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

 描述（由申请人提供）：目前，中枢作用催产素受体（OTR）激动剂因其开发为一系列神经精神障碍（包括自闭症、精神分裂症、创伤后应激障碍、强迫症和更广泛的情绪和焦虑障碍）的新型治疗剂的潜力而引起相当大的兴趣。事实上，大量的文献暗示催产素在配对和社会互动中起着中枢作用，并进一步强调了催产素产生抗抑郁和抗焦虑作用的潜力。由于外周的催产素是血脑屏障的一个非常差的穿透者，所以这种广泛的强大的中枢效应很可能取决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;下丘脑视上核和室旁核是唯一大量产生催产素的中枢核。这些区域中的催产素能神经元与CNS中的许多可兴奋细胞不同，因为它们具有两种明显不同的方式来释放肽：旁分泌和突触（分别依赖于树突和轴突结构）。到目前为止，人们对大脑中催产素的旁分泌或突触释放最终调节情绪影响和社会行为的中枢回路的明显不同的机制知之甚少。从广义上讲，该项目旨在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传导所涉及的神经生理机制来解决这一差距。更具体地说，目前的目标将激励持续旁分泌释放催产素的PVN使用系统渗透应激，最近已被证明钝化的生理反应心因性应激，并产生明确的抗焦虑行为表型在测试中的社会和广泛性焦虑。基于广泛的初步数据，目的1将测试的假设，催产素的旁分泌释放下丘脑有助于抗焦虑表型在很大程度上通过直接抑制小细胞神经分泌神经元表达促肾上腺皮质激素释放因子（目的1）。目的2，然后将揭示一个以前意想不到的和可能的双突触机制，通过旁分泌释放催产素可以解除抑制PVN的小细胞前自主神经元。最后，目的3将检查自分泌受体激活的树突和突触前OTR的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，因为它将表明一种明确的机制，通过该机制，中枢作用的催产素可以有效调节长期以来与情绪和焦虑症病因有关的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的功能方面来增强该项目的整体意义，这些功能方面可能有助于指导和促进寻求瞬时激活中枢OTR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.