Mu Opioid Receptors in Habenular Networks: Reward and/or Aversion?

摘要 当娱乐性吸毒转变为强制吸毒时，就会形成成瘾。而前者是 后者的主要动机是寻求回报，也受到其他因素的推动，包括增强 应激反应、戒毒的厌恶方面以及对旷日持久的负面影响的出现 禁欲。近年来，奖励和厌恶加工的概念涉及到重叠的大脑 已经建立了电路，以及奖励/厌恶网络的概念。缰核(Hb) 编码外部刺激的奖赏和厌恶两个方面，因此可能代表中央 奖励/厌恶电路积分器。值得注意的是，缰核内侧亚区(MHB)显示 Mu阿片受体(MORS)在大脑中的密度最高，但这种特殊受体的作用 人口是未知的。该项目将检验在MHB中表达的MORS调节 与药物滥用有关的奖励和厌恶过程的具体方面。 我们将利用上一个资助期的工具和初步调查结果。在目标1中，我们 将广泛描述内侧隔-MHB-脚间核中MOR表达的神经元 病毒示踪剂结合敲入的Mor-mCherry、Cnrb4-Cre或NOVICE的(MS-MHB-IPN)途径 我们目前开发的MOR-CRE小鼠。这一目标将提供电路级别的理解，将 补充目标2和3。目标2将识别行为和潜在的电路机制，由 MHB中的摩尔斯。我们将研究一系列可能在HB调节的奖励/厌恶行为 水平(奖励和奖励驱动的决策、吗啡和尼古丁戒断、对吗啡的厌恶 戒断和戒断)使用一种新的条件Cnrb4-MOR小鼠品系。减量物理吗啡 已经检测到撤资，将使用DREADD方法来概括这一行为， 可能还有其他表型。目标3将确定MOR和MOR阳性神经元的因果影响 MS-MHB-IPN网络中的活动及其对大脑的更广泛影响。我们将用开拓性 在活体小鼠中的功能磁共振成像(FMRI)，以及在 技术进步核心，绘制全脑功能连接、基于种子的连接模式 以及静息和吗啡治疗后Cnrb4-MOR小鼠的节间方向性。的后果 DREADD介导的对MHB中MOR+神经元的刺激也将通过活体动物的fMRI进行检测。 总而言之，这一提议将揭示人口密度最大、研究最少的人口(S)的作用。 这三个目标共同决定了这些受体在奖赏/厌恶相关行为中的重要性。 并阐明了潜在的电路机制。该项目还将为人类提供新的遗传小鼠品系 CSORDA(CnRb4-MOR，项目III)和神经科学界(MOR-CRE)，以及尖端非 侵入性动物成像将适用于创伤后应激障碍模型(PTSD模型，项目IV)和CSORDA之外。

ABSTRACT Addiction develops when recreational drug use switches to compulsive drug taking. While the former is predominantly motivated by reward seeking, the latter is also driven by other factors that include enhanced stress reactivity, aversive aspects of drug withdrawal and emergence of a negative affect upon protracted abstinence. In recent years the notion that reward and aversion processing engage overlapping brain circuits has been established, together with the concept of a reward/aversion network. The habenula (Hb) encodes both rewarding and aversive aspects of external stimuli, and may therefore represent a central integrator of reward/aversion circuits. Remarkably, the medial subdivision of habenula (MHb) shows highest density of mu opioid receptors (MORs) in the brain, but the role of this particular receptor population is unknown. This project will test the hypothesis that MORs expressed in the MHb regulate specific aspects of reward and aversion processes related to drug abuse. We will capitalize on tools and preliminary findings from the previous funding period. In Aim 1, we will extensively characterize MOR-expressing neurons in the medial septum-MHb-interpeduncular nucleus (MS-MHb-IPN) pathway using viral tracers combined with knock-in MOR-mcherry, Cnrb4-Cre or novel MOR-Cre mice that we currently develop. This Aim will provide circuit-level understanding that will complement Aims 2 and 3. Aim 2 will identify behaviors, and underlying circuit mechanisms, controlled by MORs in the MHb. We will examine a range of reward/aversion behaviors potentially mediated at the Hb level (reward and reward-driven decision-making, morphine and nicotine withdrawal, aversion to morphine withdrawal and abstinence) using a novel conditional Cnrb4-MOR mouse line. Reduced physical morphine withdrawal has already been detected and DREADD approaches will be used to recapitulate this behavior, and possibly other phenotypes. Aim 3 will identify the causal impact of MOR and MOR-positive neuron activities in MS-MHB-IPN networks, and their broader impact on the brain. We will use pioneering functional magnetic resonance imaging (fMRI) in live mice, and further fMRI strategies developed in the Technical Advancement Core, to map brain-wide functional connectivity, seed-based connectional patterns and inter-node directionality in Cnrb4-MOR mice at rest and after morphine treatment. Consequences of DREADD-mediated stimulation of MOR+ neurons in the MHb will also be examined by fMRI in live animals. In sum, this proposal will reveal the role(s) of the densest and less-well studied MOR population. The three aims together will determine importance of these receptors in reward/aversion-related behaviors and elucidate the underlying circuit mechanisms. The project will also provide novel genetic mouse lines for CSORDA (Cnrb4-MOR, Project III) and the neuroscience community (MOR-Cre), and cutting edge non- invasive animal imaging that will be applicable within (PTSD model, Project IV) and outside of CSORDA.