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Mitochondrial function in the brain links anxiety with social subordination
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved October 29, 2015 (received for review June 27, 2015)

Significance
Within a dominance hierarchy, low social status strongly reduces individual well-being. In socially living species, rank in a hierarchy is determined through competitive encounters. Despite the numerous health consequences, the ability of personality traits to predispose individuals to a particular social rank remains largely unclear. Our work identifies trait anxiety as a predisposing factor to a subordinate rank. We demonstrate that mitochondrial function in the nucleus accumbens, a brain region relevant for motivation and depression, is a critical mediating factor in the subordinate status displayed by high-anxious rats. These findings highlight a role for cerebral energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for mood disorders.
Abstract
Dominance hierarchies are integral aspects of social groups, yet whether personality traits may predispose individuals to a particular rank remains unclear. Here we show that trait anxiety directly influences social dominance in male outbred rats and identify an important mediating role for mitochondrial function in the nucleus accumbens. High-anxious animals that are prone to become subordinate during a social encounter with a low-anxious rat exhibit reduced mitochondrial complex I and II proteins and respiratory capacity as well as decreased ATP and increased ROS production in the nucleus accumbens. A causal link for these findings is indicated by pharmacological approaches. In a dyadic contest between anxiety-matched animals, microinfusion of specific mitochondrial complex I or II inhibitors into the nucleus accumbens reduced social rank, mimicking the low probability to become dominant observed in high-anxious animals. Conversely, intraaccumbal infusion of nicotinamide, an amide form of vitamin B3 known to enhance brain energy metabolism, prevented the development of a subordinate status in high-anxious individuals. We conclude that mitochondrial function in the nucleus accumbens is crucial for social hierarchy establishment and is critically involved in the low social competitiveness associated with high anxiety. Our findings highlight a key role for brain energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for anxiety-related social disorders.
Footnotes
↵1F.H. and M.A.v.d.K. contributed equally to this work.
↵2Present address: Johannes Gutenberg University Medical Centre, Department of Psychiatry and Psychotherapy and Focus Program, Translational Neurosciences, 55128 Mainz, Germany.
- ↵3To whom correspondence should be addressed. Email: carmen.sandi{at}epfl.ch.
Author contributions: F.H., M.A.v.d.K., C.C., and C.S. designed research; F.H., M.A.v.d.K., O.Z., L.L., and C.C. performed research; F.H., M.A.v.d.K., and C.S. analyzed data; and F.H., M.A.v.d.K., C.C., and C.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1512653112/-/DCSupplemental.
Freely available online through the PNAS open access option.