Psychedelic control of neuroimmune interactions governing fear
Elizabeth N. Chung, Jinsu Lee, C. Polonio, Joshua Choi, Camilo Faust Akl, Michael Kilian, Wiebke M Weiß, Georgia Gunner, Ming Ye, T. Heo, Sienna S. Drake, Liu Yang, Catarina R G L d'Eca, Joon-Hyuk Lee, Liwen Deng, Daniel Farrenkopf, Anton M. Schüle, Hong-Gyun Lee, Oreoluwa Afolabi, Sharmin Ghaznavi, S. Smirnakis, I. Chiu, V. Kuchroo, F. Quintana, Michael A. Wheeler
Nature April 23, 2025 DOI: 10.1038/s41586-025-08880-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study combining genomic and behavioural screens with clinical sample validation Peer reviewed |
|---|---|
| Population | Mice, with validation in clinical samples |
| Intervention | Psychedelic compounds |
| Key points | Astrocytic EGFR signalling in the amygdala limits stress-induced fear behaviour by inhibiting a pro-inflammatory cascade involving neuronal NR2F2; chronic stress recruits monocytes to the brain meninges, and psychedelic compounds reversed both monocyte accumulation and fear behaviour. The authors suggest these neuroimmune interactions are therapeutically targetable for neuropsychiatric and possibly other inflammatory disorders. |
Abstract
Neuroimmune interactions—signals transmitted between immune and brain cells—regulate many aspects of tissue physiology1, including responses to psychological stress2, 3, 4–5, which can predispose individuals to develop neuropsychiatric diseases6, 7, 8–9. Still, the interactions between haematopoietic and brain-resident cells that influence complex behaviours are poorly understood. Here, we use a combination of genomic and behavioural screens to show that astrocytes in the amygdala limit stress-induced fear behaviour through epidermal growth factor receptor (EGFR). Mechanistically, EGFR expression in amygdala astrocytes inhibits a stress-induced, pro-inflammatory signal-transduction cascade that facilitates neuron–glial crosstalk and stress-induced fear behaviour through the orphan nuclear receptor NR2F2 in amygdala neurons. In turn, decreased EGFR signalling and fear behaviour are associated with the recruitment of meningeal monocytes during chronic stress. This set of neuroimmune interactions is therapeutically targetable through the administration of psychedelic compounds, which reversed the accumulation of monocytes in the brain meninges along with fear behaviour. Together with validation in clinical samples, these data suggest that psychedelics can be used to target neuroimmune interactions relevant to neuropsychiatric disorders and potentially other inflammatory diseases. Inflammatory monocytes in the brain meninges promote stress-induced fear behaviour, and the pathways involved can be modulated using psychedelic compounds.