Psychedelic control of neuroimmune interactions governing fear

• 成果类型: Article
• 署名作者: Chung, Elizabeth N.; Lee, Jinsu; Polonio, Carolina M.; Choi, Joshua; Akl, Camilo Faust; Kilian, Michael; Weiss, Wiebke M.; Gunner, Georgia; Ye, Mingyu; Heo, Tae Hyun; Drake, Sienna S.; Yang, Liu; d'Eca, Catarina R. G. L.; Lee, Joon-Hyuk; Deng, Liwen; Farrenkopf, Daniel; Schuele, Anton M.; Lee, Hong-Gyun; Afolabi, Oreoluwa; Ghaznavi, Sharmin; Smirnakis, Stelios M.; Chiu, Isaac M.; Kuchroo, Vijay K.; Quintana, Francisco J.; Wheeler, Michael A.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Brigham & Women's Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2075
• DOI: 10.1038/s41586-025-08880-9
• 发表日期: 2025-05-29
• 关键词: set enrichment analysis; 3; 4-methylenedioxymethamphetamine mdma; gene-expression; in-vivo; mouse; amygdala; pharmacology; mechanisms; psilocybin; receptors

摘要

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.