EPH MOLECULES IN OTOGENY OF BRAIN REWARD CIRCUITS

描述（申请人摘要）： 本研究的长期目标是阐明 成年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代谢中起关键作用， 依赖和大脑奖励。 多巴胺系统的神经结构 在地形上是相互联系的。 腹侧多巴胺能神经元 被盖区（VTA）主要投射到腹内侧纹状体（ 包括嗅核、嗅结节和腹内侧部 的尾壳核），而黑质（SN）的神经元项目 背外侧纹状体（对应背外侧尾状核） 壳核）。 虽然近两年来人们已经知道了地形关系， 几十年，似乎是身体和心理依赖的关键 在药物方面，这种拓扑投影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 突触前和突触后的化学亲和标记梯度 神经元 与此建议一致，我们已经显示了麋鹿，和Eph家庭 受体及其配体Lerk 5以互补模式表达， 腹侧被盖区/黑质，以及靶核， 尾壳核 此外，我们还证明了Lerk 5是 在成年小鼠中不受可卡因治疗的调节。 进行的既往研究 在我们的实验室和其他实验室已经证明， 在互补梯度中表达的配体和受体指定了 大脑中的地形投影图。 总之，这些观察结果导致了 假设Elk及其配体调节轴突靶向， 多巴胺能系统的可塑性 为了验证这一假设 并检查麋鹿和Lerk 5在多巴胺个体发育中的作用， 系统，我们建议首先检查的空间和时间模式， 投射发育过程中麋鹿及其配体的表达。 我们 还将研究Lerk 5对VTA/SN多巴胺能神经元的生物学效应。 神经元在体外使用共培养试验，我们已经开发。 此外，委员会认为， 体外Elk和Lerk 5的表达将被改变， 转基因技术，以审查对发展的影响， 提升多巴胺系统 为了研究Elk和Lerk 5是否也扮演了 在药物诱导的可塑性中，我们将研究药物治疗如何改变他们的神经系统。 成人的表达。 了解控制 轴突的连接和修饰可能会揭示潜在的 药物成瘾的机制，以及涉及这一系统的疾病， 帕金森氏症

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.