Leptin enhances social motivation and reverses chronic unpredictable stress-induced social anhedonia during adolescence

Yun Lei, Dan Wang, Yu Bai, Jayvon Nougaisse, Neal L. Weintraub, Ming Guo, Xin Yun Lu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Social anhedonia, a loss of interest and pleasure in social interactions, is a common symptom of major depression as well as other psychiatric disorders. Depression can occur at any age, but typically emerges in adolescence or early adulthood, which represents a sensitive period for social interaction that is vulnerable to stress. In this study, we evaluated social interaction reward using a conditioned place preference (CPP) paradigm in adolescent male and female mice. Adolescent mice of both sexes exhibited a preference for the social interaction-associated context. Chronic unpredictable stress (CUS) impaired the development of CPP for social interaction, mimicking social anhedonia in depressed adolescents. Conversely, administration of leptin, an adipocyte-derived hormone, enhanced social interaction-induced CPP in non-stressed control mice and reversed social anhedonia in CUS mice. By dissecting the motivational processes of social CPP into social approach and isolation avoidance components, we demonstrated that leptin treatment increased isolation aversion without overt social reward effect. Further mechanistic exploration revealed that leptin stimulated oxytocin gene transcription in the paraventricular nucleus of the hypothalamus, while oxytocin receptor blockade abolished the leptin-induced enhancement of socially-induced CPP. These results establish that chronic unpredictable stress can be used to study social anhedonia in adolescent mice and provide evidence that leptin modulates social motivation possibly via increasing oxytocin synthesis and oxytocin receptor activation.

Original languageEnglish (US)
Pages (from-to)4948-4958
Number of pages11
JournalMolecular Psychiatry
Issue number12
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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