Novel Aspects of Central Oxytocin Signaling Relevant to Mood/Anxiety Disorders

与情绪/焦虑障碍相关的中枢催产素信号的新方面

• 批准号: 9014566
• 负责人: CHARLES J FRAZIER
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014566
• 关键词: Acute; Address; Affect; Agonist; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Area; Autistic Disorder; Behavioral; Blood - brain barrier anatomy; Brain; Cell Nucleus; Cells; Corticotropin-Releasing Hormone; Coupled; Data; Development; Disinhibition; Drug Kinetics; Electrophysiology (science); Etiology; Feedback; Future; Genetic; Goals; Health; Hour; Hypernatremia; Hypothalamic structure; Laboratories; Literature; Midbrain structure; Modality; Mood Disorders; Moods; Neurons; Neuropeptides; Obsessive-Compulsive Disorder; Output; Oxytocin; Oxytocin Receptor; Pair Bond; Paracrine Communication; Peptides; Phenotype; Physiological; Physiology; Plasma; Post-Traumatic Stress Disorders; Receptor Activation; Regulation; Reporting; Research; Schizophrenia; Signal Transduction; Social Behavior; Social Interaction; Sodium; Stress; Structure; Synapses; Techniques; Testing; Therapeutic Agents; Therapeutic Uses; Work; anxiety-like behavior; autocrine; base; biological adaptation to stress; generalized anxiety; insight; interest; magnocellular; neurophysiology; neuropsychiatric disorder; novel; novel strategies; novel therapeutics; paracrine; paraventricular nucleus; parvocellular; presynaptic; response; social anxiety; stressor; supraoptic nucleus; tool

 DESCRIPTION (provided by applicant: Currently, centrally acting oxytocin receptor (OTR) agonists are generating considerable interest for their potential to be developed as novel therapeutics for a range of neuropsychiatric disorders including autism, schizophrenia, post-traumatic stress disorder, obsessive compulsive disorder, and more generalized mood and anxiety disorders. Indeed, an extensive literature implicates centrally acting oxytocin in pair bonding and social interactions, and further highlights well noted potential for oxytocin to produce antidepressive and anxiolytic effects. Because oxytocin in the periphery is a very poor penetrator of the blood brain barrier, it is likely that this wide array of powerful central effect depends on oxytocin released by magnocellular neurosecretory neurons located in the supraoptic and paraventricular nuclei of the hypothalamus; the only central nuclei to produce oxytocin in abundance. Oxytocinergic neurons in these areas are unlike many excitable cells in the CNS in that they have two distinctly different ways to release peptide: paracrine and synaptic (which depend on dendritic and axonal structures, respectively). To date, very little is known about the distinctly different mechanisms though which paracrine or synaptic release of oxytocin in the brain ultimately modulates central circuits underlying mood affect and social behavior. In a broad sense, this project seeks to address that gap by developing techniques to independently evaluate neurophysiological mechanisms engaged by these distinct types of endogenous oxytocinergic signaling. More specifically, current Aims will motivate sustained paracrine release of oxytocin in the PVN using a systemic osmotic stressor that has recently been demonstrated to blunt the physiological response to psychogenic stress, and to produce a clear anxiolytic behavioral phenotype in tests for social and generalized anxiety. Based on extensive preliminary data, Aim 1 will test the hypothesis that paracrine release of oxytocin in the hypothalamus contributes to an anxiolytic phenotype in large part by directly inhibiting parvocellular neurosecretory neurons that express corticotropin releasing factor (Aim 1). Aim 2 will then reveal a previously unexpected and likely disynaptic mechanism through which paracrine release of oxytocin can disinhibit parvocellular preautonomic neurons in the PVN. Finally, Aim 3 will examine the effect of autocrine receptor activation of both dendritic and presynaptic OTRs on PVN magnocellular neurons. This work is expected to reveal a powerful positive feedback loop that supports both sustained paracrine and enhanced synaptic oxytocin release. Overall, Aim 1 has high potential significance because it will indicate a clear mechanism through which centrally acting oxytocin can effectively modulate key aspects of the stress response that have long been implicated in the etiology of mood and anxiety disorders. Further, Aims 2-3 enhance the overall significance of the project by revealing several new functional aspects of the central paracrine oxytocin signal that are likely to help guide and infor rational development of new therapeutics that seek to transiently activate central OTRs.

 描述（由申请人提供：目前，中枢作用的催产素受体（OTR）激动剂因其被开发为治疗一系列神经精神疾病（包括自闭症、精神分裂症、创伤后应激障碍、强迫症、事实上，大量文献表明催产素在夫妻关系和社交互动中发挥着中枢作用，并进一步强调了众所周知的潜力。由于外周催产素对血脑屏障的穿透性非常差，因此这种广泛的强大中枢作用可能依赖于位于视上核和室旁核的大细胞神经分泌神经元释放的催产素。下丘脑的唯一中央核团，这些区域中的催产素能神经元与许多兴奋性细胞不同。在中枢神经系统中，它们有两种截然不同的释放肽的方式：旁分泌和突触（分别取决于树突和轴突结构）迄今为止，对于旁分泌或突触释放催产素的截然不同的机制知之甚少。从广义上讲，大脑中的神经元最终调节情绪影响和社会行为的中枢回路，该项目旨在通过开发独立评估这些不同类型的内源性神经生理机制的技术来解决这一差距。更具体地说，当前的目标将使用全身渗透应激源刺激 PVN 中催产素的持续旁分泌释放，最近已证明该应激源可以减弱对心因性应激的生理反应，并在社交和测试中产生明显的抗焦虑行为表型。基于广泛的初步数据，目标 1 将检验下丘脑中催产素的旁分泌释放有助于抗焦虑表型的假设。很大程度上是通过直接抑制表达促肾上腺皮质激素释放因子的小细胞神经分泌神经元（目标 1），然后将揭示一种先前意想不到的、可能的非突触机制，通过该机制，催产素的旁分泌释放可以抑制 PVN 中的小细胞前自主神经元。这项工作研究了树突状和突触前 OTR 的自分泌受体激活对 PVN 大细胞神经元的影响。预计将揭示一个强大的正反馈循环，支持持续的旁分泌和增强的突触催产素释放。总体而言，目标 1 具有很高的潜在意义，因为它将表明一个明确的机制，通过该机制，中枢作用的催产素可以有效地调节应激反应的关键方面。此外，目标 2-3 通过揭示中枢旁分泌催产素信号的几个新功能方面增强了该项目的整体意义。帮助指导和指导合理开发旨在暂时激活中枢 OTR 的新疗法。