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

• 批准号: 8515980
• 负责人: Stewart Donaldson Clark
• 金额: $ 23.9万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 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/8515980
• 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

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.

腹侧被盖区神经元释放多巴胺的中脑边缘通路 投射到伏隔核(NAC)的伏隔核(VTA)被认为在动机和奖赏中起作用 流程。一些成瘾药物通过增强中脑边缘而对行为产生强有力的影响 多巴胺活性。VTA神经元的多巴胺释放受多种因素和神经元的控制 结构。向VTA提供调节输入的一条通路起源于脑桥中核。 脑干。我们先前已经证明，中桥脑-VTA-NAC通路受新的 神经肽尾加压素II(UIL)。 为了便于我们的研究，我们开发并验证了白喉毒素与联合国的融合(DTX-ULi)。这 毒素能选择性地消融桥小脑中Ull-R表达的神经元而不损伤 周围的组织。通过将这种毒素与微透析和行为模式相结合 (自治和条件性地点偏好)，我们将确定UIL是否可以调节 强化的行为。此外，为了更好地了解桥中核的功能，DTX-ULI将 被用来消融这一区域的神经元。随后，提出了中桥函数的不同方面 将进行测试(例如脉冲前抑制、条件性位置偏好)。 吸毒成瘾是一种多因素的情况。这种异质性在一定程度上是遗传易感性造成的。任何 在神经元回路中表达的基因，已知的调节获得和维持 成瘾可能会影响成瘾的发展，尽管该基因可能不是 那药。UIL是一种新兴的神经调节剂，它可能与成瘾和成瘾的发展有关 上瘾的人。此外，在其他工作中，联合国已被证明产生细胞重塑，这可能表明 在神经可塑性中发挥作用。因此，未来的研究将包括研究Ull-R在 分子神经生物学变化与成瘾的发展。