Alcohol-Chemokine Interactions and Neurotransmission

酒精-趋化因子相互作用和神经传递

• 批准号: 7937083
• 负责人: DONNA L GRUOL
• 金额: $ 42.27万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937083
• 关键词: Acute; Address; Adult; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Area; Astrocytes; Behavior; Behavior assessment; Behavioral; Biochemical; Brain; Brain region; CCL2 gene; Cell physiology; Chronic; Cognitive deficits; Collaborations; Development; Disease; Exposure to; Funding; Hippocampus (Brain); Immune system; Impaired cognition; Knowledge; Learning; Mediating; Memory; Methods; Microglia; Mitogen-Activated Protein Kinases; Mus; Neurons; Normal Cell; Pathway interactions; Play; Prevention; Production; Property; Rattus; Regulation; Research; Research Institute; Role; Short-Term Memory; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Simulate; Site; Slice; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Tissues; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; alcohol effect; alcohol exposure; behavior test; brain pathway; cell type; cellular development; chemokine; cognitive function; cytokine; extracellular; hippocampal pyramidal neuron; in vivo; interest; monocyte chemoattractant protein 1 receptor; neural circuit; neurotransmission; repaired; response; synaptic function; vapor

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and specific Challenge Topic, 01-AA-102*: Functional Roles of Neuroimmune Factors in Mediating Behavior. The title of this proposal is "Alcohol-chemokine interactions and neurotransmission". Emerging research implicates a role for the innate immune system of the brain in the effects of alcohol on behavior. Astrocytes and microglia, the primary cell types that comprise innate immune system of the brain, are normal components of the brain and serve essential roles in normal brain development and function. Microglia and astrocytes also play critical defensive and repair roles during adverse conditions. Basic to their roles during both normal and adverse conditions is the production of neuroimmune factors such as cytokines and chemokines, which are signaling molecules that initiate or coordinate cellular actions appropriate to the need, be it cellular development, normal cell function or a defense/repair response to adverse conditions. Recent studies provide strong support for a role of neuroimmune factors, and in particular the chemokine CCL2, in alcohol use and abuse. Importantly, acute alcohol has been shown to increase levels of CCL2 in the hippocampus, a brain structure that is essential for cognitive functions such as short-term memory. CCR2, the receptor for CCL2, has been shown to be expressed in abundance in the hippocampus. Moreover, research has identified the hippocampus as one of several brain regions that play a central role in the cognitive deficits produce by alcohol abuse. An important target of alcohol action in the hippocampus is synaptic transmission and plasticity at the Schaffer collateral to CA1 synapse. Our studies show that CCL2 also alters the functional properties of this synaptic pathway. Thus, hippocampal synaptic function is a target of both CCL2 and alcohol action and a likely site for interactions between alcohol and CCL2 that could be a critical factor in the behavioral effect of alcohol. Alcohol actions in the hippocampus have been well documented but Information on the effects of CCL2 on hippocampus function is limited and interactions between alcohol and CCL2 at the level of neuronal function and synaptic transmission have not been studied. This information is critical to an understanding of the role of CCL2 in alcohol use and abuse and is the topic of the proposed studies. The studies will test the hypothesis that activation of the CCL2 signaling pathway in the hippocampus alters the actions of alcohol on hippocampal synaptic function and that these interactions between CCL2 and alcohol are also manifested at the behavioral level. To test this hypothesis, we will use variety of experimental approaches including electrophysiological recording of synaptic function, biochemical assessment of signal transduction pathway activation and behavioral testing. The studies will be carried out in transgenic mice that express elevated levels of CCL2 in the brain and their non-transgenic littermates as controls. Taken together, these studies will provide important new information that will significantly advance our understanding of the role of neuroimmune factors in alcoholism.

描述（由申请人提供）：此申请解决了广泛的挑战领域（01）行为，行为改变以及预防和特定挑战主题，01-AA-102*：神经免疫因素在中介行为中的功能作用。该提议的标题是“酒精化学相互作用和神经传递”。新兴的研究暗示了大脑先天免疫系统在酒精对行为的影响中的作用。星形胶质细胞和小胶质细胞是构成大脑先天免疫系统的主要细胞类型，是大脑的正常成分，在正常的大脑发育和功能中起着重要作用。在不利条件下，小胶质细胞和星形胶质细胞也起关键的防御和修复作用。在正常条件和不利条件下它们的作用是基本的是产生神经免疫因子（例如细胞因子和趋化因子），这些因子和趋化因子是启动或协调适合需求的细胞作用的信号分子，无论是细胞发育，正常细胞功能还是对不良条件的防御/修复反应。最近的研究为神经免疫因子（尤其是趋化因子CCL2）在酒精使用和滥用中的作用提供了强有力的支持。重要的是，急性酒精已被证明可以增加海马中的CCL2水平，这是一种对诸如短期记忆等认知功能至关重要的大脑结构。 CCR2是CCL2的受体，已显示在海马中以丰富的形式表达。此外，研究已经确定海马是在通过酗酒产生的认知缺陷中起着核心作用的几个大脑区域之一。海马中酒精作用的一个重要目标是Schaffer侧支到CA1突触的突触传播和可塑性。我们的研究表明，CCL2还改变了该突触途径的功能特性。因此，海马突触功能是CCL2和酒精作用的目标，也是酒精和CCL2之间相互作用的可能位置，这可能是酒精行为效应的关键因素。海马中的酒精作用已经有充分的记录，但是有关CCL2对海马功能的影响的信息有限，并且在神经元功能和突触传播水平下酒精和CCL2之间的相互作用尚未研究。该信息对于理解CCL2在酒精使用和滥用中的作用至关重要，这是拟议研究的主题。研究将检验以下假设：海马中CCL2信号通路的激活改变了酒精对海马突触功能的作用，并且在行为水平上也表现出了CCL2和酒精之间的这些相互作用。为了检验这一假设，我们将使用多种实验方法，包括突触功能的电生理记录，信号转导途径激活的生化评估和行为测试。这些研究将在转基因小鼠中进行，该小鼠表达大脑中CCL2水平升高，其非转基因同窝窝作为对照。综上所述，这些研究将提供重要的新信息，从而大大提高我们对神经免疫因素在酒精中毒中作用的理解。