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（由适用：目前提供的描述，目前，中央作用的氧合蛋白受体（OTR）激动剂正在引起人们的考虑，因为它们的潜力是作为一系列神经精神疾病的新治疗而引起的，包括自闭症，精神分裂症，后压力障碍，创伤后压力障碍，强迫性障碍和更多的经典情绪和焦虑症的经历。粘合和社交相互作用，并进一步凸显了氧气素产生抗抑郁和抗焦虑作用的潜力，因为外周中的氧毒素是血脑屏障的非常差的渗透者在这些区域中产生催产素神经元的唯一中央核核能与中枢神经系统中的许多令人兴奋的细胞不同，因为它们具有释放肽的两种明显不同的方式：旁分泌和突触（分别取决于树突状结构和轴突结构）。迄今为止，关于旁分泌或突触在大脑中的突触释放的机制鲜为不同的机制知之甚少，最终会调节中央电路的情绪影响和社会行为。从广义上讲，该项目试图通过开发技术来解决这些差距，以独立评估这些不同类型的内源性羟基毒素能信号传导所参与的神经生理机制。更具体地说，当前的目标将使用全身性渗透应激元素融合PVN中持续的旁分泌释放，最近已证明，该应激剂在社交和普遍的动画测试中产生明确的抗焦虑行为表型。基于广泛的初步数据，AIM 1将检验以下假设：下丘脑中氧气释放的旁分泌释放在很大程度上是通过直接抑制副细胞神经分泌元的抗焦虑表型，这些神经元神经元表达表达皮质激素释放因子（AIM 1）。然后，AIM 2将揭示出一种以前出乎意料的和可能的脱节机制，氧气的旁分泌释放。可以抑制PVN中的副细胞前体神经元。最后，AIM 3将检查树突状受体和突触前OTR对PVN磁神经元的自分泌受体激活的影响。预计这项工作将揭示出强大的积极反馈回路，该反馈循环支持持续的旁分泌和增强的突触氧释放。总体而言，AIM 1具有很高的潜在意义，因为它将表明一种清晰的机制，通过该机制，中央作用的氧气可以有效地调节长期以来在情绪和焦虑症的病因学中实施的压力反应的关键方面。此外，AIMS 2-3通过揭示了中央旁分泌氧信号的几个新功能方面，从而提高了项目的整体意义，这些功能可能有助于指导和信息为试图暂时激活中央OTR的新疗法的合理发展。