Socially responsive effects of brain oxidative metabolism on aggression

Abstract

Despite ongoing high energetic demands, brains do not always use glucose and oxygen in a ratio that produces maximal ATP through oxidative phosphorylation. In some cases glucose consumption exceeds oxygen use despite adequate oxygen availability, a phenomenon known as aerobic glycolysis. Although metabolic plasticity seems essential for normal cognition, studying its functional significance has been challenging because few experimental systems link brain metabolic patterns to distinct behavioral states. Our recent transcriptomic analysis established a correlation between aggression and decreased whole-brain oxidative phosphorylation activity in the honey bee (Apis mellifera), suggesting that brain metabolic plasticity may modulate this naturally occurring behavior. Here we demonstrate that the relationship between brain metabolism and aggression is causal, conserved over evolutionary time, cell type-specific, and modulated by the social environment. Pharmacologically treating honey bees to inhibit complexes I or V in the oxidative phosphorylation pathway resulted in increased aggression. In addition, transgenic RNAi lines and genetic manipulation to knock down gene expression in complex I in fruit fly (Drosophila melanogaster) neurons resulted in increased aggression, but knockdown in glia had no effect. Finally, honey bee colony-level social manipulations that decrease individual aggression attenuated the effects of oxidative phosphorylation inhibition on aggression, demonstrating a specific effect of the social environment on brain function. Because decreased neuronal oxidative phosphorylation is usually associated with brain disease, these findings provide a powerful context for understanding brain metabolic plasticity and naturally occurring behavioral plasticity.M etabolic dynamics are critical to brain function in both vertebrate and invertebrate species (1-3). In mammals, cognitive and behavioral tasks result in increased glucose metabolism and minor increases in oxygen consumption (relative to availability), and similar processes have been shown to occur in insects (3, 4). These metabolic changes underlie widely used technologies that measure brain activity (e.g., functional MRI and PET) (5-7). Because the brain is an energetically demanding organ with high ATP requirements (8), temporal and spatial variation in glucose metabolism is generally assumed to fulfill the energetic demands of signaling and recovery (5). Paradoxically, in humans, less than 10% of the glucose that is taken up as a result of brain activity is fully oxidized through oxidative phosphorylation (OX) to produce ATP, despite adequate oxygen availability, a phenomenon known as aerobic glycolysis (6, 9-11). Furthermore total glucose uptake by the adult human brain exceeds oxygen use by 10-12% (12). Thus, increased demand for high levels of ATP is inadequate to explain the function of variation in glucose metabolism in the brain. Understanding the functional significance of metabolic plasticity, which is essential for cognition but also l...

Neuromolecular responses to social challenge: Common mechanisms across mouse, stickleback fish, and honey bee

“…A recent study demonstrated a negative causal relationship between brain oxidative phosphorylation activity and territorial aggression in honey bees and fruit flies (24). Consistent with that study, we here specifically identified modulation of NADH dehydrogenase, the oxidative phosphorylation enzyme complex with the best-known relationship to territorial aggression (7,24). Oxidative phosphorylation genes were generally down-regulated in response to territory intrusion in mouse and honey bee, as in previous studies (7,24).…”

“…Consistent with that study, we here specifically identified modulation of NADH dehydrogenase, the oxidative phosphorylation enzyme complex with the best-known relationship to territorial aggression (7,24). Oxidative phosphorylation genes were generally down-regulated in response to territory intrusion in mouse and honey bee, as in previous studies (7,24). The stickleback diencephalon showed the opposite pattern, possibly indicative of brain regional heterogeneity or species-level variation in the timing of the metabolic response.…”

The defensive response of the honeybee Apis mellifera

“…These results were confirmed recently by studies revealing that mitochondrial oxidative phosphorylation is inhibited in the brain of aggressive bees in favour of aerobic glycolysis (Barros et al, 2015;Chandrasekaran et al, 2015;Li-Byarlay et al, 2014;Rittschof et al, 2015b). This holds true when comparing genetically aggressive bees with gentle ones, but also when comparing bees from the same background before and after exposure to IAA (Chandrasekaran et al, 2015).…”

“…This holds true when comparing genetically aggressive bees with gentle ones, but also when comparing bees from the same background before and after exposure to IAA (Chandrasekaran et al, 2015). Direct manipulation of the brain metabolism of bees confirmed this relation to be causal, because inhibiting oxidative phosphorylation increased the aggressiveness of treated bees (Li-Byarlay et al, 2014). How this shift in energy metabolism is acting is unknown.…”

Social complexity influences brain investment and neural operation costs in ants

“…This appears counterintuitive, although neurons may be optimized to reduce ATP consumption [74] and thus COX activity, which is linked to neural activation [35] and not necessarily directly correlated with neuron size. Behavioural phenotype also may be related to brain metabolic activity [75]. The variation in total brain metabolic activity in our study species indicates that F. subsericea worker task performance within and outside the nest may contribute to increased brain operation costs.…”