Mitochondrial function in the brain links anxiety with social subordination

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 anxietymatched 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 highanxious 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.anxiety | mitochondria | nucleus accumbens | social dominance | social competition

Acute embryonic anoxia exposure favours the development of a dominant and aggressive phenotype in adult zebrafish

“…In general, the scototaxic response of adult zebrafish to the light/dark box test in this study was consistent with the behavioural response previously observed for this paradigm [18]. In mammals, highly anxious individuals often display a subordinate status [26]. Therefore, assuming that trait anxiety also has an important consequence for social status in zebrafish, we would predict that adults derived from embryonic anoxia would have lower anxiety levels.…”

Maternal exposure to environmental enrichment before and during gestation influences behaviour of rat offspring in a sex-specific manner

“…ACCEPTED MANUSCRIPT 26 Concerning behavioural outcomes in the EPM and OF, we showed an increase of closed arms entries in the EPM and an increase of line crossing in the OF in male and female offspring.…”

An energetic view of stress: Focus on mitochondria

“…Further insights for a key role of mitochondrial function in specific brain regions in influencing complex social behaviors have been provided by a series of studies in rats relating anxiety with diminished social competitiveness (Hollis et al, 2015; van der Kooij et al, 2017), a phenomenon that has also been highlighted in humans (Goette et al, 2015). In rats, lower mitochondrial function in the nucleus accumbens was observed in high-anxious animals compared to their less anxious littermates, and was causally implicated in their low social competitiveness (Hollis et al, 2015).…”

“…In rats, lower mitochondrial function in the nucleus accumbens was observed in high-anxious animals compared to their less anxious littermates, and was causally implicated in their low social competitiveness (Hollis et al, 2015). More specifically, high-anxious animals that are prone to become subordinate during a social encounter exhibited reduced mitochondrial respiratory capacity, decreased ATP levels, and increased ROS production in the nucleus accumbens.…”

“…Furthermore, micro-infusing specific mitochondrial electron transport chain inhibitors into the nucleus accumbens reduced social rank, recapitulating the low probability to become dominant in 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 anxious rats (Hollis et al, 2015). Additionally, treatment with a low dose of the anxiolytic diazepam was effective to facilitate social dominance, ameliorating both the competitive disadvantage and low mitochondrial function in the nucleus accumbens displayed by high-anxious rats (van der Kooij et al, 2017).…”