- The transcriptomic signature of low aggression in honey bees resembles a response to infection. - We sequenced the transcriptomes of the brain, fat body, and midgut of adult sibling worker bees who developed as pre-adults in relatively high versus low aggression colonies. - We further assessed whether the transcriptomic signature of aggression in the brain is similar to the neuromolecular response to acute predator threat, exposure to a high-aggression environment as an adult, or adult behavioral maturation.. - In the fat body, and to some degree the midgut, our data specifically support the hypothesis that low aggression resembles a diseased or parasitized state. - However, we find little evidence of active infection in individuals from the low aggression group. - Conclusions: Results support the hypothesis that low aggression resembles a molecular state of infection. - This pattern is most robust in the peripheral fat body, an immune responsive tissue in the honey bee. - We find no evidence of acute infection in bees from the low aggression group, suggesting the physiological state. - Previous studies in the honey bee have associ- ated some behavioral responses with specific infectious agents but no generalized sickness behavior has been identified in honey bees.. - Honey bee aggression is exhibited by worker bees in the context of nest defense. - Because nest defense is a collective behavior, aggression is highly socially and environmentally responsive in the honey bee . - How- ever, transcriptomic studies suggest that the brain mo- lecular profile associated with high aggression shows some similarities whether the source of behavioral vari- ation is genetic or environmental and this brain transcriptomic state has been connected to higher physiological levels in the brain . - In the current study, we use a molecular approach to determine whether variation in aggression resembles a generalized response to infec- tion and parasitic feeding, recently identified in honey bees [18].. - The diverse health outcomes associated with high aggres- sion in the honey bee implicate a number of tissues includ- ing the brain as a regulator of behavior, the fat body, a metabolic tissue that is involved in immune response [88], and the midgut, which is involved in pesticide detoxifica- tion [54]. - Communication between peripheral, immune responsive tissues and the brain is characteristic of sickness behavior in vertebrates [17], but in the context of honey bee aggression, no study has evaluated tissues other than the brain to establish a role for peripheral systems in behav- ioral variation.. - In a previous study, we fostered these siblings in high and low aggression colonies during their egg, larval, and pupal stages. - We assess whether dif- ferentially expressed genes in our study are enriched for those rapidly modulated by social alarm cues indicating a predator threat, genes modulated by prolonged exposure to aggressive nestmates during adulthood, or genes modulated in the context of behavioral maturation, the process by which adult honey bees progress through different behav- ioral tasks as they age (older adult bees are generally more responsive to aggressive cues [6. - We performed an analysis to determine which genes were differentially expressed among siblings who developed in a high versus low aggression environment. - 85, 1571, and 312 genes were differentially expressed in the brain, fat body, and midgut tissues, respectively (Additional file 1: Tables S1, S2 and S3). - Genes in the brain were significantly biased to- wards upregulation in low aggression bees (81%, binomial test, P <. - 0.0001), while direction of expression was not signifi- cantly biased in the fat body (49% upregulated, binomial test, P = 0.27) or midgut (55%, binomial test, P = 0.07).. - Differentially expressed genes in the brain were significantly enriched for 23 GO terms (Additional file 1: Table S4). - These results suggest strong roles for transcriptional regulation, sensory development, and carbohydrate metabolism in differentiating brain gene expression profiles for high versus low aggression bees.. - Relationship between low aggression and disease state Are low aggression bees infected with a pathogen?. - No pathogen was significantly more abundant or more likely to be present in low aggression samples (Additional file 1: Table S6, S7 and S8), suggest- ing molecular differences as a function of aggression were not caused by acute pathogen infection.. - directional concordance, with the hypothesis that genes upregulated with infection would be upregulated in low aggression bees, and genes downregulated with infection would be downregulated in low aggression bees if it is a phenotype associated with disease.. - In the brain, only one differentially expressed gene over- lapped with the Doublet et al. - This single gene, GB42523 (an uncharacterized non-coding RNA), was upregulated in low aggression bees, consistent with the hypothesis that low aggression resembles a diseased state. - GB45913 (le- thal (2) essential for life, related to heat-shock proteins) was downregulated in low aggression bees, while the sec- ond, GB50116 (chymotrypsin inhibitor) was upregulated in low aggression bees.. - In the fat body, 13 genes overlapped with the 56 up- regulated genes in the Doublet et al. - Moreover, 10 of the 13 genes were upregulated in low aggression bees, 77% directional concordance with the hypothesis that the fat body molecular signature of low aggression resembles a diseased state (a signifi- cant directional bias, binomial test, P <. - Seventeen Table 1 The median number of reads (per million in the library) that mapped to each pathogen in high and low aggression samples. - In the midgut, 3 genes overlapped with the 56 upregu- lated Doublet et al. - all three were upregulated in low aggression bees. - Five of seven showed concordance with the Table 2 Genes differentially expressed in the fat body as a function of aggression and upregulated as a result of immune activation [18]. - Table 3 Genes differentially expressed in the fat body as a function of aggression and downregulated as a result of immune activation [18]. - hypothesis that low aggression resembles a diseased state (a non-significant result, P = 0.23). - Overall, across all three tissues, we find evidence to support the hypothesis that the molecular signature of low aggression resembles the molecular signature of pathogen infection and para- sitic feeding.. - The pre-adult developmental environment could cause low aggression by modulating the baseline expression of genes that are responsive to alarm cues. - To test this possi- bility, we compared our list of genes differentially expressed in the brain as a function of aggression to genes differen- tially expressed following alarm pheromone exposure [3], which induces a rapid, aggressive anti-predator response.. - Using a series of experiments that involved housing adult worker bees from high and low aggression strains in colonies with the opposite genotype and ag- gression levels, Alaux et al. - [3] found that certain genes in the brain are differentially expressed as a consequence of colony environment, irrespective of individual genotype. - To assess whether the molecular signature of aggression in our study resembles the signature of adult behavioral maturation, we compared differentially expressed genes in the brain to those differentially expressed between foragers (older adult workers) and nurses (younger adult workers) [3]. - We found signifi- cant enrichment for infection-responsive genes in all three tissues, and in the fat body, and to some degree the midgut, we find evidence of directional concordance consistent with the hypothesis that low aggression resembles a diseased or parasitized state. - However, we found little evidence of acute infection in low aggression individuals. - We also found lim- ited evidence that the brain molecular signature in the current study is enriched for genes modulated by social cues that induce aggression in adults. - Interestingly, we Table 4 Genes differentially expressed in the brain as a function of aggression and differentially regulated in the brain between older, foraging adults compared to younger nurse bees. - do see a signature of carbohydrate metabolism among genes differentially expressed in the brain in our study, consistent with studies linking glycolysis and oxidative phosphorylation to social and environmental modulation of aggression . - Finally, enrichment analyses provide some support for the hypothesis that variation in aggression in our study reflects variation in the pacing of behavioral maturation in adults. - Our study provides evidence that the molecular state associated with low aggression resembles a diseased state, providing a potential physiological link between high aggression and resilience to health stressors.. - Using these estimates, we find no significant differences in the abundance of any pathogen between high and low aggression bees, indi- cating that variation in aggression as a result of. - Other studies have noted parallels in the molecular signatures of aggression arising from genetic and environmental factors [3, 27], and genetic variation in aggression is associated. - 1 This schematic provides a summary of enrichment analysis results in the present study. - indicate brain enrichment comparisons of genes differentially expressed as a funciton of aggression in the current study with a previous microarray study [3], which evaluated genes differentially expressed following exposure to aggression-inducing alarm cues (Predator threat), exposure to a high versus low aggression environment as an adult (Adult environment), and adult behavioral changes with aging (Behavioral maturation). - In our data analysis, gene lists up and downregulated with infection or parasitic feeding were analyzed separately, while other aggression comparisons in the brain were analyzed irrespective of expression direction because the brain differentially expressed gene list in our study was short. - Gene numbers listed for each tissue sum to the total differentially expressed genes in the current study, not the total genes incorporated in the enrichment analyses. - In the current study, we did not directly evaluate resilience to health stressors as a function of aggression, and so it is possible that low aggression bees here are protected against infection. - However, in our previous study, low aggression bees were more susceptible to topical pesti- cide treatments, and low aggression hives generally had higher parasitic mite levels [66]. - Other studies show that at the colony level, low aggression hives have worse survival outcomes and lower foraging activity [69, 94].. - low aggression bees may be more susceptible to a pesticide, but less susceptible to a pathogen (the latter was not measured).. - In the brain, we found evidence that genes differentially expressed between high and low aggression siblings are significantly enriched for genes differentially expressed be- tween nurse and forager worker bees [3, 89]. - This discrepancy could reflect differences in the stability of social effects experienced at these two different life stages. - Similarly, variation in the honey bee developmental environment is known to cause changes in adult brain structure [34]. - In the current results, changes in brain molecular state are accompanied by shifts in gene expression in both the fat body and midgut. - This result is consistent with patterns of sickness behavior in other animals, where molecular signals of peripheral infection impact aggression-relevant signaling in the brain [57]. - In the honey bee, no previous study of aggression has assessed molecular variation in per- ipheral tissues, although recent work suggests there may be some common master regulatory genes associated with age-related behavioral changes across diverse tissues in the honey bee [5, 44]. - Similarly, chronic stress impacts how in- dividuals respond to social cues in the context of aggression [64]. - In keeping with this idea, we find that differentially expressed genes as a function of aggression in the current study are enriched for processes related to sensory development. - Understanding how aggression relates to other social behaviors in the con- text of infection is an important area of future study.. - In the honey bee, where multiple stressors increase mortality risk by acting in con- cert on the same physiological pathways within individ- uals, a physiological phenotype that resembles infection may increase the severity of the health consequences of additional stressors. - Likewise, low aggression bees are more likely to show negative health impacts of disease and other stressors compared to high. - As in verte- brate species, behavior could be used to predict resilience to health stressors in the honey bee. - Links between aggres- sion and disease resilience in the honey bee should be considered in the context of future management and breeding efforts aimed at improving health outcomes.. - The samples used in the current study (preserved from one of the experiments above) were siblings from a sin- gle queen kept in one high and one low aggression hive.. - were kept in the same apiary, and originated from the same commer- cial source. - Sub-sampling is particularly relevant in the current molecular analysis, as behavioral and physiological re- sults from our prior study were highly consistent across hives and genotypes [66]. - Furthermore, because the queen mother of the siblings sequenced in the current analysis was outbred and naturally-mated (honey bee queens mate with 17–20 males [82. - For our two target hives used in the current molecular study, honeycomb frames containing pupating workers were removed from the hives 1 day prior to adult emer- gence (calculated based on known worker honey bee devel- opmental timing [91. - Thus, the molecular analysis in the current study assesses individuals drawn from a larger group for which we collected behavioral data. - The final sequencing results include N = 11 individuals from each colony with all three tissues se- quenced, and N = 1 low aggression and N = 2 high aggres- sion individuals with the brain and midgut only sequenced (72 samples total).. - This file contains complete lists of differentially expressed genes in the brain (Table S1), fat body (Table S2), and midgut (Table S3), GO term lists in the brain (Table S4) and fat body (Table S5), pathogen data for the brain (Table S6), fat body (Table S7), and midgut (Table S8), and data accession numbers (Table S9).. - The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.. - The datasets supporting the conclusions of this article are deposited in the NCBI SRA repository. - Oxytocin and vasopressin in the medial amygdala differentially modulate approach and avoidance behavior toward illness-related social odor. - Aggression is associated with aerobic glycolysis in the honey bee brain(1). - Novel insect Picorna-like virus identified in the brains of aggressive worker honeybees. - Genetic variation in worker temporal polyethism and colony defensiveness in the honey bee Apis mellifera. - Synaptic organization in the adult honey bee brain is influenced by brood-temperature control during pupal development. - Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. - In: The Hive and the Honey bee, editor. - Honey constituents up-regulate detoxification and immunity genes in the western honey bee Apis mellifera.. - The impacts of maternal stress on worker phenotypes in the honey bee. - Sequential social experiences interact to modulate aggression but not brain gene expression in the honey bee (Apis mellifera). - Brain mitochondrial bioenergetics change with rapid and prolonged shifts in aggression in the honey bee, Apis mellifera. - Biogenic amines and activity levels alter the neural energetic response to aggressive social cues in the honey bee Apis mellifera. - Mating frequencies of honey bee queens (Apis mellifera L.) in a population of feral colonies in the northeastern United States. - Annotated expressed sequence tags and cDNA microarrays for studies of brain and behavior in the honey bee. - The biology of the honey bee. - Selective neuroanatomical plasticity and division of labour in the honeybee. - Life expectancy and onset of foraging in the honeybee (Apis mellifera)
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