Ferrum Phos
Banned
Full text: http://www.pnas.org/content/112/50/15486.full.pdf
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, intra-accumbal 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.
We then investigated whether we could reverse the disadvantage exhibited by high-anxious animals in the acquisition of social dominance by boosting NAc mitochondrial function. Nicotinamide adenine dinucleotide (NAD+) is a metabolic cofactor present in cells that has been implicated in a wide range of critical metabolic activities (28). Treatment with the NAD+ precursor nicotinamide (NAM; ref. 28), an amide form of vitamin B3 that boosts mitochondrial respiration (29), into the NAc of high-anxious rats at a time point before the social encounter and at a dose that increased accumbal mitochondrial respiration (Fig. 5A), abolished the disadvantage of high-anxious animals to become dominant against low-anxious animals (Fig. 5B).
Inhibition of either complex I or complex II in the NAc markedly reduced social rank, whereas the competitive disadvantage of high-anxious animals to achieve a dominant rank against a low anxious male could be overcome by intra-NAc infusion of the mitochondrial booster vitamin B3 (NAM). Control experiments excluded that the observed differences in social dominance between animals differing in anxiety and those impinged by the pharmacological treatments were not due to broad alterations in social behavior or confounded by perturbations in locomotion or general behavior. Nutritional interventions, such as vitamin B3, have previously been proposed as therapeutics for depression and age-related neurodegenerative diseases (43, 44). Our results attribute a previously unidentified role for vitamin B3 as a potential target to deal with anxiety-related deficits in competitiveness.
Substantial evidence implicates the NAc in depression (51, 52) and “anergia,” or lack of energy at the core of depression and anxiety disorders (53, 54). Furthermore, mitochondrial deficiency is frequently observed in brain disorders (55), including depression (13, 14, 26, 31, 56) and anxiety (9). Moreover, individuals with mitochondrial disorders often express symptoms of depression and anxiety (10–13). High anxiety trait is a known vulnerability factor to develop depression, particularly if individuals are exposed to stress (57, 58), with stress impinging energetically costly neuronal adaptations (59, 60). Limited energy production due to reduced mitochondrial function may impair adaptive neuronal capacity to life challenges (32) and contribute to the development of psychopathologies (9, 10, 13, 14). Therefore, our results highlight differences in mitochondrial function in the NAc as a potential mechanism underlying the susceptibility or resilience to develop depression, and may open new prospects for the advancement of preventive therapeutic approaches to 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, intra-accumbal 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.
We then investigated whether we could reverse the disadvantage exhibited by high-anxious animals in the acquisition of social dominance by boosting NAc mitochondrial function. Nicotinamide adenine dinucleotide (NAD+) is a metabolic cofactor present in cells that has been implicated in a wide range of critical metabolic activities (28). Treatment with the NAD+ precursor nicotinamide (NAM; ref. 28), an amide form of vitamin B3 that boosts mitochondrial respiration (29), into the NAc of high-anxious rats at a time point before the social encounter and at a dose that increased accumbal mitochondrial respiration (Fig. 5A), abolished the disadvantage of high-anxious animals to become dominant against low-anxious animals (Fig. 5B).
Inhibition of either complex I or complex II in the NAc markedly reduced social rank, whereas the competitive disadvantage of high-anxious animals to achieve a dominant rank against a low anxious male could be overcome by intra-NAc infusion of the mitochondrial booster vitamin B3 (NAM). Control experiments excluded that the observed differences in social dominance between animals differing in anxiety and those impinged by the pharmacological treatments were not due to broad alterations in social behavior or confounded by perturbations in locomotion or general behavior. Nutritional interventions, such as vitamin B3, have previously been proposed as therapeutics for depression and age-related neurodegenerative diseases (43, 44). Our results attribute a previously unidentified role for vitamin B3 as a potential target to deal with anxiety-related deficits in competitiveness.
Substantial evidence implicates the NAc in depression (51, 52) and “anergia,” or lack of energy at the core of depression and anxiety disorders (53, 54). Furthermore, mitochondrial deficiency is frequently observed in brain disorders (55), including depression (13, 14, 26, 31, 56) and anxiety (9). Moreover, individuals with mitochondrial disorders often express symptoms of depression and anxiety (10–13). High anxiety trait is a known vulnerability factor to develop depression, particularly if individuals are exposed to stress (57, 58), with stress impinging energetically costly neuronal adaptations (59, 60). Limited energy production due to reduced mitochondrial function may impair adaptive neuronal capacity to life challenges (32) and contribute to the development of psychopathologies (9, 10, 13, 14). Therefore, our results highlight differences in mitochondrial function in the NAc as a potential mechanism underlying the susceptibility or resilience to develop depression, and may open new prospects for the advancement of preventive therapeutic approaches to mood disorders.
Watch their girl take another pee pee.