Mitochondrial function in the brain links anxiety with social subordination

Fiona Hollis, Michael A. van der Kooij, Olivia Zanoletti, Laura Lozano, Carles Cantó, and Carmen SandiPNAS December 15, 2015 112 (50) 15486-15491; first published November 30, 2015

  1. Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved October 29, 2015 (received for review June 27, 2015)


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.


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.

In most socially living species, the social rank of an individual is established during competitive encounters with conspecifics. The outcome of these encounters determines the allocation of territory, resources and access to reproduction (1), and greatly influences physiology and health (2). Winning a social competition is rewarding, enhances rank in social hierarchies, and increases the probability of winning future contests (34). In contrast, losing a social encounter typically undermines one’s social rank. In humans, a low social status predicts morbidity and survival (5) and has also been linked to the development of psychopathologies (6). Despite the important consequences of social rank on health, little is known regarding the mechanisms underlying the establishment of social hierarchies.

One of the main reasons for the paucity of neurobiological mechanisms determining social hierarchies may be that social competition involves interacting subjects that both need to be taken into account. The competitors may exhibit different features such as size, age, gender, as well as previous social experience, all known to influence social competitiveness. However, when subjects are matched for these characteristics, the impact of innate personality traits on social competitiveness may be investigated. One such personality trait, anxiety, may have important consequences for the outcome of social competitions. In humans, high-anxious individuals often display a subordinate status and report feelings of being overlooked and rejected (7), and their competitive self-confidence becomes undermined under stress (8). Thus, interindividual differences in anxiety could predetermine the outcome of a competitive encounter and, as such, trait anxiety may have important consequences for social status. However, the neural mechanisms whereby anxiety might affect social hierarchy formation are largely unknown.

We addressed this question by examining social competitiveness between male rats characterized for trait anxiety. Recent work has highlighted the potential for individual differences in mitochondrial function and, more broadly, energy metabolism to influence vulnerability to develop psychopathological disorders, such as anxiety and depression (914). Here, we demonstrate that trait anxiety is a determining factor of social rank that is mediated by brain region-specific mitochondrial function. We show that manipulation of mitochondrial function in the nucleus accumbens (NAc) is sufficient to influence social rank, highlighting a key role for brain mitochondrial function in social behavior.

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About S. R. Zelenz 102 Articles
S.R. Zelenz has worked in education for 20 years. Working with students from all walks of life, cultures, races, and social diversity, Zelenz’s research in Educational Leadership led to finding a better way to approach learning for students with trauma histories. Many were juvenile offenders, gang members, diagnosed with varying behavioral disorders, or had family histories of violence, murder, or narcissistic parenting. This research could not be effectively accomplished without further understanding: how epigenetic trauma inheritance may be impacting these students; how brain development from trauma may be impacting their behavioral and emotional development; as well as deep understanding of psychology and its varying classifications for behavioral and personality disorders. The goal is to find solutions for changing the conversation and making a real difference for these students. She has also worked with nonprofits of varying focus areas for the last 25 years. Her undergraduate degree in Arts Administration and Music prepared her for managing nonprofits of any size as well as procuring funding so that they can achieve their goals. Pairing her nonprofit background with her education background, she has been able to make a difference for over 200 nonprofits worldwide, written curriculum for schools across the globe, and assisted many arts organizations through performance and management.