Individuals that have been exposed to a traumatic event are at risk for developing a set of symptoms known as post-traumatic stress disorder (PTSD). Evidence suggests that there is a high comorbidity between PTSD and alcohol use disorders (AUDs), with a three-fold increased risk for experiencing an AUD in sufferers of PTSD. While it is generally thought PTSD proceeds, and is a risk factor for, AUDs, there is also evidence that a prior history of AUDs may leave individuals biologically more vulnerable to the impact of severe stress and thus more likely to develop PTSD. Despite converging evidence of co-morbidity between PTSD and AUDs, our understanding of the underlying neuronal substrates mediating these comorbid disorders, as well as available pharmaceutical treatments, are limited. This application brings together a team of investigators to address this scientific question in a convergent manner with the expertise of the neural immune mechanisms that underlie PTSD-like behavior (Lysle), the neurobiology of excessive alcohol (ethanol) intake (Thiele), and the understanding of astrocyte physiology (Reissner). Interestingly, a comparison of the present team?s research suggests that common overlapping neuroimmune mechanisms may underlie the development of each pathology. Dr. Lysle has discovered that severe stress induces a time-dependent increase in dorsal hippocampal (DH) interleukin-1? (IL-1?), and that directly blocking IL-1 signaling in the DH after severe stress (repeated unpredictable foot shock) prevents stress-enhanced fear learning (SEFL), an animal model of PTSD. Consistently, the present research team has found that withdrawal following chronic ethanol exposure increases hippocampal IL-1? mRNA, and a recent collaborative pilot project between the research team revealed that ethanol withdrawal potentiates the magnitude of SEFL. These observations support our overarching hypothesis, that hippocampal IL-1? represents a cellular mechanism for exacerbated stress response in alcohol- withdrawn/dependent individuals.
Specific Aim 1 will test the hypothesis that withdrawal-induced potentiation of SEFL is associated with (A) a potentiation of IL-1? signaling specifically in astrocytes that correlates with the magnitude of SEFL, (B) pharmacological blockade of DH IL-1R during withdrawal will protect against withdrawal- induced potentiation of PTSD-like phenotypes, and (C) that DH-infusion of exogenous IL-1? will substitute for the effects of ethanol withdrawal.
Specific Aim 2 will test the hypothesis that changes in the morphometric properties of astrocytes, and/or alterations of astrocyte/neuron interactions, correlate with increased astrocyte IL-1? levels stemming from ethanol withdrawal and the severe stress used in SEFL. The studies proposed here are appropriate for the R21 grant mechanism because they are high-reward, potentially filling a gap in our understanding of the role that astrocyte-derived cytokines play in co-morbid PTSD and AUD disorders. They are also high-risk because we currently do not have direct evidence that IL-1? signaling in the DH is a mechanism for withdrawal-induced potentiation of PTSD-like phenotypes.

Public Health Relevance

Co-morbid alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) is a complex psychiatric condition for which there is currently no effective pharmacological treatment. The present project will provide exciting new insights into the neural immune mechanisms that drive co-morbid AUD and PTSD. The project establishes pre-clinical evidence supporting the potential use of compounds that block the cytokine interleukin-1 and regulate astrocyte function as new treatment approaches for protecting individuals experiencing AUDs from increased vulnerability to PTSD.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Patterson, Jenica Dawn
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
Zip Code