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1.
Nature ; 583(7816): 415-420, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32555456

RESUMO

Animals coexist in commensal, pathogenic or mutualistic relationships with complex communities of diverse organisms, including microorganisms1. Some bacteria produce bioactive neurotransmitters that have previously been proposed to modulate nervous system activity and behaviours of their hosts2,3. 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 ß-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.


Assuntos
Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/fisiologia , Comportamento Alimentar/fisiologia , Intestinos/microbiologia , Neurotransmissores/metabolismo , Providencia/metabolismo , Olfato/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Microbioma Gastrointestinal/fisiologia , Metabolômica , Mutação , Octanóis/farmacologia , Octopamina/biossíntese , Octopamina/metabolismo , Providencia/enzimologia , Providencia/fisiologia , Receptores de Amina Biogênica/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriais/metabolismo , Olfato/efeitos dos fármacos , Tiramina/biossíntese , Tiramina/metabolismo , Tirosina Descarboxilase/deficiência , Tirosina Descarboxilase/genética
2.
PLoS Biol ; 20(6): e3001677, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35696430

RESUMO

The valence and salience of individual odorants are modulated by an animal's innate preferences, learned associations, and internal state, as well as by the context of odorant presentation. The mechanisms underlying context-dependent flexibility in odor valence are not fully understood. Here, we show that the behavioral response of Caenorhabditis elegans to bacterially produced medium-chain alcohols switches from attraction to avoidance when presented in the background of a subset of additional attractive chemicals. This context-dependent reversal of odorant preference is driven by cell-autonomous inversion of the response to these alcohols in the single AWC olfactory neuron pair. We find that while medium-chain alcohols inhibit the AWC olfactory neurons to drive attraction, these alcohols instead activate AWC to promote avoidance when presented in the background of a second AWC-sensed odorant. We show that these opposing responses are driven via engagement of distinct odorant-directed signal transduction pathways within AWC. Our results indicate that context-dependent recruitment of alternative intracellular signaling pathways within a single sensory neuron type conveys opposite hedonic valences, thereby providing a robust mechanism for odorant encoding and discrimination at the periphery.


Assuntos
Neurônios Receptores Olfatórios , Receptores Odorantes , Álcoois , Animais , Caenorhabditis elegans/fisiologia , Odorantes , Neurônios Receptores Olfatórios/fisiologia , Células Receptoras Sensoriais , Olfato/fisiologia
3.
Mol Psychiatry ; 26(6): 1808-1831, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32071385

RESUMO

Maternal immune activation (MIA) disrupts the central innate immune system during a critical neurodevelopmental period. Microglia are primary innate immune cells in the brain although their direct influence on the MIA phenotype is largely unknown. Here we show that MIA alters microglial gene expression with upregulation of cellular protrusion/neuritogenic pathways, concurrently causing repetitive behavior, social deficits, and synaptic dysfunction to layer V intrinsically bursting pyramidal neurons in the prefrontal cortex of mice. MIA increases plastic dendritic spines of the intrinsically bursting neurons and their interaction with hyper-ramified microglia. Treating MIA offspring by colony stimulating factor 1 receptor inhibitors induces depletion and repopulation of microglia, and corrects protein expression of the newly identified MIA-associated neuritogenic molecules in microglia, which coalesces with correction of MIA-associated synaptic, neurophysiological, and behavioral abnormalities. Our study demonstrates that maternal immune insults perturb microglial phenotypes and influence neuronal functions throughout adulthood, and reveals a potent effect of colony stimulating factor 1 receptor inhibitors on the correction of MIA-associated microglial, synaptic, and neurobehavioral dysfunctions.


Assuntos
Microglia , Efeitos Tardios da Exposição Pré-Natal , Animais , Comportamento Animal , Encéfalo , Modelos Animais de Doenças , Feminino , Inflamação , Fator Estimulador de Colônias de Macrófagos , Camundongos , Neurônios , Gravidez , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos
4.
PLoS Genet ; 14(2): e1007213, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29415022

RESUMO

Animals integrate external cues with information about internal conditions such as metabolic state to execute the appropriate behavioral and developmental decisions. Information about food quality and quantity is assessed by the intestine and transmitted to modulate neuronal functions via mechanisms that are not fully understood. The conserved Target of Rapamycin complex 2 (TORC2) controls multiple processes in response to cellular stressors and growth factors. Here we show that TORC2 coordinates larval development and adult behaviors in response to environmental cues and feeding state in the bacterivorous nematode C. elegans. During development, pheromone, bacterial food, and temperature regulate expression of the daf-7 TGF-ß and daf-28 insulin-like peptide in sensory neurons to promote a binary decision between reproductive growth and entry into the alternate dauer larval stage. We find that TORC2 acts in the intestine to regulate neuronal expression of both daf-7 and daf-28, which together reflect bacterial-diet dependent feeding status, thus providing a mechanism for integration of food signals with external cues in the regulation of neuroendocrine gene expression. In the adult, TORC2 similarly acts in the intestine to modulate food-regulated foraging behaviors via a PDF-2/PDFR-1 neuropeptide signaling-dependent pathway. We also demonstrate that genetic variation affects food-dependent larval and adult phenotypes, and identify quantitative trait loci (QTL) associated with these traits. Together, these results suggest that TORC2 acts as a hub for communication of feeding state information from the gut to the brain, thereby contributing to modulation of neuronal function by internal state.


Assuntos
Encéfalo/metabolismo , Proteínas de Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/genética , Mucosa Intestinal/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/fisiologia , Plasticidade Neuronal/genética , Proteína Companheira de mTOR Insensível à Rapamicina/fisiologia , Adaptação Fisiológica/genética , Animais , Animais Geneticamente Modificados , Encéfalo/citologia , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Intestinos/citologia , Intestinos/inervação , Fenótipo , Células Receptoras Sensoriais/fisiologia , Transdução de Sinais/genética , Temperatura
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