Role of sexually dimorphic oxytocin receptor expressing neurons in the preoptic area

视前区表达性二形性催产素受体神经元的作用

• 批准号: 9895320
• 负责人: RYOICHI TERUYAMA
• 金额: $ 21.67万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895320
• 关键词: Address; Anatomy; Anxiety; Area; Attention; Behavior; Behavioral; Binding; Brain; Caring; Cell Nucleus; Cells; Characteristics; Clinical Trials; Clozapine; Designer Drugs; Development; Discipline of Nursing; Disease; Dopamine; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Estrogens; Female; Fluorescence; G-Protein-Coupled Receptors; Hormones; Image; In Vitro; Intervention; Lactation; Ligands; Maintenance; Manuscripts; Maternal Behavior; Medial; Mediating; Mental disorders; Milk Ejection; Mus; Mutate; Neurons; Neurotransmitters; Optic tract structure; Oxides; Oxytocin; Oxytocin Receptor; Pair Bond; Pharmaceutical Preparations; Pharmacology; Physiological; Postpartum Depression; Preoptic Areas; Proteins; Receptor Cell; Regulation; Reproductive Physiology; Research; Role; Sex Differences; Signal Transduction; Site; Social Behavior; System; Techniques; Uterine Contraction; Variant; Venus; Viral; Viral Vector; autism spectrum disorder; base; behavior influence; cell behavior; in vivo; insight; male; nanomolar; nerve supply; neural circuit; optimal treatments; prenatal; receptor; receptor expression; relating to nervous system; reproductive; sex; sexual dimorphism; sexual role; social; vector

Project Summary / Abstract The neurohypophysial hormone, oxytocin, is known for its critical role in female reproductive physiology, such as uterine contraction during labor and milk ejection while nursing. Oxytocin is also released in the brain and modulates many aspects of social behaviors, including social recognition, maternal behavior and pair bonding. Oxytocin influences social behaviors by binding to the oxytocin receptor (OXTR) located in various parts of the brain. In recent years, the oxytocin system in the brain has received tremendous attention as a potential pharmacological target for the treatment of many psychiatric disorders, such as anxiety, autism spectrum disorders, and postpartum depression. Despite the importance, the cellular characterization, connectivity, and regulation of OXTR expressing neurons in the brain is still largely unknown. We recently discovered a group of estrogen-dependent OXTR neurons that is exclusively present in the anteroventral periventricular nucleus (AVPV) in females, but not in males. The overall long-term objective of our project is to elucidate the behavioral significance and regulatory mechanisms of OXTR neurons in the AVPV. Because the AVPV is known to regulate parental behavior in a sex-specific manner, we hypothesize that oxytocin exerts parental behavior via OXTR neurons in the AVPV. To address this hypothesis, we will employ a "Designer Receptors Exclusively Activate by Designer Drug" (DREADD)-based approach to specifically manipulate activity of OXTR neurons in the AVPV in vivo and in vitro. DREADDs are mutated G-protein coupled receptors that are exclusively activated by the pharmacologically inert ligand clozapine-N-oxide (CNO) at nanomolar potency. Both the stimulatory and inhibitory DREADD will be introduced specifically to OXTR neurons using Cre-recombinase-dependent viral vectors. Neural activity of the DREADD-expressing OXTR neurons will be manipulated by CNO. In Aim 1, the effect of inhibition/activation of OXTR neurons in the AVPV on maternal behavior will be examined. In Aim 2, anatomical and functional connectivity of OXTR neurons in the AVPV will be examined using the Channelrhodopsin-assisted circuit mapping (CRACM) technique combined with electrophysiology and Ca++ imaging. The proposed studies will elucidate the sex-specific oxytocin neural circuitry system that regulates sex- specific social behaviors. The findings from this project will provide useful insight into sex-specific pharmacological interventions that may likely treat sex typical psychiatric disorders, such as postpartum depression (PPD).

项目摘要/摘要 神经垂体激素，催产素，因其在女性生殖生理中的关键作用而闻名，如 分娩时子宫收缩，哺乳时排乳。催产素也会在大脑中释放， 调节社会行为的许多方面，包括社会认可、母性行为和配对关系。 催产素通过与位于大脑不同部位的催产素受体结合来影响社会行为。 大脑。近年来，大脑中的催产素系统作为一种潜在的 治疗许多精神疾病的药物靶点，如焦虑症、自闭症 精神障碍和产后抑郁症。尽管很重要，但蜂窝特性、连接性和 大脑中表达OXTR的神经元的调控在很大程度上仍不清楚。我们最近发现了一组 仅存在于前腹侧脑室周围核的雌激素依赖型OXTR神经元 (AVPV)在女性，但在男性不是。我们项目的总体长期目标是阐明行为 OXTR神经元在动静脉动静脉畸形中的意义及调控机制。因为AVPV是已知的调节 在特定性别的父母行为中，我们假设催产素通过OXTR施加父母行为 动静脉动静脉内的神经元。为了解决这一假说，我们将采用一种“设计者受体，其唯一激活方式 基于“设计药物”(DREADD)的Avpv内OXTR神经元活动的特异性调控 体内和体外。DREADD是突变的G蛋白偶联受体，仅由 具有纳摩尔效力的药理惰性配体氯氮平-N-氧化物(CNO)。无论是刺激性的还是 抑制性DREADD将通过依赖Cre重组酶的病毒特异性地引入OXTR神经元 向量。表达DREADD的OXTR神经元的神经活动将受到CNO的调控。在目标1中， 我们将研究AVPV中OXTR神经元的抑制/激活对母体行为的影响。在目标2中， 我们将使用 电生理与钙离子结合的通道视紫红质辅助电路标测技术 成像。这项拟议的研究将阐明性别特有的催产素神经回路系统，该系统调节性别- 特定的社会行为。该项目的发现将为了解特定性别提供有用的见解。 可能治疗性典型精神障碍的药物干预，如产后 抑郁(PPD)。