Uncovering the signal pathways that underlie chronic stress

We examined the role of microglia and interleukin-1 receptor 1 (IL-1R1) signaling in neurons in the development of stress-sensitization and increased fear memory after repeated social defeat (RSD) in mice. RSD accelerated fear acquisition, delayed fear extinction, and increased fear memory. Microglia depletion blocked monocyte recruitment to the brain, but did not affect neuronal reactivity, IL-1β RNA expression in the hippocampus, or fear memory after RSD. However, IL-1R1 signaling in glutamatergic neurons was essential for RSD-induced neuronal reactivity and fear memory.

Lastly, we sequenced wildtype and neuronal IL-1R1 (nIL-1R1) hippocampal nuclei after exposure to repeated social defeat. We identified and characterized different neuronal subpopulations and cell types based on their unique gene expression profiles. RSD influenced transcription in specific hippocampal neurons (dentate gyrus neurons, CA2/3 neurons, CA1 neurons, inhibitory neurons) associated with glutamate signaling, inflammation and synaptic plasticity. Notably, these RSD-induced neuronal changes across the hippocampus were dependent on neuronal IL-1R1 signaling.

Overall, the findings suggest a crucial role for IL-1R1-mediated signaling in glutamatergic neurons in the development of enhanced fear memory after RSD. Moreover, the study provides insights into the molecular mechanisms associated with stress-sensitization.

Publication:
Goodman, E.J., Biltz, R.G., Packer, J.M. et al. Enhanced fear memory after social defeat in mice is dependent on interleukin-1 receptor signaling in glutamatergic neurons. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02456-1