Astrocytes and Interleukin-1β in the Dorsal Hippocampus Contribute to Enhanced Fear Learning Following Ethanol and...

Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, and prior alcohol use may increase susceptibility to PTSD. We recently showed that prior chronic ethanol consumption and withdrawal potentiate future stress-enhanced fear learning. However, the neurobiological mechanism underlying this behavior is unknown. Given the role of astrocytes in the neuroimmune system, we investigated the relationship between the pro-inflammatory cytokine interleukin-1β (IL-1β) and dorsal hippocampal astrocytes in this behavior.

Experiments 1 and 2 assessed the expression of IL-1β and glial fibrillary acidic protein (GFAP) and their relationship through colocalization in the dentate gyrus (DG) of the dorsal hippocampus (DH) following chronic ethanol consumption and withdrawal and severe stress exposure. Experiments 3 and 4 used an AAV-based clustered regularly interspaced short palindromic repeats (CRISPR) approach to knock down Il1b selectively in dorsal hippocampal astrocytes to test the role of astrocyte-derived IL-1β in ethanol- and stress-enhanced fear learning.

We found that severe stress increased IL-1β expression, whereas ethanol consumption and withdrawal increased GFAP expression and the colocalization of IL-1β with GFAP. Knockdown of Il1b in dorsal hippocampal astrocytes was achievable and partially reduced enhanced fear learning following the combination of ethanol withdrawal and severe stress.

Collectively, these results suggest that a complex relationship between IL-1β, astrocyte reactivity, and IL-1β produced by astrocytes may occur in the DH, where ethanol and stress differentially impact these neuroimmune components that are partially involved in the augmentation of stress-enhanced fear learning following prior ethanol dependence and withdrawal.