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Animals coexist in commensal, pathogenic or mutualistic relationships with complex communities of diverse organisms, including microorganisms 1 . Some bacteria produce bioactive neurotransmitters that have previously been proposed to modulate nervous system activity and behaviours of their hosts 2 , 3 . However, the mechanistic basis of this microbiota–brain signalling and its physiological relevance are largely unknown. Here we show that in Caenorhabditis elegans , the neuromodulator tyramine produced by commensal Providencia bacteria, which colonize the gut, bypasses the requirement for host tyramine biosynthesis and manipulates a host sensory decision. Bacterially produced tyramine is probably converted to octopamine by the host tyramine β-hydroxylase enzyme. Octopamine, in turn, targets the OCTR-1 octopamine receptor on ASH nociceptive neurons to modulate an aversive olfactory response. We identify the genes that are required for tyramine biosynthesis in Providencia , and show that these genes are necessary for the modulation of host behaviour. We further find that C. elegans colonized by Providencia preferentially select these bacteria in food choice assays, and that this selection bias requires bacterially produced tyramine and host octopamine signalling. Our results demonstrate that a neurotransmitter produced by gut bacteria mimics the functions of the cognate host molecule to override host control of a sensory decision, and thereby promotes fitness of both the host and the microorganism. A neuromodulator produced by commensal Providencia bacteria that colonize the gut of Caenorhabditis elegans mimics the functions of the cognate host molecule to manipulate a sensory decision of the host.

While research into the biology of animal behaviour has primarily focused on the central nervous system, cues from peripheral tissues and the environment have been implicated in brain development and function 1 . There is emerging evidence that bidirectional communication between the gut and the brain affects behaviours including anxiety, cognition, nociception and social interaction 1 – 9 . Coordinated locomotor behaviour is critical for the survival and propagation of animals, and is regulated by internal and external sensory inputs 10 , 11 . However, little is known about how the gut microbiome influences host locomotion, or the molecular and cellular mechanisms involved. Here we report that germ-free status or antibiotic treatment results in hyperactive locomotor behaviour in the fruit fly Drosophila melanogaster . Increased walking speed and daily activity in the absence of a gut microbiome are rescued by mono-colonization with specific bacteria, including the fly commensal Lactobacillus brevis . The bacterial enzyme xylose isomerase from L. brevis recapitulates the locomotor effects of microbial colonization by modulating sugar metabolism in flies. Notably, thermogenetic activation of octopaminergic neurons or exogenous administration of octopamine, the invertebrate counterpart of noradrenaline, abrogates the effects of xylose isomerase on Drosophila locomotion. These findings reveal a previously unappreciated role for the gut microbiome in modulating locomotion, and identify octopaminergic neurons as mediators of peripheral microbial cues that regulate motor behaviour in animals. Female Drosophila that lack a microbiota are hyperactive, and xylose isomerase from Lactobacillus brevis is sufficient to reverse this effect.

The monoamines octopamine (OA) and tyramine (TA) modulate numerous behaviours and physiological processes in invertebrates. Nevertheless, it is not clear whether these invertebrate counterparts of norepinephrine are important regulators of metabolic and life history traits. We show that flies ( Drosophila melanogaster ) lacking OA are more resistant to starvation, while their overall life span is substantially reduced compared with control flies. In addition, these animals have increased body fat deposits, reduced physical activity and a reduced metabolic resting rate. Increasing the release of OA from internal stores induced the opposite effects. Flies devoid of both OA and TA had normal body fat and metabolic rates, suggesting that OA and TA act antagonistically. Moreover, OA-deficient flies show increased insulin release rates. We inferred that the OA-mediated control of insulin release accounts for a substantial proportion of the alterations observed in these flies. Apparently, OA levels control the balance between thrifty and expenditure metabolic modes. Thus, changes in OA levels in response to external and internal signals orchestrate behaviour and metabolic processes to meet physiological needs. Moreover, chronic deregulation of the corresponding signalling systems in humans may be associated with metabolic disorders, such as obesity or diabetes.

The Varroa destructor mite is a devastating parasite of Apis mellifera honeybees. They can cause colonies to collapse by spreading viruses and feeding on the fat reserves of adults and larvae. Amitraz is used to control mites due to its low toxicity to bees; however, the mechanism of bee resistance to amitraz remains unknown. In this study, we found that amitraz and its major metabolite potently activated all four mite octopamine receptors. Behavioral assays using Drosophila null mutants of octopamine receptors identified one receptor subtype Octβ2R as the sole target of amitraz in vivo. We found that thermogenetic activation of octβ2R- expressing neurons mimics amitraz poisoning symptoms in target pests. We next confirmed that the mite Octβ2R was more sensitive to amitraz and its metabolite than the bee Octβ2R in pharmacological assays and transgenic flies. Furthermore, replacement of three bee-specific residues with the counterparts in the mite receptor increased amitraz sensitivity of the bee Octβ2R, indicating that the relative insensitivity of their receptor is the major mechanism for honeybees to resist amitraz. The present findings have important implications for resistance management and the design of safer insecticides that selectively target pests while maintaining low toxicity to non-target pollinators.

Essential oils (EOs) are lipophilic secondary metabolites obtained from plants; terpenoids represent the main components of them. A lot of studies showed neurotoxic actions of EOs. In insects, they cause paralysis followed by death. This feature let us consider components of EOs as potential bioinsecticides. The inhibition of acetylcholinesterase (AChE) is the one of the most investigated mechanisms of action in EOs. However, EOs are rather weak inhibitors of AChE. Another proposed mechanism of EO action is a positive allosteric modulation of GABA receptors (GABArs). There are several papers that prove the potentiation of GABA effect on mammalian receptors induced by EOs. In contrast, there is lack of any data concerning the binding of EO components in insects GABArs. In insects, EOs act also via the octopaminergic system. Available data show that EOs can increase the level of both cAMP and calcium in nervous cells. Moreover, some EO components compete with octopamine in binding to its receptor. Electrophysiological experiments performed on Periplaneta americana have shown similarity in the action of EO components and octopamine. This suggests that EOs can modify neuron activity by octopamine receptors. A multitude of potential targets in the insect nervous system makes EO components interesting candidates for bio-insecticides.

Octopamine regulates various physiological phenomena including memory, sleep, grooming and aggression in insects. In Drosophila, four types of octopamine receptors have been identified: Oamb, Oct/TyrR, OctβR and Octα2R. Among these receptors, Octα2R was recently discovered and pharmacologically characterized. However, the effects of the receptor on biological functions are still unknown. Here, we showed that Octα2R regulated several behaviors related to octopamine signaling. Octα2R hypomorphic mutant flies showed a significant decrease in locomotor activity. We found that Octα2R expressed in the pars intercerebralis, which is a brain region projected by octopaminergic neurons, is involved in control of the locomotor activity. Besides, Octα2R hypomorphic mutants increased time and frequency of grooming and inhibited starvation‐induced hyperactivity. These results indicated that Octα2R expressed in the central nervous system is responsible for the involvement in physiological functions. Octα2R signaling regulated activation of locomotor activity, inhibition of grooming and starvation‐induced hyperactivity.

Octopamine, the functional equivalent of noradrenaline in invertebrates, is a key neuromodulator that also influences immune functions. However, the receptor‑specific roles of octopamine in regulating innate immunity in remain incompletely understood. Using loss‑of‑function mutants for the two major octopamine receptors Octβ1R and Octβ2R, combined with systemic bacterial infection models, bacterial clearance assays, in vivo and in vitro phagocytosis assays, and quantification of antimicrobial peptide (AMP) gene expression, we dissected the contribution of each receptor to distinct immune effector modules. Flies deficient in Octβ1R or Octβ2R exhibited reduced survival and impaired bacterial clearance following systemic infection, which was associated with increased bacterial persistence. This phenotype correlated with reduced phagocytic activity of hemocytes in both and assays. In contrast, deficiency of Octβ1R or Octβ2R led to enhanced induction of a subset of essential AMP genes upon infection, indicating that octopamine signaling dampens specific humoral immune outputs. Our data demonstrate that octopamine exerts a decisive influence on the performance of the Drosophila innate immune system by differentially modulating cellular (phagocytosis) and humoral (AMP expression) immune modules in a receptor‑specific manner. These findings establish octopaminergic signaling through Octβ1R and Octβ2R as an important node of neuro‑immune regulation in invertebrates.

We present an LC–MS/MS method that enables reproducible, quantitative detection of multiple biogenic amines—including octopamine, dopamine, serotonin, and their precursors—from single Drosophila individuals. The workflow involves only a minimal extraction in methanol prior to direct injection, eliminating the need for derivatization or laborious purification steps. Its simplicity ensures high reproducibility and broad applicability across experimental settings. Pilot applications revealed distinct neurochemical responses across biologically relevant conditions: a circadian rise in octopamine at dusk, acute increases in octopamine, dopamine, and serotonin under cold stress, and elevations of octopamine, serotonin, and tryptophan during starvation. These findings highlight the utility of single-head LC–MS/MS for dissecting neuromodulator dynamics at the level of individual organisms.

The aim of this study was to examine the influence of octopamine supplementation on endurance performance and exercise metabolism. Double-blind cross-over study. Ten healthy, recreationally active men (Mean±SD; age: 24±2 years; body mass: 78.4±8.7kg; VO2peak: 50.5±6.8 mLkg−1min−1) completed one VO2peak test, one familiarisation trial and two experimental trials. After an overnight fast, participants ingested either a placebo or 150mg of octopamine 60min prior to exercise. Trials consisted of 30min of cycle exercise at 55% peak power output, followed by a 30min performance task whereby participants completed as much work (kJ) as possible. Performance was similar between the experimental trials (placebo: 352.8±39kJ; octopamine: 350.9±38.3kJ; Cohen’s d effect size=0.05; p=0.380). Substrate oxidation and circulating concentrations of free fatty acids, prolactin and cortisol were similar between trial conditions (all p>0.05). There were also no differences across trials for heart rate or perceived exertion during exercise (both p>0.05). Acute supplementation with a low dose of octopamine did not influence endurance cycle performance, substrate oxidation or circulating hormonal concentrations, which could be due to the low serum octopamine concentrations observed. Future studies should investigate the influence of larger doses of octopamine in recreationally active and well-trained individuals during prolonged exercise in temperate and high ambient conditions.

▪ Abstract  Octopamine (OA) and tyramine (TA) are the invertebrate counterparts of the vertebrate adrenergic transmitters. They are decarboxylation products of the amino acid tyrosine, with TA as the biological precursor of OA. Nevertheless, both compounds are independent neurotransmitters that act through G protein–coupled receptors. OA modulates a plethora of behaviors and peripheral and sense organs, enabling the insect to respond correctly to external stimuli. Because these two phenolamines are the only biogenic amines whose physiological significance is presumably restricted to invertebrates, pharmacologists have focused their attention on the corresponding receptors, which are still believed to represent promising targets for new insecticides. Recent progress made on all levels of OA and TA research has enabled researchers to understand better the molecular events underlying the control of complex behaviors.