Hippocampal interleukin-1 mediates stress-enhanced fear learning: A potential role for astrocyte-derived interleukin-1β

Brain Behav Immun. 2018 Jan:67:355-363. doi: 10.1016/j.bbi.2017.09.016. Epub 2017 Sep 28.


Post-traumatic stress disorder (PTSD) is associated with immune dysregulation. We have previously shown that severe stress exposure in a preclinical animal model of the disorder, stress-enhanced fear learning (SEFL), is associated with an increase in hippocampal interleukin-1β (IL-1β) and that blocking central IL-1 after the severe stress prevents the development of SEFL. Here, we tested whether blocking hippocampal IL-1 signaling is sufficient to prevent enhanced fear learning and identified the cellular source of stress-induced IL-1β in this region. Experiment 1 tested whether intra-dorsal hippocampal (DH) infusions of interleukin-1 receptor antagonist (IL-1RA, 1.25µg per hemisphere) 24 and 48h after stress exposure prevents the development of enhanced fear learning. Experiment 2 used triple fluorescence immunohistochemistry to examine hippocampal alterations in IL-1β, glial fibrillary acidic protein (GFAP), an astrocyte-specific marker, and ionized calcium binding adaptor molecule -1 (Iba-1), a microglial-specific marker, 48h after exposure to the severe stressor of the SEFL paradigm. Intra-DH IL-1RA prevented SEFL and stress-induced IL-1β was primarily colocalized with astrocytes in the hippocampus. Further, hippocampal GFAP immunoreactivity was not altered, whereas hippocampal Iba-1 immunoreactivity was significantly attenuated following severe stress. These data suggest that hippocampal IL-1 signaling is critical to the development of SEFL and that astrocytes are a predominant source of stress-induced IL-1β.

Keywords: Astrocytes; Cytokines; Fear; Hippocampus; Microglia; PTSD; SEFL; Stress.

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Conditioning, Classical
  • Fear / physiology*
  • Hippocampus / metabolism*
  • Interleukin-1 / metabolism*
  • Interleukin-1beta / metabolism*
  • Male
  • Rats, Sprague-Dawley
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Signal Transduction
  • Stress, Psychological / metabolism*


  • Interleukin-1
  • Interleukin-1beta
  • Receptors, Interleukin-1