Psychedelic control of neuroimmune interactions governing fear

  • Nature. 2025 May;641(8065):1276-1286. doi: 10.1038/s41586-025-08880-9.
Elizabeth N Chung  #  1  2 ,  Jinsu Lee  #  1  2 ,  Carolina M Polonio  1  2 ,  Joshua Choi  1  2 ,  Camilo Faust Akl  1  2 ,  Michael Kilian  1  2 ,  Wiebke M Weiß  1  2 ,  Georgia Gunner  3 ,  Mingyu Ye  4 ,  Tae Hyun Heo  1  2 ,  Sienna S Drake  1  2 ,  Liu Yang  1  2 ,  Catarina R G L d'Eca  1  2 ,  Joon-Hyuk Lee  1  2 ,  Liwen Deng  3 ,  Daniel Farrenkopf  1  2 ,  Anton M Schüle  1  2 ,  Hong-Gyun Lee  1  2 ,  Oreoluwa Afolabi  1  2 ,  Sharmin Ghaznavi  5  6 ,  Stelios M Smirnakis  4 ,  Isaac M Chiu  3 ,  Vijay K Kuchroo  1  2  7 ,  Francisco J Quintana  1  2  7 ,  Michael A Wheeler  8  9
Affiliations
  • 1. The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 2. Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA.
  • 3. Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 4. Department of Neurology, Brigham and Women's Hospital and Jamaica Plain Veterans Administration Hospital, Harvard Medical School, Boston, MA, USA.
  • 5. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 6. Center for the Neuroscience of Psychedelics, Massachusetts General Hospital, Boston, MA, USA.
  • 7. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 8. The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
  • 9. Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 40269152 DOI: 10.1038/s41586-025-08880-9
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.