EPH MOLECULES IN OTOGENY OF BRAIN REWARD CIRCUITS

EPH 分子在大脑奖赏电路发育中的作用

基本信息

批准号：
6342273
负责人：
RENPING ZHOU
金额：
$ 22.83万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-02-01 至 2002-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6342273
关键词：
brain mapping caudate nucleus developmental neurobiology dopamine receptor drug addiction genetic promoter element genetically modified animals in situ hybridization laboratory mouse laboratory rat mixed tissue /cell culture neural plasticity neuronal guidance nucleus accumbens receptor expression reinforcer tissue /cell culture tyrosine 3 monooxygenase

项目摘要

DESCRIPTION (Applicant's Abstract): The long term goal of this study is to elucidate the molecular mechanisms of axonal targeting during development and plasticity in the adult in the mesencephalic dopaminergic system, which plays key roles in mediating drug dependence and brain reward. The neural structures in the dopamine system are interconnected topographically. Dopaminergic neuron in the ventral tegmental area (VTA) project primarily to the ventromedial striatum (which include the nucleus accumbens, olfactory tubercle and ventromedial portion of the caudate putamen), while neurons in the substantia nigra (SN) project to dorsolateral striatum (which corresponds to dorsolateral caudate putamen). Although the topographic relations have been known for nearly two decades, and appear to be critical for physical and psychological dependence on drugs, the molecular basis for this topographic projection is unknown. It has been proposed that topographic mapping is accomplished by matching gradients of chemoaffinity labels on the presynaptic and postsynaptic neurons. Consistent with this proposal, we have shown Elk, and Eph family receptor, and its ligand, Lerk5, are expressed in complementary patterns in the ventral tegmental area/substantial nigra, and the targets, nucleus accumbens/caudate-putamen. Furthermore, we have shown that Lerk5 is unregulated by cocaine treatment in adult mice. Previous studies conducted in our laboratory and in others have shown that interactions between Eph ligands and receptors expressed in complementary gradients specify the topographic projection maps in the brain. Together, these observations led to the hypothesis that Elk and its ligand regulate axonal targeting and plasticity in the ascending dopaminergic system. To test this hypothesis and examine the roles of Elk and Lerk5 in the ontogeny of the dopamine system, we propose to first examine the spatial and temporal patterns of expression of Elk and its ligand during the development of projection. We will also study the biological effects of Lerk5 on the VTA/SN dopaminergic neurons in vitro using a co-culture assay we have developed. Furthermore, the expression of Elk and Lerk5 expression in vitro will be altered using transgenic technology to examine the effects on the development of the ascending dopamine system. To study whether Elk and Lerk5 also play roles in drug-induced plasticity, we will examine how drug treatment alters their expression in the adult. Understanding the molecular basis governing the axonal connections and modifications may shed new light on the underlying mechanism of drug addiction, as well as diseases involving this system such as Parkinson's disease.

描述（申请人的摘要）：这项研究的长期目标是阐明成年人的发展和可塑性期间的轴突靶向中脑多巴胺能系统，在介导药物中起关键作用依赖和大脑奖励。多巴胺系统中的神经结构在地形上相互联系。腹侧多巴胺能神经元支盖区域（VTA）主要针对腹侧纹状体（包括伏隔核，嗅觉结节和腹侧部分尾状壳），而黑质nigra（SN）项目中的神经元到背外侧纹状体（对应于背外侧尾状 putamen）。虽然地形关系已有近两个数十年，似乎对于身体和心理依赖至关重要在药物上，该地形投影的分子基础尚不清楚。已经提出，通过匹配来完成地形映射突触前和突触后的化学亲和标签梯度神经元。与此提案一致，我们已经向麋鹿和埃夫家族展示了受体及其配体LERK5以互补的方式表示腹侧对段区域/实质性NIGRA和靶标的核伏伏剂/尾状驾驶员。此外，我们已经证明LERK5是在成年小鼠中可卡因治疗不受管制。先前的研究进行了在我们的实验室和其他实验室中，EPH之间的相互作用在互补梯度中表达的配体和受体指定大脑中的地形投影图。这些观察结果在一起关于麋鹿及其配体调节轴突靶向的假设和上升多巴胺能系统中的可塑性。检验这一假设并检查麋鹿和LERK5在多巴胺个体发育中的作用系统，我们建议首先检查麋鹿及其配体在投射过程中的表达。我们还将研究LERK5对VTA/SN多巴胺能的生物学作用使用我们开发的共培养测定法进行体外神经元。此外， Elk和LERK5表达在体外的表达将改变使用转基因技术检查对发展的影响上升多巴胺系统。研究麋鹿和LERK5是否也扮演角色在药物诱导的可塑性中，我们将研究药物治疗如何改变其成人的表达。了解分子基础管理轴突连接和修改可能会在基础上散发出新的灯光吸毒的机制以及涉及该系统的疾病作为帕金森氏病。