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Nature. 2019 May;569(7754):116-120. doi: 10.1038/s41586-019-1075-9. Epub 2019 Apr 3.

Oxytocin-dependent reopening of a social reward learning critical period with MDMA.

Nardou R1,2,3, Lewis EM1,2,3, Rothhaas R1,2,3, Xu R4,5, Yang A4,5,6, Boyden E4,5,6, Dölen G7,8,9.

Author information

1
The Solomon H. Snyder Department of Neuroscience, Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
The Solomon H. Snyder Department of Neuroscience, Wendy Klag Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
3
The Solomon H. Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA.
5
McGovern Institute, MIT, Cambridge, MA, USA.
6
Department of Biological Engineering, Media Laboratory, Koch Institute, MIT, Cambridge, MA, USA.
7
The Solomon H. Snyder Department of Neuroscience, Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. gul@jhu.edu.
8
The Solomon H. Snyder Department of Neuroscience, Wendy Klag Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. gul@jhu.edu.
9
The Solomon H. Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. gul@jhu.edu.

Abstract

A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures1. In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen critical periods has been a priority for translational neuroscience2. Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a critical period for social reward learning. Furthermore, we show that a single dose of (+/-)-3,4-methylendioxymethamphetamine (MDMA) reopens the critical period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this critical period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neurodevelopmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury3.

PMID:
30944474
DOI:
10.1038/s41586-019-1075-9
[Indexed for MEDLINE]

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