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.

Public Health Relevance

Recent studies indicate that neuroimmune factors are important signaling molecules in the brain and contribute to both normal brain function and cognitive dysfunction associated with a variety of disorders including alcoholism. Our knowledge about the role of neuroimmune factors in alcoholism is limited. Progress in this area will require a basic understanding of the interactions between neuroimmune factors and alcohol at the level of cellular and synaptic mechanisms that mediate normal brain function. The proposed studies will address this issue.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
NIH Challenge Grants and Partnerships Program (RC1)
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Special Emphasis Panel (ZRG1-IFCN-A (58))
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Cui, Changhai
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Scripps Research Institute
La Jolla
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Bray, Jennifer G; Reyes, Kenneth C; Roberts, Amanda J et al. (2018) Altered hippocampal synaptic function in transgenic mice with increased astrocyte expression of CCL2 after withdrawal from chronic alcohol. Neuropharmacology 135:113-125
Olde Engberink, Anneke; Hernandez, Ruben; de Graan, Pierre et al. (2017) Rapamycin-Sensitive Late-LTP is Enhanced in the Hippocampus of IL-6 Transgenic Mice. Neuroscience 367:200-210
Bray, Jennifer G; Roberts, Amanda J; Gruol, Donna L (2017) Transgenic mice with increased astrocyte expression of CCL2 show altered behavioral effects of alcohol. Neuroscience 354:88-100
Hernandez, Ruben V; Puro, Alana C; Manos, Jessica C et al. (2016) Transgenic mice with increased astrocyte expression of IL-6 show altered effects of acute ethanol on synaptic function. Neuropharmacology 103:27-43
Gruol, Donna L (2016) Impact of Increased Astrocyte Expression of IL-6, CCL2 or CXCL10 in Transgenic Mice on Hippocampal Synaptic Function. Brain Sci 6:
Gruol, Donna L (2015) IL-6 regulation of synaptic function in the CNS. Neuropharmacology 96:42-54
Gruol, Donna L (2013) Neuroimmune regulation of neurophysiology in the cerebellum. Cerebellum 12:307-9
Bray, Jennifer G; Reyes, Kenneth C; Roberts, Amanda J et al. (2013) Synaptic plasticity in the hippocampus shows resistance to acute ethanol exposure in transgenic mice with astrocyte-targeted enhanced CCL2 expression. Neuropharmacology 67:115-25
Gruol, Donna; Manto, Mario; Haines, Duane (2012) Ca2+ signaling in cerebellar Purkinje neurons--editorial. Cerebellum 11:605-8
Nelson, Thomas E; Hao, Christine; Manos, Jessica et al. (2011) Altered hippocampal synaptic transmission in transgenic mice with astrocyte-targeted enhanced CCL2 expression. Brain Behav Immun 25 Suppl 1:S106-19

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