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Role of laterodorsal tegmental nucleus cholinergic and glutamatergic inputs to the ventral tegmental area in drug reward and sensitization

背侧被盖核胆碱能和谷氨酸能输入腹侧被盖区在药物奖赏和致敏中的作用

基本信息

批准号：
9097279
负责人：
Stephan Steidl
金额：
$ 41.52万
依托单位：
LOYOLA UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The contributions of midbrain dopamine (DA) systems to drug reward and to drug sensitization are clear. It is not clear which brain circuits most importantly contribute to changes in DA neurons following drug exposure. The laterodorsal tegmental nucleus (LDTg) provides parallel cholinergic (ACh) and glutamatergic (GLU) inputs to ventral tegmental area (VTA) DA neurons that importantly control the activity of midbrain DA systems. In rats and mice ACh and GLU inputs to the VTA modulate the rewarding effects of cocaine and of opiates. Understanding the contributions of LDTg ACh or GLU inputs to the VTA to drug reward and addiction requires a means of selectively targeting these inputs. Preliminary results in Cre transgenic mice indicate that selective optogenetic excitation (via channelrhodopsin 2) of LDTg ACh but not GLU axons in the VTA is rewarding. Selective optogenetic inhibition of LDTg GLU cells (via halorhodopsin) reduces the induction of cocaine locomotor sensitization (an established model that quantifies behavioral adaptations induced by repeated drug exposure thought to reflect underlying neural changes important for drug addiction) but does not affect the acquisition of cocaine conditioned place preference (CPP - an established model that tests primary drug reward). This suggests that these LDTg GLU afferents to the VTA may be a site at which GLU plasticity is important for addictive behaviors to occur. Considering the above, this project will test the hypothesis that LDTg ACh afferents to the VTA are important for reinforcement and for drug reward, and that LDTg GLU afferents to the VTA are important for the induction of sensitization following repeated drug exposure. Aim 1 focuses on establishing that excitation of LDTg ACh but not GLU axons to the VTA is rewarding. Aim 2 focuses on determining the contributions of LDTg ACh afferents to the VTA to cocaine (typical stimulant drug) and to morphine (typical opiate drug) CPP, by optogenetically inhibiting LDTg ACh or GLU axons in the VTA during drug conditioning. Aim 3 focuses on establishing the importance of LDTg GLU inputs to the VTA in the induction of drug sensitization by inhibiting LDTg GLU axons in the VTA during repeated cocaine- or morphine-induced locomotion testing. The critical contribution of the proposed research will be to define, for the first time, the sourc of VTA glutamate and acetylcholine that are important for drug reward and for sensitization. Characterizing the role of select LDTg inputs to the VTA in drug reward and locomotor sensitization will inform future studies aimed at developing mechanistically based interventions, targeting a specific neural circuit, seeking to prevent the long-lasting adaptations in DA neuron function that underlie addictive behaviors. In line with the goals of the R15 funding mechanism these experiments will continue to expose several Loyola University Chicago (a primary educational institution) undergraduate students to research in Behavioral Neuroscience.

描述（由申请人提供）：中脑多巴胺（DA）系统对药物奖赏和药物致敏的作用是明确的。目前尚不清楚哪些脑回路对药物暴露后DA神经元的变化最重要。背外侧被盖核（LDTg）为腹侧被盖区（VTA）DA神经元提供平行的胆碱能（ACh）和谷氨酸能（GLU）输入，腹侧被盖区（VTA）DA神经元重要地控制中脑DA系统的活动。在大鼠和小鼠中，ACh和GLU对VTA的输入调节可卡因和阿片类药物的奖励作用。了解LDTg ACh或GLU输入到VTA的药物奖励和成瘾的贡献，需要一种有选择地针对这些输入的手段。Cre转基因小鼠的初步结果表明，选择性光遗传学激发（通过通道视紫红质2）的LDTg ACh，而不是GLU轴突在腹侧被盖区是有益的。LDTg GLU细胞的选择性光遗传学抑制（通过盐视紫红质）减少可卡因运动敏化的诱导（一种量化由重复药物暴露诱导的行为适应的已建立模型，其被认为反映了对药物成瘾重要的潜在神经变化），但不影响可卡因条件性位置偏好（CPP -一种测试初级药物奖励的已建立模型）的获得。这表明，这些LDTg GLU传入腹侧被盖区可能是一个网站，在那里GLU可塑性是重要的成瘾行为发生。考虑到上述情况，本项目将测试的假设，即LDTg乙酰胆碱传入腹侧被盖区是重要的强化和药物奖励，和LDTg葡萄糖传入腹侧被盖区是重要的诱导敏化重复药物暴露后。目的1的重点是建立LDTg ACh，而不是GLU轴突的腹侧被盖区的兴奋是有益的。目的2的重点是确定的贡献LDTg ACh传入VTA可卡因（典型的兴奋剂药物）和吗啡（典型的阿片类药物）CPP，通过光遗传学抑制LDTg ACh或GLU轴突在药物条件反射过程中的VTA。目的3的重点是建立LDTg GLU输入的VTA在诱导药物致敏的重要性，通过抑制LDTg GLU轴突在重复可卡因或吗啡诱导的运动测试的VTA。拟议研究的关键贡献将是首次定义VTA谷氨酸和乙酰胆碱的来源，这对药物奖励和致敏很重要。描述选择LDTg输入到腹侧被盖区在药物奖励和运动敏感化中的作用将为未来的研究提供信息，这些研究旨在开发基于机制的干预措施，针对特定的神经回路，寻求防止成瘾行为背后的DA神经元功能的长期适应。在与R15资助机制的目标线这些实验将继续暴露几个洛约拉大学芝加哥（小学教育机构）的本科生在行为神经科学的研究。