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心绞痛的分子机制。 成人发育过程中轴突靶向性和可塑性的研究 中脑多巴胺能系统在药物中介中的关键作用 依赖和大脑奖励。多巴胺系统中的神经结构 在地形上是相互关联的。腹侧的多巴胺能神经元 被盖区(VTA)主要投射到腹内侧纹状体( 包括伏核、嗅结节和腹内侧部 尾壳核)，而黑质(SN)神经元投射 至背外侧纹状体(对应于背外侧尾状核 壳核)。尽管近两年来已知的地形关系 几十年，而且似乎对身体和心理依赖至关重要 在药物方面，这种地形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 突触前和突触后化学亲和力标记的梯度 神经元。与这项提议一致，我们已经向Elk和Eph家人展示了 受体及其配体Lerk5以互补模式表达。 腹侧被盖区/实质黑质，靶核 伏隔/尾壳核。此外，我们已经证明了Lerk5是 成年小鼠不受可卡因治疗的影响。先前进行的研究 在我们的实验室和其他实验室已经证明了Eph之间的相互作用 以互补梯度表达的配体和受体指定 大脑中的地形图。总而言之，这些观察结果导致 对ELK及其配体调节轴突靶向和 上升的多巴胺能系统的可塑性。为了检验这一假说 并研究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多巴胺能神经元的生物学作用 利用我们开发的一种共培养方法进行神经元体外培养。此外， ELK和Lerk5在体外的表达将被改变 转基因技术，以检查对人类发育的影响 提升的多巴胺系统。为了研究Elk和Lerk5是否也扮演着角色 在药物诱导的可塑性中，我们将研究药物治疗如何改变它们的 在成人中的表达。了解支配基因的分子基础 轴突的连接和修饰可能会为潜在的 药物成瘾的机制，以及涉及该系统的疾病 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.