Alcohol-Chemokine Interactions and Neurotransmission

描述(由申请人提供)：本申请涉及广泛的挑战领域(01)行为，行为改变，以及预防和特定挑战主题，01-AA-102*：神经免疫因素在行为调节中的功能作用。这项提议的标题是“酒精-趋化因子相互作用和神经传递”。新出现的研究表明，大脑的先天免疫系统在酒精对行为的影响中发挥了作用。星形胶质细胞和小胶质细胞是组成大脑天然免疫系统的主要细胞类型，是大脑的正常组成部分，在正常的大脑发育和功能中起着至关重要的作用。在不利条件下，小胶质细胞和星形胶质细胞也发挥关键的防御和修复作用。它们在正常和不利条件下的基本作用是产生神经免疫因子，如细胞因子和趋化因子，这些因子是启动或协调细胞活动的信号分子，无论是细胞发育、正常细胞功能还是对不利条件的防御/修复反应。最近的研究有力地支持了神经免疫因子，特别是趋化因子CCL2在酒精使用和滥用中的作用。重要的是，急性酒精被证明会增加海马体中CCL2的水平，海马体是一种对认知功能(如短期记忆)至关重要的大脑结构。CCL2的受体CCR2已被证明在海马区大量表达。此外，研究还发现，海马体是在酗酒造成的认知缺陷中发挥核心作用的几个大脑区域之一。酒精在海马体中作用的一个重要靶点是CA1突触的Schaffer侧支的突触传递和可塑性。我们的研究表明，CCL2也改变了这条突触通路的功能特性。因此，海马区突触功能既是CCL2和酒精作用的靶点，也是酒精和CCL2相互作用的可能部位，这可能是酒精行为效应的关键因素。酒精在海马区的作用已有很好的文献记载，但关于CCL2对海马区功能影响的信息有限，在神经元功能和突触传递水平上酒精与CCL2之间的相互作用尚未被研究。这一信息对于了解CCL2在酒精使用和滥用中的作用至关重要，也是拟议研究的主题。这些研究将检验一种假设，即激活海马区的CCL2信号通路改变了酒精对海马区突触功能的作用，并且CCL2和酒精之间的这些相互作用也在行为水平上表现出来。为了验证这一假说，我们将使用多种实验方法，包括突触功能的电生理记录、信号转导通路激活的生化评估和行为测试。这项研究将在大脑中表达高水平CCL2的转基因小鼠身上进行，并将它们的非转基因小鼠作为对照。综上所述，这些研究将提供重要的新信息，大大促进我们对神经免疫因素在酒精中毒中的作用的理解。

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.