Excessive alcohol consumption, the defining characteristic of an alcohol use disorder (AUD), damages the nervous system, producing the cognitive impairments observed in those afflicted with an AUD. Preclinical and clinical evidence from our lab and others suggest that microglia play a key role in alcohol-induced neuroinflammation and neurotoxicity. Various types of microglia have been categorized based on their function: classically activated (M1) proinflammatory microglia and alternatively activated (M2) growth-promoting microglia. However, the mechanisms responsible for alcohol activating microglia and polarizing them to either phenotype are poorly understood. MicroRNAs (miRNAs) are an abundant class of small noncoding RNA molecules that play an important role in the regulation of microglia polarization. Although miRNAs act mainly in a cell- autonomous manner, accumulating evidence suggests that miRNAs can be packaged into exosomes for intercellular signaling. Exosomes are small, 50-150 nm vesicles that are secreted into the extracellular space, fuse to neighboring cells, and release their contents (proteins, mRNAs, and miRNAs), thus serving as a novel intercellular genetic regulatory mechanism. Many cells in the nervous systems have the capacity to release exosomes, including neurons. Our preliminary data demonstrated that neuronal exosomes contain miRNAs that can alter microglia activation. Therefore, we hypothesize that miRNA-containing exosomes derived from alcohol-treated neurons transport messages, namely miRNA, to microglia and modulate their activation and function, and thus potentially contribute to neuroinflammation in AUDs. We will test this hypothesis with the following specific aims:
Aim 1 : Identify the miRNA elements that regulate microglia activation and function in alcohol-treated neuronal exosomes.
Aim 2. Determine the role of brain exosomes derived from 4-day binge alcohol-exposed rat brains in mediating brain inflammation and microglia activation. This proposal is novel in exploring the role of exosomes in cellular communication between neurons and microglia in AUDs. This unique and novel regulatory mechanism in neuron-to-microglia communication will provide new insight into miRNA- mediated microglia activation in pathological conditions such as AUDs.

Public Health Relevance

Excessive alcohol consumption damages the nervous system, producing the cognitive impairments observed in those individuals with an alcohol use disorder (AUD). Microglia, the immune cells of the central nervous system (CNS), play a key role in alcohol-induced neuroinflammation and neurotoxicity, but the mechanisms responsible for microglia phenotype regulation under alcohol exposure are poorly understood. In this proposal we will explore the role of a new neuron-to-microglia intracellular signaling pathway: the exosome- mediated transfer of miRNA in exosomes and how they regulate microglia function.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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Neuroscience Review Subcommittee (AA-4)
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Regunathan, Soundar
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University of Kentucky
Schools of Pharmacy
United States
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