PSYCHEDELIC-INDUCED SUBCORTICAL NEUROPLASTICITY PROMOTES STRESS RESILIENCE

Stress resilience determines animals' vulnerability to external disturbances and is a crucial factor in the treatment of mood-related disorders. We investigated how neuroplasticity mechanisms promote stress resilience by examining the brain-wide effects of psilocybin, a psychedelic agonist of excitatory serotonin receptors. Pretreatment with psilocybin promotes persistent stress resilience in larval zebrafish. Whole-brain imaging of the sequential activation of brain areas at stress onset revealed that recurrent flows of neural activity between primary sensory areas and forebrain areas trigger a brain-wide stress response, and that psilocybin mitigates this process by suppressing the stress response in HTR2A+ habenular neurons. Interestingly, psilocybin transiently activates these neurons during pretreatment, potentially highlighting the dichotomy of HTR2A-Gq receptor signaling, which triggers temporary excitation and later long-term synaptic depression. These results suggest the presence of subcortical networks that can be modulated to enhance stress resilience and combat mood-related disorders.