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 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.

Keywords: anxiety; mitochondria; nucleus accumbens; social competition; social dominance.

Fig. 1.

High anxiety predisposes for social submission. (A) Classification for anxiety-profiles was based on the elevated plus maze (EPM; HA, high-anxious; IA, intermediate-anxious; LA, low-anxious). Time spent in the open arm of the EPM (B and C) and in the lit compartment of the light–dark test (D and E) was lower for HA animals, n = 24 per group. When competing against an LA rat, HA rats display reduced offensive behavior (F) and show low social dominance (G) emerging throughout time (H), n = 24 pairs. (I) Both HA and LA rats display similar levels of social preference. (J) Levels of zif268 were increased following social competition in the nucleus accumbens (NAc), prefrontal cortex (PFC), and basolateral (BLA), but not central (CeA), amygdala in both groups, n = 10–20 per group. (K) Local inactivation with muscimol in the NAc, but not BLA, reduced social dominance, n = 11–13 pairs. Data are mean ± SEM (*P < 0.05, **P < 0.01, ***P < 0.001, Student’s t test or one-sample t test against chance, 50%, level).

Fig. 2.

D1-containing cells are activated by social competition. (A and B) cFOS activation of substance P (SubP; D1-containing cells), enkephalin (ENK; D2-containing cells), S100, and vesicular acetylcholine transporter (VAChT) in the NAc after social competition (SC) was compared with basal levels (B) and only substance P⁺ cells displayed cFOS activation in response to social competition. (C) cFOS activation in substance P⁺ cells significantly correlated with the duration of competitive offensive behavior. cFOS activation is presented as percentage of basal cFOS activation induced by social competition (n = 6 pairs per group) as mean ± SEM (*P < 0.05).

Fig. 3.

High-anxious rats (HA) exhibit lower mitochondrial function that is specific to the nucleus accumbens (NAc). HA exhibit lower expression of complex I and II protein levels in the NAc than low-anxious rats (LA), n = 5–12 per group (A), but no significant difference in mitochondrial number, n = 9 per group (B). (C) HA display lower mitochondrial respiration in the NAc than LA, n = 6 per group. (D) These differences were also detected two months following anxiety characterization, n = 8 per group. (E) Mitochondrial respiration in the basolateral amygdala (BLA) does not differ between groups, n = 11 per group. ATP-levels in the NAc are lower in HA than LA, n = 9–10 per group (F), whereas ROS products are higher in HA, n = 5–6 per group (G). Synaptoneurosomes were separated from glia (H), and then mitochondrial respiration was measured in three independent experiments. The mitochondrial respiration deficit of HA is present in synaptoneurosomes (I) but not in glia-enriched fractions (J). Data are mean ± SEM. Respiration data are presented as estimated marginal means ± SEM of oxygen flux per mg tissue (*P < 0.05; **P < 0.01, Linear Mixed Model).

Fig. 4.

Inhibition of mitochondrial complexes I and II in nucleus accumbens (NAc) decreased social dominance. Intra-NAc infusion of rotenone (ROT, n = 12 pairs), 3-nitropropionic acid (3-NP, n = 10 pairs), or malonic acid (MA, n = 12 pairs) reduced social dominance (A), without affecting locomotion in the Open Field, n = 5–6 per group (B). Intra-BLA infusions of ROT, 3-NP, or MA had no effect on social dominance, n = 6, 9, or 10 pairs, respectively (C), or locomotion, n = 5 per group (D). Data are mean ± SEM (**P < 0.01, ***P < 0.001, Student’s t test or one-sample t test against chance level).

Fig. 5.

Enhancing nucleus accumbens (NAc) energy stores via nicotinamide (NAM) infusion abolished the competitive disadvantage in high-anxious (HA) animals. (A) Intra-NAc infusion of NAM before social competition increased mitochondrial respiration in HA rats, n = 7 per group. (B) NAM-treated HA rats had similar chances to become dominant as low-anxious (LA) rats, n = 9–11 pairs. Intra-NAc infusion of mitoquinone mesylate (mitoQ) reduced local ROS products (C), n = 5, but did not enhance social competition in HA rats (D), n = 8 pairs. Data are presented as mean ± SEM (*P < 0.05, ***P < 0.001, one sample t test against baseline or chance level).