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Kappa Opioid Receptor in Paraventricular Nucleus of Thalamus

丘脑室旁核中的 Kappa 阿片受体

基本信息

批准号：
10659960
负责人：
LEE-YUAN LIU-CHEN
金额：
$ 60.74万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659960
关键词：
Abbreviations Absence of pain sensation Addictive Behavior Amygdaloid structure Analgesics Anterior Anti-Anxiety Agents Antidepressive Agents Antipruritic Effect Anxiety Area Arousal Behavior Brain Brain Stem Brain region California Cell Nucleus Chronic Collaborations Coping Behavior Coupled Diuresis Dorsal Drug Addiction Drug abuse Dynorphins Enterobacteria phage P1 Cre recombinase Exhibits Fright Homeostasis Human Hypothalamic structure In Situ Hybridization Injections Knock-in Mouse Knockout Mice Knowledge acquisition Limbic System Link Literature LoxP-flanked allele Mediating Mental Depression Mental Health Messenger RNA Midline Thalamic Nuclei Morphine Mus Mutant Strains Mice Naloxone Neuroanatomy Neurons Nucleus Accumbens Opioid Antagonist Opioid Receptor Opioid agonist Pathway interactions Pennsylvania Peptides Play Prefrontal Cortex Proteins Psychopathology Publishing Rabies Rabies virus Reporter Research Rewards Rodent Role Secure Seminal Services Source Stress Stress and Coping Structure Structure of paraventricular nucleus of thalamus Structure of terminal stria nuclei of preoptic region Tamoxifen Testing Time Universities Ventral Tegmental Area Viral Viral Vector Virus Visceral pain Water Withdrawal Work anxiety-like behavior base behavioral response biological adaptation to stress clinical development conditional knockout conditioned fear dysphoria experience genetic approach in vivo inducible Cre kappa opioid receptors negative affect nerve supply neuronal circuitry pain model receptor response side effect

项目摘要

The kappa opioid receptor (KOR) is one of the three opioid receptors. KOR agonists produce analgesic and anti-pruritic effects, but their development for clinical use has been limited by side effects, most importantly dysphoria and psychotomimesis. KOR antagonists display antidepressant- and anti-anxiety-like effects in rodents and may be useful for the treatment of drug addiction in humans. The paraventricular nucleus of the thalamus (PVT), the most dorsal nucleus of the thalamic midline nuclei, is among the brain regions that express high levels of KOR. The PVT receives inputs from the prelimbic, infralimbic and insular cortices, the ventral subiculum and many hypothalamic and brain stem nuclei. The PVT sends dense projections to several limbic structures including the amygdala, the bed nucleus of the stria terminalis, and the core and shell of the nucleus accumbens. The PVT is part of the brain anxiety network and is involved in stress responses, fear, anxiety, arousal, reward, and homeostasis. The KOR level in the PVT is similar to that in the ventral tegmental area, but KOR in the PVT has not yet been characterized. For the proposed studies, we have generated a mutant mouse line expressing tamoxifen-inducible Cre conjugated to KOR (KOR-iCre). In this application, we propose the following three specific aims. For the Aim 1, the origins of afferent projections to PVT KOR- expressing neurons will be determined by Cre-dependent rabies virus-mediated monosynaptic retrograde tracing. The brain regions of efferent projections of PVT KOR-expressing neurons will then be characterized using Cre-dependent anterograde tracing. Whether KOR+ neurons in the PVT projecting to different brain regions receive innervations from different brain areas will also be investigated. Finally, the origin of dynorphin inputs into the PVT will be explored. For the Aim 2, we will elucidate the functions of PVT KOR by examining the effects of conditional deletion of PVT KOR on behaviors such as KOR agonist-induced analgesia in a visceral pain model, conditioned place aversion, naloxone-precipitated withdrawal signs, aversion after chronic morphine and anxiety-like behaviors. For the Aim 3, we will examine the roles of PVT KOR-expressing neurons in stress-related behaviors, fear conditioning and aversion by activation and inhibition of these neurons via chemogenetic approaches. This will be the first time that these PVT KOR-expressing neurons and KOR per se are investigated in a comprehensive manner. Determining the neuronal circuitries in which the KOR is involved and the functional significance of KOR+ circuits will enhance our understanding of KOR functional neuroanatomy and KOR-mediated aversion, anxiety, stress responses and other psychopathology. The knowledge acquired may provide the neuronal basis for developing KOR antagonists as anti-anxiety agents.

Kappa阿片受体（KOR）是三种阿片受体之一。KOR激动剂产生镇痛剂，但其临床应用的发展受到副作用的限制，最重要的是焦虑症和拟精神病KOR拮抗剂显示抗抑郁和抗焦虑样作用，啮齿类动物，并可用于治疗人类的药物成瘾。脑室旁核丘脑（PVT）是丘脑中线核的最背侧核，是表达高水平的KOR。PVT接收来自前边缘、下边缘和岛叶皮质的输入，腹侧下托和许多下丘脑和脑干核团。PVT将密集的投影发送到几个边缘系统结构包括杏仁核、终纹的床核以及丘脑核PVT是大脑焦虑网络的一部分，涉及压力反应，恐惧，焦虑，兴奋，奖励，和内稳态PVT的KOR水平与腹侧被盖相似地区，但在PVT的KOR尚未被定性。对于建议的研究，我们已生成一个表达与KOR缀合的他莫昔芬诱导型Cre的突变小鼠系（KOR-iCre）。在本申请中，我们提出以下三个具体目标。对于目的1，PVT-KOR的传入投射的起源- 表达神经元将通过依赖于Cre的狂犬病毒介导的单突触逆行来确定追踪然后将表征表达PVT KOR的神经元的传出投射的脑区域使用依赖于Cr的顺行追踪。PVT中KOR+神经元是否投射到不同脑区接受来自不同脑区的神经支配的区域也将被研究。最后，强啡肽的起源将探讨对PVT的输入。对于目标2，我们将通过检查研究PVT KOR条件性缺失对行为的影响，如KOR激动剂诱导的镇痛，内脏痛模型，条件性位置厌恶，纳洛酮催促戒断症状，慢性吗啡和类似焦虑的行为对于目标3，我们将研究PVT KOR表达神经元的作用，在与压力相关的行为中，通过激活和抑制这些神经元来调节恐惧和厌恶，化学遗传学方法这将是第一次，这些PVT KOR表达神经元和KOR本身以全面的方式进行调查。确定KOR参与的神经元回路以及KOR+电路的功能意义，将加深我们对KOR功能的理解神经解剖学和KOR介导的厌恶、焦虑、应激反应和其他精神病理学。的所获得的知识可以为开发作为抗焦虑剂的KOR拮抗剂提供神经元基础。