A critical period is a developmental window when the nervous system is especially sensitive to environmental stimuli needed for proper circuit organization and learning. In disease, closure of these periods limits the brain's ability to adapt. This work provides evidence that developmental regulation of oxytocin-mediated synaptic plasticity in the nucleus accumbens establishes a critical period for social reward learning. A single dose of MDMA reopens this critical period and upregulates oxytocin-dependent long-term depression. Reopening requires activation of oxytocin receptors in the nucleus accumbens and is recapitulated by stimulating oxytocin terminals there. These findings have implications for neurodevelopmental diseases with social impairments and disorders influenced by social factors.
Psychedelic drugs share the ability to reopen a critical period for social reward learning in adult mice, and the duration of this reopening matches the length of subjective effects in humans. The reinstatement of social reward learning is accompanied by a metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Analysis of gene expression in the open versus closed state indicates that reorganization of the extracellular matrix is a common downstream mechanism. These findings suggest a unifying mechanism for psychedelics' therapeutic properties and may guide clinical use and drug design for neuropsychiatric diseases.