Activation of the innate immune system results in the release of pro-inflammatory cytokines, which may lead to changes in neuroimmune signaling and behavioral abnormalities, such as high alcohol (ethanol) consumption, which may ultimately lead to the development of alcohol use disorder (AUD). We lack understanding of how changes in neuroimmune signaling are integrated into neuronal networks that mediate the transition from normal (social) drinking to excessive alcohol consumption. Here, we propose the neuroimmune model of excessive alcohol consumption, where repeated injections of the immune activator Poly(I:C) produce progressive escalation of alcohol intake over several weeks of drinking. We hypothesize that immune activation induces cell type-specific changes in gene expression, which are integrated to affect neuronal functions and drive excessive drinking. We will use a combination of molecular, cellular, behavioral and computational approaches to test this hypothesis. Gene expression will be measured in neurons, astrocytes and microglia to investigate cell type-specific molecular mechanisms of immune activation. We will then use molecular signatures from different cell types and computationally-driven drug-repurposing approaches to identify and test pharmacological compounds with the potential to reduce high alcohol drinking. We will investigate roles of specific neural networks in immune-induced escalation of drinking by measuring neuronal functions and manipulating excitability of critical projection neurons. Temporal profiling across three critical time points will identify dynamic changes in cell type-specific transcriptomes and neuronal functions. Results of the proposed experiments will advance our understanding of the role of neuroimmune signaling in the transition to AUD and will be widely applicable to brain disorders with pro- inflammatory phenotypes.

Public Health Relevance

There is an emerging appreciation of the role of neuroimmune factors in alcohol use disorder (AUD). The current proposal addresses the role of neuroimmune activation and its effects on the brain in the development of AUD using a combination of molecular, cellular, behavioral and computational approaches. This knowledge may be used to develop new therapies for the prevention and treatment of AUD and other brain disorders with a neuroimmune component.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA027096-01
Application #
9610195
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Cui, Changhai
Project Start
2018-09-10
Project End
2023-06-30
Budget Start
2018-09-10
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759