Modulation of Dopaminergic VTA Neurons by Urotensin II

尾加压素 II 对多巴胺能 VTA 神经元的调节

基本信息

批准号：
8675360
负责人：
Stewart Donaldson Clark
金额：
$ 3.84万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675360
关键词：
Award Behavior Behavioral Paradigm Binding Biological Assay Brain Stem Cell Nucleus Complex Development Diphtheria Toxin Dopamine Drug Addiction Drug Targeting Electron Microscopy Fusion Toxin Future Genes Genetic Predisposition to Disease Goals Heterogeneity In Vitro Instruction Investigation Maintenance Microdialysis Molecular Motivation Neurobiology Neuromodulator Neuronal Plasticity Neurons Neuropeptides Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Postdoctoral Fellow Production Psychotropic Drugs Quality Control Recombinants Regulation Role Self Administration Side Structure Synapses System Testing Tissues Toxin Ventral Tegmental Area Work addiction dopaminergic neuron in vivo motivational processes neuronal circuitry novel preference prepulse inhibition radioligand receptor reinforced behavior reward processing urotensin II

项目摘要

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. We have previously shown that the mesopontine-VTA-NAc pathway is modulated by the novel neuropeptide urotensin II (Uil). To facilitate our studies we have developed and validated a fusion of diphtheria toxin with UN (Dtx-Uli). This toxin is able to selectively ablate Ull-R expressing neurons of the mesopontine without damage to surrounding tissue. Through the combination ofthis toxin with microdialysis and behavioral paradigms (self-administration and conditioned place preference), we will establish whether Uil can modulate reinforced behaviors. In addition, to better understand the function ofthe mesopontine nuclei, the Dtx-Uli will be used to ablate neurons of this region. Subsequently, different aspects of proposed mesopontine function will be tested ( ex. prepulse inhibition, conditioned place preference). Drug addiction is a multifactorial condition. This heterogeneity is partly due to genetic predisposition. Any gene that is expressed in the neuronal circuitry known to modulate the acquisition and maintenance of addiction could impact the development of an addiction, although that gene may not be the direct target of the drug. Uil is an emerging neuromodulator which may have implications in addiction and the development of addiction. Furthermore, in other work UN has been shown to produce cellular remolding, which may point to a role in neuroplasticity. Therefore, future studies will include the investigation ofthe role of Ull-R in molecular neurobiological changes and the development of addiction.

通过腹侧被盖区神经元释放多巴胺的中脑边缘通路（VTA）投射到伏隔核（NAc），被认为在动机和奖励中发挥作用流程。一些成瘾药物通过增强中脑边缘对行为产生有效影响多巴胺活性。 VTA 神经元释放多巴胺受多种因素和神经元控制结构。向 VTA 提供调节输入的一种途径起源于中脑桥核脑干。我们之前已经表明，中脑桥-VTA-NAc 途径受新的调节神经肽尾加压素 II (Uil)。为了促进我们的研究，我们开发并验证了白喉毒素与 UN (Dtx-Uli) 的融合。这毒素能够选择性地消融表达 Ull-R 的中脑桥神经元，而不损伤周围组织。通过将该毒素与微透析和行为范式相结合（自我管理和条件位置偏好），我们将确定 Uil 是否可以调节强化行为。此外，为了更好地了解中脑桥核的功能，Dtx-Uli 将用于消融该区域的神经元。随后，提出的中脑桥功能的不同方面将进行测试（例如前脉冲抑制、条件位置偏好）。吸毒成瘾是一种多因素的病症。这种异质性部分是由于遗传倾向造成的。任何在已知调节神经元回路的获取和维持的基因中表达的基因成瘾可能会影响成瘾的发展，尽管该基因可能不是成瘾的直接目标药物。 Uil 是一种新兴的神经调节剂，可能对成瘾和发育产生影响的成瘾。此外，在其他工作中，联合国已被证明可以产生细胞重塑，这可能表明在神经可塑性中发挥作用。因此，未来的研究将包括Ull-R在分子神经生物学变化和成瘾的发展。