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 represents a cellular mechanism for exacerbated stress response in alcohol- withdrawn/dependent individuals.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.
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.