Analysis of Aldh1l1-tdTomato+ cells during chronic stress by scRNA-seq

Neuroimmune interactions—signals transmitted between immune and brain cells—regulate many aspects of tissue physiology including responses to psychological stress, which can predispose individuals to develop neuropsychiatric diseases. Still, the interactions between hematopoietic and brain-resident cells that influence complex behaviors are poorly understood. Here, we used a combination of genomic and behavioral screens to demonstrate that astrocytes in the amygdala limit stress-induced fear behavior through EGFR. Mechanistically, amygdala astrocyte EGFR expression inhibits a stress-induced pro-inflammatory signal transduction cascade that facilitates neuro-glial cross-talk and stress-induced fear behavior through the orphan nuclear receptor NR2F2 in amygdala neurons. We uncovered that, in turn, decreased EGFR signaling and fear behavior were associated with meningeal monocyte recruitment during chronic stress. This set of neuroimmune interactions was therapeutically targetable by psychedelic administration, which reversed monocyte accumulation in the brain meninges along with fear behavior. 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.