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

项目总结/摘要 神经垂体激素催产素因其在女性生殖生理学中的关键作用而闻名， 如分娩时子宫收缩和哺乳时乳汁排出。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。 催产素通过与位于脑内不同部位的催产素受体（OXTR）结合来影响社会行为。 个脑袋近年来，大脑中的催产素系统作为一种潜在的 药理学靶点用于治疗许多精神障碍，如焦虑症、自闭症谱系 失调和产后抑郁症尽管重要性，细胞表征，连接性， 脑中表达OXTR的神经元的调节仍然是未知的。我们最近发现了一群 雌激素依赖性OXTR神经元，仅存在于前腹侧室周核 （AVPV）在女性中，但不在男性中。我们项目的总体长期目标是阐明 AVPV中OXTR神经元的意义和调控机制。因为已知AVPV调节 父母的行为在性别特异性的方式，我们假设催产素发挥父母的行为，通过OXTR AVPV中的神经元。为了解决这一假设，我们将采用“设计器受体排他性激活， 设计药物”（DREADD）的方法来特异性地操纵AVPV中OXTR神经元的活性， 体内和体外。DREADDs是突变的G蛋白偶联受体，其仅由 在纳摩尔效力下，抑制惰性配体氯氮平-N-氧化物（CNO）。无论是刺激和 抑制性DREADD将使用Cre重组酶依赖性病毒特异性引入OXTR神经元 向量。表达DREADD的OXTR神经元的神经活性将由CNO操纵。在目标1中， 将检查AVPV中OXTR神经元的抑制/激活对母体行为的影响。在目标2中， AVPV中OXTR神经元的解剖和功能连接将使用 视紫红质辅助电路标测（CRACM）技术结合电生理和Ca++ 显像拟议的研究将阐明调节性别的性别特异性催产素神经回路系统， 具体的社会行为。该项目的发现将为性别特异性提供有用的见解。 可能治疗性典型精神疾病的药物干预，如产后 抑郁症（PPD）。

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).