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1.
Cell ; 167(6): 1469-1480.e12, 2016 Dec 01.
Article in English | MEDLINE | ID: mdl-27912057

ABSTRACT

The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.


Subject(s)
Parkinson Disease/microbiology , Parkinson Disease/pathology , Animals , Brain/pathology , Dysbiosis/pathology , Fatty Acids/metabolism , Gastrointestinal Microbiome , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/physiopathology , Humans , Inflammation/metabolism , Inflammation/microbiology , Inflammation/pathology , Mice , Microglia/pathology , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , alpha-Synuclein/metabolism
2.
Nature ; 595(7867): 409-414, 2021 07.
Article in English | MEDLINE | ID: mdl-34194038

ABSTRACT

Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence1,2. The gut microbiota contribute to social activity in mice3,4, but the gut-brain connections that regulate this complex behaviour and its underlying neural basis are unclear5,6. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus-pituitary-adrenal (HPA) axis. Adrenalectomy, antagonism of glucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis, that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain.


Subject(s)
Brain/cytology , Brain/physiology , Gastrointestinal Microbiome/physiology , Neurons/metabolism , Social Behavior , Stress, Psychological , Animals , Corticosterone/blood , Corticotropin-Releasing Hormone/metabolism , Enterococcus faecalis/metabolism , Germ-Free Life , Glucocorticoids/metabolism , Hypothalamus/metabolism , Male , Mice , Mice, Inbred C57BL , Receptors, Glucocorticoid/metabolism , Signal Transduction
3.
Nature ; 563(7731): 402-406, 2018 11.
Article in English | MEDLINE | ID: mdl-30356215

ABSTRACT

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 function1. There is emerging evidence that bidirectional communication between the gut and the brain affects behaviours including anxiety, cognition, nociception and social interaction1-9. Coordinated locomotor behaviour is critical for the survival and propagation of animals, and is regulated by internal and external sensory inputs10,11. 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.


Subject(s)
Carbohydrate Metabolism , Drosophila melanogaster/microbiology , Drosophila melanogaster/physiology , Gastrointestinal Microbiome/physiology , Levilactobacillus brevis/enzymology , Levilactobacillus brevis/metabolism , Locomotion/physiology , Aldose-Ketose Isomerases/metabolism , Animals , Anti-Bacterial Agents/pharmacology , Carbohydrate Metabolism/drug effects , Drosophila melanogaster/drug effects , Drosophila melanogaster/metabolism , Female , Gastrointestinal Microbiome/drug effects , Germ-Free Life , Levilactobacillus brevis/isolation & purification , Locomotion/drug effects , Motor Activity/drug effects , Motor Activity/physiology , Neural Pathways , Neurons/drug effects , Neurons/metabolism , Octopamine/metabolism , Octopamine/pharmacology , Symbiosis
4.
bioRxiv ; 2024 Mar 17.
Article in English | MEDLINE | ID: mdl-38559111

ABSTRACT

Animals are often bombarded with visual information and must prioritize specific visual features based on their current needs. The neuronal circuits that detect and relay visual features have been well-studied. Yet, much less is known about how an animal adjusts its visual attention as its goals or environmental conditions change. During social behaviors, flies need to focus on nearby flies. Here, we study how the flow of visual information is altered when female Drosophila enter an aggressive state. From the connectome, we identified three state-dependent circuit motifs poised to selectively amplify the response of an aggressive female to fly-sized visual objects: convergence of excitatory inputs from neurons conveying select visual features and internal state; dendritic disinhibition of select visual feature detectors; and a switch that toggles between two visual feature detectors. Using cell-type-specific genetic tools, together with behavioral and neurophysiological analyses, we show that each of these circuit motifs function during female aggression. We reveal that features of this same switch operate in males during courtship pursuit, suggesting that disparate social behaviors may share circuit mechanisms. Our work provides a compelling example of using the connectome to infer circuit mechanisms that underlie dynamic processing of sensory signals.

5.
Gut Microbes ; 11(2): 245-248, 2020.
Article in English | MEDLINE | ID: mdl-31345081

ABSTRACT

The gut microbiota is known to regulate multiple aspects of host physiology, including metabolism and behavior. Locomotion, which is closely intertwined with metabolism, is an important component of complex behaviors, such as foraging, mating, and evading predators. Our recent work revealed that certain bacterial species and their products modulate motor behavior in the fruit fly Drosophila melanogaster via metabolic and neuronal pathways. In the context of our previously published findings and recent work by others, I will discuss potential avenues for future research at the intersection of the microbiota, metabolism, and host behavior.


Subject(s)
Behavior , Drosophila melanogaster/microbiology , Gastrointestinal Microbiome , Gastrointestinal Tract/metabolism , Animals , Bacteria/metabolism , Drosophila melanogaster/physiology , Gastrointestinal Tract/microbiology , Host Microbial Interactions , Locomotion , Octopamine/metabolism , Sugars/metabolism
6.
Elife ; 92020 11 03.
Article in English | MEDLINE | ID: mdl-33141021

ABSTRACT

Aggressive social interactions are used to compete for limited resources and are regulated by complex sensory cues and the organism's internal state. While both sexes exhibit aggression, its neuronal underpinnings are understudied in females. Here, we identify a population of sexually dimorphic aIPg neurons in the adult Drosophila melanogaster central brain whose optogenetic activation increased, and genetic inactivation reduced, female aggression. Analysis of GAL4 lines identified in an unbiased screen for increased female chasing behavior revealed the involvement of another sexually dimorphic neuron, pC1d, and implicated aIPg and pC1d neurons as core nodes regulating female aggression. Connectomic analysis demonstrated that aIPg neurons and pC1d are interconnected and suggest that aIPg neurons may exert part of their effect by gating the flow of visual information to descending neurons. Our work reveals important regulatory components of the neuronal circuitry that underlies female aggressive social interactions and provides tools for their manipulation.


Subject(s)
Aggression/physiology , Drosophila melanogaster/physiology , Neural Pathways/physiology , Animals , Brain/cytology , Brain/physiology , Drosophila melanogaster/cytology , Female , Neural Pathways/cytology , Neurons/cytology , Neurons/physiology , Optogenetics
7.
Cell Metab ; 27(2): 267-268, 2018 02 06.
Article in English | MEDLINE | ID: mdl-29414679

ABSTRACT

While the gut microbiome largely benefits host physiology, the impact of symbiosis on bacterial fitness has not been rigorously investigated. In this issue, Storelli et al. (2018) provide evidence that Drosophila actively cultivate a relationship with the growth-promoting bacterium Lactobacillus plantarum, delivering mutual benefits under nutrient-poor conditions.


Subject(s)
Drosophila , Lactobacillus plantarum , Animals , Bacteria , Drosophila melanogaster , Symbiosis
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