Enhanced fear memory after social defeat in mice is dependent on interleukin-1 receptor signaling in glutamatergic neurons

Ethan J Goodman; Rebecca G Biltz; Jonathan M Packer; Damon J DiSabato; Samuel P Swanson; Braeden Oliver; Ning Quan; John F Sheridan; Jonathan P Godbout

doi:10.1038/s41380-024-02456-1

Enhanced fear memory after social defeat in mice is dependent on interleukin-1 receptor signaling in glutamatergic neurons

Mol Psychiatry. 2024 Mar 8. doi: 10.1038/s41380-024-02456-1. Online ahead of print.

Authors

Ethan J Goodman^{1

2}, Rebecca G Biltz^{1

2}, Jonathan M Packer^{1

2}, Damon J DiSabato¹, Samuel P Swanson^{1

2}, Braeden Oliver³, Ning Quan⁴, John F Sheridan^{5

6

7}, Jonathan P Godbout^{8

9}

Affiliations

¹ Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
² Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH, USA.
³ Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, USA.
⁴ Department of Biomedical Science, Brain Institute, Florida Atlantic University, Boca Raton, FL, USA.
⁵ Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA. John.Sheridan@osumc.edu.
⁶ Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH, USA. John.Sheridan@osumc.edu.
⁷ Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, USA. John.Sheridan@osumc.edu.
⁸ Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA. Jonathan.Godbout@osumc.edu.
⁹ Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH, USA. Jonathan.Godbout@osumc.edu.

PMID: 38459193
DOI: 10.1038/s41380-024-02456-1

Abstract

Chronic stress is associated with increased anxiety, cognitive deficits, and post-traumatic stress disorder. Repeated social defeat (RSD) in mice causes long-term stress-sensitization associated with increased microglia activation, monocyte accumulation, and enhanced interleukin (IL)-1 signaling in endothelia and neurons. With stress-sensitization, mice have amplified neuronal, immune, and behavioral responses to acute stress 24 days later. This is clinically relevant as it shares key aspects with post-traumatic stress disorder. The mechanisms underlying stress-sensitization are unclear, but enhanced fear memory may be critical. The purpose of this study was to determine the influence of microglia and IL-1R1 signaling in neurons in the development of sensitization and increased fear memory after RSD. Here, RSD accelerated fear acquisition, delayed fear extinction, and increased cued-based freezing at 0.5 day. The enhancement in contextual fear memory after RSD persisted 24 days later. Next, microglia were depleted with a CSF1R antagonist prior to RSD and several parameters were assessed. Microglia depletion blocked monocyte recruitment to the brain. Nonetheless, neuronal reactivity (pCREB) and IL-1β RNA expression in the hippocampus and enhanced fear memory after RSD were microglial-independent. Because IL-1β RNA was prominent in the hippocampus after RSD even with microglia depletion, IL-1R1 mediated signaling in glutamatergic neurons was assessed using neuronal Vglut2⁺/IL-1R1^-/- mice. RSD-induced neuronal reactivity (pCREB) in the hippocampus and enhancement in fear memory were dependent on neuronal IL-1R1 signaling. Furthermore, single-nuclei RNA sequencing (snRNAseq) showed that RSD influenced transcription in specific hippocampal neurons (DG neurons, CA2/3, CA1 neurons) associated with glutamate signaling, inflammation and synaptic plasticity, which were neuronal IL-1R1-dependent. Furthermore, snRNAseq data provided evidence that RSD increased CREB, BDNF, and calcium signaling in DG neurons in an IL-1R1-dependent manner. Collectively, increased IL-1R1-mediated signaling (monocytes/microglia independent) in glutamatergic neurons after RSD enhanced neuronal reactivity and fear memory.

Abstract

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