Kappa Opioid Receptor in Paraventricular Nucleus of Thalamus

Kappa阿片受体(KOR)是三种阿片受体之一。KOR激动剂产生止痛剂和 止痒作用，但其临床应用受到副作用的限制，最重要的是 烦躁不安和精神分裂。KOR拮抗剂显示出抗抑郁和抗焦虑的作用 它是一种啮齿动物，可用于治疗人类的药物成瘾。下丘脑室旁核 丘脑(PVT)是丘脑中线核团的最背侧核，是大脑中 表达高水平的KOR。PVT接受来自前皮质、下缘皮质和岛叶皮质的输入， 腹侧下丘脑束核和许多下丘脑、脑干核团。PVT将密集投影发送到几个 边缘结构，包括杏仁核、终纹的床核以及扁桃体的核和壳 伏隔核。PVT是大脑焦虑网络的一部分，参与应激反应、恐惧、 焦虑、兴奋、奖励和动态平衡。PVT的KOR水平与腹侧被盖的KOR水平相似 该地区，但科索沃特派团在PVT尚未确定其特征。对于拟议的研究，我们已经制定了一个 KOR-ICRE偶联他莫昔芬诱导型Cre的突变小鼠株系。在此应用程序中，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- 依赖Cre的狂犬病病毒介导的单突触逆行反应将决定神经元的表达 追踪。然后将对PVT KOR表达神经元的传出投射的大脑区域进行表征 使用依赖Cre的顺行追踪。PVT内KOR+神经元是否投射到不同的脑 接受来自不同大脑区域的神经支配的区域也将被调查。最后，强啡肽的起源 将探索对PVT的投入。对于目标2，我们将通过研究PVT KOR的功能来阐明其功能 PVT KOR基因条件性缺失对小鼠KOR激动剂镇痛等行为的影响 内脏痛模型、条件性位置厌恶、纳洛酮催促戒断体征、慢性厌恶 吗啡和焦虑样行为。对于目标3，我们将研究PVT KOR表达神经元的作用 在应激相关行为中，通过激活和抑制这些神经元，恐惧条件反射和厌恶 化学发生学方法。这将是这些PVT KOR表达神经元和KOR本身第一次 以全面的方式进行调查。确定KOR参与的神经元回路 而KOR+回路的功能意义将加深我们对KOR泛函的理解 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。这个 所获得的知识可能为开发KOR拮抗剂作为抗焦虑药物提供神经元基础。

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.