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

 描述(申请人提供：目前，中枢作用催产素受体激动剂正在引起相当大的兴趣，因为它们有潜力被开发为一系列神经精神疾病的新疗法，包括自闭症、精神分裂症、创伤后应激障碍、强迫症以及更广泛的情绪和焦虑症。事实上，一篇广泛的文献表明，催产素在夫妻关系和社会互动中起着中心作用，并进一步强调了众所周知的催产素产生抗抑郁和缓解焦虑作用的潜力。由于外周的催产素对血脑屏障的穿透能力很差，这种广泛而强大的中枢效应很可能依赖于位于下丘脑视上核和室旁核的大细胞神经分泌神经元释放的催产素，而大细胞神经分泌神经元是唯一大量产生催产素的中央核团。这些区域的氧化胆碱能神经元不同于中枢神经系统中的许多可兴奋细胞，因为它们有两种截然不同的释放肽的方式：旁分泌和突触(分别依赖于树突和轴突结构)。到目前为止，人们对大脑中旁分泌或突触释放催产素最终调节情绪情绪和社交行为的中枢回路的截然不同的机制知之甚少。在广义上，该项目试图通过开发技术来独立评估这些不同类型的内源性催产素能信号所涉及的神经生理机制来解决这一差距。更具体地说，目前的AIMS将利用一种全身渗透应激源激发PVN中催产素的持续旁分泌释放，该应激源最近被证明削弱了对心理应激的生理反应，并在社交和广泛性焦虑测试中产生明显的焦虑行为表型。基于大量的初步数据，Aim 1将检验这一假说，即下丘脑中催产素的旁分泌释放在很大程度上通过直接抑制表达促肾上腺皮质激素释放因子(Aim 1)的小细胞神经分泌神经元而有助于缓解焦虑表型。目标2随后将揭示一种先前意想不到的和可能的双突触机制，通过这种机制，催产素的旁分泌释放可以抑制PVN中的小细胞自主前神经元。最后，目标3将研究树突状和突触前OTRs的自分泌受体激活对PVN大细胞神经元的影响。这项工作有望揭示一个强大的正反馈回路，支持持续的旁分泌和突触催产素的增强释放。总体而言，目标1具有很高的潜在意义，因为它将表明一种明确的机制，通过该机制，中枢作用的催产素可以有效地调节压力反应的关键方面，这些方面长期以来一直与情绪和焦虑症的病因有关。此外，目标2-3通过揭示中枢旁分泌催产素信号的几个新的功能方面来增强该项目的整体意义，这些新功能方面可能有助于指导和促进寻求瞬时激活中枢OTRs的新疗法的合理开发。

 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.