The transcriptome of playfulness is sex biased in the juvenile rat medial amygdala: A role for inhibitory neurons

Ashley E Marquardt; Mahashweta Basu; Jonathan W VanRyzin; Seth A Ament; Margaret M McCarthy

doi:10.1016/j.celrep.2025.115782

The transcriptome of playfulness is sex biased in the juvenile rat medial amygdala: A role for inhibitory neurons

Cell Rep. 2025 Jun 24;44(6):115782. doi: 10.1016/j.celrep.2025.115782. Epub 2025 Jun 4.

Authors

Ashley E Marquardt¹, Mahashweta Basu², Jonathan W VanRyzin³, Seth A Ament⁴, Margaret M McCarthy⁵

Affiliations

¹ Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201, USA; University of Maryland - Medicine Institute for Neuroscience Discovery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
² Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
³ University of Maryland - Medicine Institute for Neuroscience Discovery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁴ University of Maryland - Medicine Institute for Neuroscience Discovery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁵ University of Maryland - Medicine Institute for Neuroscience Discovery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: mmccarthy@som.umaryland.edu.

PMID: 40478737
DOI: 10.1016/j.celrep.2025.115782

Abstract

Social play is a well-conserved, dynamic behavior known to be sexually differentiated. In most species, males play more than females, a sex difference largely driven by the medial amygdala (MeA), yet the full mechanism establishing this bias is unknown. Here, we explore "the transcriptome of playfulness" in both sexes, demonstrating that the transcriptomic profile in the juvenile rat MeA associated with playfulness is markedly distinct in males and females. Parallel single-cell RNA sequencing experiments from newborn rats suggest that inhibitory neurons drive this sex difference. Furthermore, we show that inhibitory neurons comprise the majority of play-active cells in the juvenile MeA, with males having more play-active cells than females, of which a greater proportion are GABAergic. Through integrative bioinformatic analyses, we further explore the expression, function, and cell-type specificity of key play-associated gene modules, providing valuable insight into the sex-biased mechanisms underlying this fundamental social behavior.

Keywords: CP: Cell biology; CP: Neuroscience; RNAseq; WGCNA; amygdala; medial amygdala; scRNA-seq; sex differences; social behavior; social play.

MeSH terms

Amygdala* / metabolism
Animals
Corticomedial Nuclear Complex* / metabolism
Female
GABAergic Neurons / metabolism
Male
Neurons* / metabolism
Play and Playthings*
Rats
Rats, Sprague-Dawley
Sex Characteristics*
Social Behavior
Transcriptome* / genetics