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）：本研究的长期目标是阐明其分子机制成人发育和可塑性过程中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性和大脑奖励。多巴胺系统的神经结构在地形上是相互关联的。腹侧多巴胺能神经元被盖区（VTA）主要投射到腹内侧纹状体（包括伏隔核、嗅结节和腹内侧部分尾壳核），而黑质（SN）项目中的神经元到背外侧纹状体（对应于背外侧尾状核）壳门）。尽管地形关系已为人所知近两年数十年，并且似乎对身体和心理依赖至关重要在药物方面，这种地形预测的分子基础尚不清楚。有人提出，地形测绘是通过匹配来完成的突触前和突触后化学亲和标签的梯度神经元。与此提案一致，我们展示了 Elk 和 Eph 家族受体及其配体 Lerk5 以互补模式表达腹侧被盖区/黑质，以及目标、核伏隔核/尾壳核。此外，我们还证明了 Lerk5 是成年小鼠中不受可卡因治疗的调节。之前进行的研究我们的实验室和其他实验室已经表明，Eph 之间的相互作用以互补梯度表达的配体和受体指定大脑中的地形投影图。这些观察结果共同导致假设 Elk 及其配体调节轴突靶向上行多巴胺能系统的可塑性。为了检验这个假设并检查 Elk 和 Lerk5 在多巴胺个体发育中的作用系统，我们建议首先检查空间和时间模式 Elk及其配体在投射发育过程中的表达。我们还将研究 Lerk5 对 VTA/SN 多巴胺能的生物效应使用我们开发的共培养测定体外神经元。此外， Elk 和 Lerk5 的体外表达将使用以下方法改变转基因技术检查其对发育的影响上行多巴胺系统。研究Elk和Lerk5是否也发挥作用在药物诱导的可塑性中，我们将研究药物治疗如何改变它们成人的表达。了解控制的分子基础轴突连接和修改可能为底层提供新的线索药物成瘾的机制，以及涉及该系统的疾病，例如如帕金森病。