Psychedelics Reopen the Social Reward Learning Critical Period

Psychedelics are a broad class of drugs defined by their ability to induce an altered state of consciousness. These drugs have been used for millennia in both spiritual and medicinal contexts, and a number of recent clinical successes have spurred a renewed interest in developing psychedelic therapies. Nevertheless, a unifying mechanism that can account for these shared phenomenological and therapeutic properties remains unknown. Here we demonstrate in mice that the ability to reopen the social reward learning critical period is a shared property across psychedelics. Interestingly, the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans. Furthermore, the ability to reinstate social reward learning in adulthood is paralleled by metaplastic restoration of oxytocin mediated long-term depression (OT-LTD) in the Nucleus Accumbens (NAc). Finally, identification of differentially expressed genes in the ‘open state’ versus ‘closed state’, provides evidence that reorganization of the extracellular matrix (ECM) is a common downstream mechanism underlying psychedelic mediated critical period reopening. Together these results have significant implications for the implementation of psychedelics in clinical practice, as well as the design of novel compounds for the treatment of neuropsychiatric disease. Bulk RNA-Seq analysis of mouse Nucleus Accumbens (NAc) at select time points after treatment with LSD, Ketamine, MDMA, or cocaine or saline controls. We analyzed the gene expression data set between conditions where the critical period is in the open state (i.e. 48 hours and two weeks post LSD treatment, 48 hours post ketamine treatment, 48 hours post MDMA treatment) versus conditions where the critical period remains in or returns to the closed state (i.e. 48 hours and two weeks post saline treatment, 48 hours and two weeks post cocaine treatment, and two weeks post ketamine treatment).