Modulation of Dopaminergic VTA Neurons by Urotensin II

描述(申请人提供)：中脑边缘通路通过腹侧被盖区(VTA)神经元释放的多巴胺投射到伏隔核(NAC)，被认为在动机和奖励过程中发挥作用。一些成瘾药物通过增强中脑边缘多巴胺的活性而对行为产生强大的影响。VTA神经元的多巴胺释放受多种因素和神经元结构的控制。向VTA提供调节输入的一条通路起源于脑干的桥中核。候选人已经证明，中桥-VTA-NAC通路受新型神经肽Urotensin II(UII)的调节。 这位候选人还展示了白喉毒素与Ull融合的实用性。这种毒素能够选择性地消融表达UII-R的神经元，而不损害周围组织。通过将这种毒素与微透析和行为模式相结合，我们将确定Ull是否可以调节强化的行为。在另一项工作中，Ull被证明能产生细胞重塑，这可能表明它在神经可塑性中发挥了作用。因此，未来的研究将包括UII-R在分子神经生物学变化和成瘾发展中的作用的研究。 加州大学欧文分校聚集了一批在新神经肽功能领域独树一帜的资深科学家。这种协作环境将使候选人接触到新神经肽系统表征的许多不同方面。在他的研究生生涯和随后的博士后研究中，候选人一直负责初步研究、发起和促进合作以及手稿的写作。因此，从建立独立研究到建立ULL系统的分子神经药理学的过渡应该是平稳的。导师的作用将是为完成足够高质量的研究提供空间和资源，使候选人能够成功竞争一所杰出研究型大学的教职。 与公共健康相关：目前的提议是相关的，因为新的神经肽尾加压素II可能是以前未被认识到的在动机过程调节中的角色。对它的研究可能会增加另一层对精神活性药物复杂作用的理解。

DESCRIPTION (provided by applicant): The mesolimbic pathway through the release of dopamine from neurons in the ventral tegmental area (VTA), which project to the nucleus accumbens (NAc), is thought to have a role in motivation and reward processes. Some addictive drugs produce their potent effects on behavior by enhancing mesolimbic dopamine activity. Release of dopamine from VTA neurons is controlled by various factors and neuronal structures. One pathway providing regulatory input to the VTA originates in the mesopontine nuclei of the brainstem. The candidate has shown that the mesopontine-VTA-NAc pathway is modulated by the novel neuropeptide urotensin II (UII). The candidate has also shown utility of a fusion of diphtheria toxin with Ull. This toxin is able to selectively ablate UII-R expressing neurons without damage to surrounding tissue. Through the combination of this toxin with microdialysis and behavioral paradigms, we will establish whether Ull can modulate reinforced behaviors. In other work Ull has been shown to produce cellular remolding, which may point to a role in neuroplasticity. Therefore, future studies will include the investigation of the role of UII-R in molecular neurobiological changes and the development of addiction. The University of California, Irvine is home to a unique concentration of established scientists in the field of novel neuropeptide function. This collaborative environment will expose the candidate to many different aspects of the characterization of novel neuropeptide systems. Throughout his graduate career, and subsequent post-doctoral research, the candidate has been responsible for the primary research, initiating and fostering of collaborations, and the writing of manuscripts. Therefore, the transition to establishing independent research in to the molecular neuropharmacology of the Ull system should be smooth. The mentors' roles will be to provide space and resources for the completion of research of sufficient quality to allow the candidate to successfully compete for a faculty position at an outstanding research university. PUBLIC HEALTH RELEVANCE: The current proposal is relevant in that the novel neuropeptide urotensin II may be a previously unrecognized player in the regulation of motivational processes. The investigation of which may add another layer of understanding the complex action of psychoactive drugs.