项目的旨在揭示氧化不良的效果。长期在体内和体外慢性应用OXT后，细​​胞质或遗传改变。我们旨在确定基本上与OXT抗焦虑作用有关的信号传导级联和转录因子，即，使用siRNA，CRISPR/CAS9对选定因素进行特定的药物遗传操纵，以及男性和女性大鼠的拮抗剂，我们将研究与焦虑相关行为的变化。尽管某些候选信号传导级联和转录因子已经与肌层或神经元细胞中的OXTR相关，但这些级联反应参与任何行为的调节都是未知的。这使我们能够将本应用的焦点缩小到可能与焦虑样行为调节有关的7种神经元因素（TRPV2，MEK1/2，ERK5，CAMKII，PKC，PKC，CREB，MEF-2）。在鉴定了由急性调节（AIM 1）或慢性（AIM 2）OXT在体内调节的神经内靶因子之后，我们将评估分子细节，并证明体外级联因子，转录因子和体外基因转录之间的因果关系。我们假设信号级联反应的独特组合会引起oxt特异性效应，这取决于治疗，性别和组织的剂量和持续时间（脑或周围，AIM 3）。总体而言，我们旨在揭示OXT的详细神经元的作用机制，对于设计有效且特定的治疗方法，例如患有焦虑症的患者。