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  • Microbiota regulate social behaviour via stress response neurons in the brain.

Microbiota regulate social behaviour via stress response neurons in the brain.

Nature (2021-07-02)
Wei-Li Wu, Mark D Adame, Chia-Wei Liou, Jacob T Barlow, Tzu-Ting Lai, Gil Sharon, Catherine E Schretter, Brittany D Needham, Madelyn I Wang, Weiyi Tang, James Ousey, Yuan-Yuan Lin, Tzu-Hsuan Yao, Reem Abdel-Haq, Keith Beadle, Viviana Gradinaru, Rustem F Ismagilov, Sarkis K Mazmanian
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Corticosterone: HBC complex, free flowing powder
Sigma-Aldrich
Mifepristone, ≥98%
Sigma-Aldrich
Anti-Fluorescent Gold Antibody, from rabbit
Sigma-Aldrich
Anti-NeuN Antibody, clone A60, clone A60, Chemicon®, from mouse
Supelco
4-Chloromethcathinone (4-CMC HCl) hydrochloride solution, 1 mg/mL in methanol (as free base), certified reference material, ampule of 1 mL, Cerilliant®