To our knowledge, this is the first study investigating the effects of sucrose consumption on aggressive behavior in a controlled setting using animal models. First, we found a dramatic elevation in serum corticosterone levels in mice that consumed high sugar for a short interval of 2 weeks in a dose-dependent manner. This observation led us to examine the long-term effects of high sugar consumption that started in infancy and continued to adulthood. We found heightened levels of serum corticosterone when treated mice matured to adulthood as compared to control mice. Corticosterone, a dominant glucocorticoid in rodents that is comparable to cortisol in humans, is widely studied as a stress hormone and a well-established target in the search for hormonal modulators of social aggression9,10. In agreement with other studies, we observed that aggressive mice had higher levels of corticosterone. Several other hormones have also been reported for their associations with aggressive behavior. Local release of vasopressin within the lateral septum of the brains was reported during a resident-intruder test in adult male rats7. Vasopressin release correlated positively with inter-male aggression, and treatment with a vasopressin V1a receptor antagonist reduced the aggression of highly aggressive rats8. Oxytocin was reported to inhibit aggressive behaviors in a study showing that oxytocin injection into the brain decreased the frequency of biting in lactating female rats4. However, conflicting results were also reported in studies showing that oxytocin knockout (OT−/−) mice exhibited a significant decrease in the duration of aggressive attacks in a resident-intruder test compared with wild-type (OT+/+) control mice6. The present study revealed that there was no significant difference in expression of vasopressin in S30 mice as compared to CT or A30 mice. On the contrary, expression of oxytocin in S30 mice was significantly higher than in the other cohorts. In view of the reported conflicting roles of oxytocin in regulating aggressive behavior, our results demonstrate that social aggression promoted by SSB consumption might be mediated by corticosterone. It is also notable that ingestion of the artificial sweetener did not mimic the role of the sugar in elevating corticosterone levels or in promoting aggressive behaviors.

The consumption of a high sucrose solution resulted not only in hormonal changes but also in alterations in transcriptional networks in the brain. The hypothalamus is one of the regions in the central nervous system in which aggressive behaviors are regulated40,41. Although we used the entire hypothalamus for a transcriptome profiling analysis with the aim of elucidating global transcriptional networks of aggressive behavior (Fig. 2) as related to physiological functions-energy balance (Supplemental Fig. 1) and endocrine functions (Fig. 1), it is worth noting that the hypothalamus is a heterogeneous region consisting of several anatomical and functional subdivisions42. The precise location and particular neurons in the hypothalamus implicated in aggressive behaviors are actively being investigated. Recent studies identified ventromedial (VMN)40,43, premammillary nuclei (PMN)40,43 and anterior hypothalamic nuclei (AHi)44 as associated with aggressive behaviors. Through extensive bioinformatic analyses of the transcriptome in the hypothalamus, we found SSB consumption activated the transcriptional network of inflammatory responses with dramatic increases in the levels of TNFα and CXCL1. Furthermore, the frequency of CD11b+ cells in PBL was significantly higher in S30 mice than in CT or A30 mice. These circulating inflammatory cells tend to be poorly responsive to corticosterone compared to the cells in CT or A30 mice. The poor responsiveness of myeloid lineage leukocytes to the hormone has been previously reported in a human study wherein chronic stress resulted in failure to down-regulate the inflammatory response39. Furthermore, it has been reported that there is an association between aggressive behavior and elevated C-reactive protein levels in schizophrenic inpatients45, and elevated plasma inflammatory markers in individuals with intermittent explosive disorder46. We also observed serum proinflammatory cytokines such as IL6 and TNFa were slightly but not significantly higher in S30 group than those in CT or A30 (Supplemental Fig. 2). In addition, several studies showed that pro-inflammatory responses of the CNS following glucocorticoid stimulation regulated the immune system, contributing to altered behaviors47,48. That is, physiological stress induced the activation of the neuroimmune system with increases in neural pro-inflammatory cytokines and chemokines which facilitate peripheral immune cell trafficking to the brain, ultimately resulting in abnormal behavioral outcomes49. These results support our findings that the aggressive behavior shown in S30 mice is related to augmented neural inflammation accompanied by dysregulated immuno-modulating functions of corticosterone.

The behavioral outcomes shown in A30 mice were different from those of S30 mice, despite equivalent sweetness of the aspartame solution to that of the sucrose solution. This indicates that sugar-induced aggressive behavior is not due to the taste of sweetness. There was a report that acute high-dose administration of aspartame reduced aggressive attacks in rats50. However, others reported that rats receiving an aspartame solution would make longer and more numerous aggressive responses in association with reduced brain tryptophan levels and serotonin synthesis51. We observed that artificial sweetener consumption changed neither the levels of aggression hormones nor the transcript levels of genes involved in serotonin metabolism. Transcriptional profiles of brains from A30 mice turned out to be dissimilar to those in S30 mice. A number of aspartame-specific genes that were altered in their expression in response to aspartame but not to sugar are involved in the development and function of the nervous system. A study reported that aspartame produced a biphasic modulation of internal calcium that was associated with up-regulation of calcium in resting neurons and down-regulation in activated neurons52. In another report, aspartame-treated animals showed an increase in the expression of apoptotic genes and consequently, enhanced neuronal cell death53. These results suggest that aspartame plays distinct roles in neuronal functions compared to the roles played by sugar in the brain.

Many studies have reported that intake of sucrose solution can induce abnormal metabolic status, including high levels of blood triglyceride, glucose and insulin, leading to body weight gain in human29,54 and animal models27,55,56,57. However, in the present study, there were no significant changes in the levels of glucose, insulin, or triglycerides in the blood of S30 mice as compared to CT or A30 mice (Supplemental Fig. 1). Unexpectedly, their body weights were significantly lower than those of CT or A30 mice, although the evaluations of growth curve in S30 mice showed that they followed a normal growth pattern unlike that of mice on an early malnutrition diet58. In keeping with our results, other studies59,60,61,62 also reported no significant changes in body weight associated with consumption of sucrose. This discrepancy might be generated, at least in part, by the fact that different experimental designs, such as experimental diet, experimental period, and animal strains have been applied. The metabolic effects of sucrose consumption examined together with a high fat diet might be different from those associated with a normal fat diet57. In addition, the initiating time point in the life cycle and duration of the sucrose challenge might be important contributing factors27,56,63. Animal strain differences might also contribute to the discrepancy as well. It was notable that analysis of intestinal sucrase showed that the enzyme was less active in C57BL/6 mice than in other strains when the diet was high in sucrose61. Furthermore, according to a study that reported higher locomotor activity in mice fed a sucrose solution55, energy expenditure due to augmented activity could possibly have contributed to reduced body weight gain and other metabolic indices, such as blood glucose or triglycerides, in mice with sucrose consumption. It is well known that glucocorticoids, in addition to functions in the CNS, have a wide range of regulatory roles not only in immune functions but also in catabolic functions in energy metabolism. In this regard, a number of studies report a link between reduced body weight and aggression. Reduction in body weight has been positively correlated to altered mood12 and hostile aggression11 in both adults and female adolescents13. In addition, chronically stressed mice showed high levels of corticosterone and, consequently, reduced body weight leading to enhanced behavioral invigoration14.

In conclusion, the present studies showed the promoting effects of long-term sucrose solution consumption on aggressive behaviors. The promoting effects were mediated by changes in serum corticosterone and body weight. The roles played by sugar in social aggression were not related to the sweet flavor, since they were clearly distinct from those played by an artificial sweetener. Further, transcriptome analyses provided molecular understandings of the underlying mechanisms by which sugar drinks induced aggressive behaviors, and showed that long-term sugar drink consumption dysregulated the transcriptional networks of inflammatory responses in the brain. Accordingly, heightened numbers of inflammatory cells in the peripheral blood were found in mice fed the sucrose solution. These results demonstrate that long-term sugar consumption from infancy to adulthood promotes aggressive behaviors and that these effects are modulated by dysregulation of inflammatory responses in the brain. Therefore, in addition to the known benefits of sugar reduction on lowering the risk for physical diseases and disorders, a reduction in sugar intake might assist in resolving social problems related to aggressive behaviors.