A new study published in Nature by researchers at Harvard Medical School has found that psychedelic compounds can reduce stress-induced fear responses by altering neuroimmune activity in the brain.
The research highlights a mechanism in which astrocytes—cells in the amygdala involved in emotional processing—help regulate fear through the epidermal growth factor receptor (EGFR). The study found that EGFR expression in these cells inhibits a pro-inflammatory signaling cascade that, if left unchecked, leads to greater interaction between neurons and glial cells. This process contributes to heightened fear behavior during psychological stress, mediated by the nuclear receptor NR2F2 in amygdala neurons.
Chronic stress was shown to decrease EGFR activity and increase the infiltration of monocytes into the brain’s meninges, which was associated with increased fear behavior. However, administration of psychedelic drugs reversed both the monocyte accumulation and the observed behavioral changes.
The findings were further validated using clinical samples, providing evidence that psychedelics may offer a novel therapeutic avenue for treating neuropsychiatric disorders with an inflammatory component.
The study supports the idea that targeting neuroimmune pathways with psychedelics could extend beyond mental health applications to other inflammation-related diseases.
The study’s full abstract can be found below:
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.
