Psychedelic control of neuroimmune interactions governing fear

Elizabeth N. Chung, Jinsu Lee, Carolina M. Polonio, Joshua Choi, Camilo Faust Akl, Michael Kilian, Wiebke M. Weiß, Georgia Gunner, Mingyu Ye, Tae Hyun 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, Stelios M. Smirnakis, Isaac M. Chiu, Vijay K. Kuchroo, Francisco J. Quintana and Michael A. Wheeler ()
Additional contact information
Elizabeth N. Chung: Harvard Medical School
Jinsu Lee: Harvard Medical School
Carolina M. Polonio: Harvard Medical School
Joshua Choi: Harvard Medical School
Camilo Faust Akl: Harvard Medical School
Michael Kilian: Harvard Medical School
Wiebke M. Weiß: Harvard Medical School
Georgia Gunner: Harvard Medical School
Mingyu Ye: Harvard Medical School
Tae Hyun Heo: Harvard Medical School
Sienna S. Drake: Harvard Medical School
Liu Yang: Harvard Medical School
Catarina R. G. L. d’Eca: Harvard Medical School
Joon-Hyuk Lee: Harvard Medical School
Liwen Deng: Harvard Medical School
Daniel Farrenkopf: Harvard Medical School
Anton M. Schüle: Harvard Medical School
Hong-Gyun Lee: Harvard Medical School
Oreoluwa Afolabi: Harvard Medical School
Sharmin Ghaznavi: Harvard Medical School
Stelios M. Smirnakis: Harvard Medical School
Isaac M. Chiu: Harvard Medical School
Vijay K. Kuchroo: Harvard Medical School
Francisco J. Quintana: Harvard Medical School
Michael A. Wheeler: Harvard Medical School

Nature, 2025, vol. 641, issue 8065, 1276-1286

Abstract: Abstract Neuroimmune interactions—signals transmitted between immune and brain cells—regulate many aspects of tissue physiology1, including responses to psychological stress2–5, which can predispose individuals to develop neuropsychiatric diseases6–9. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08880-9

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