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ResearchIn-Press PreviewAgingNeuroscience Open Access | 10.1172/jci.insight.147700

Age-associated gut microbiota impairs hippocampus-dependent memory in a vagus-dependent manner

Damien Rei,1 Soham Saha,1 Marianne Haddad,1 Anna Haider Rubio,1 Blanca Liliana Perlaza,2 Marion Berard,3 Marie-Noelle Ungeheuer,2 Harry Sokol,4 and Pierre-Marie Lledo1

1Neurosciences, Institut Pasteur de Paris, Paris, France

2ICAREB, Institut Pasteur de Paris, Paris, France

3Animalerie Centrale, Institut Pasteur de Paris, Paris, France

4Centre de Recherche Saint-Antoine, Sorbonne Université, Paris, France

Find articles by Rei, D. in: JCI | PubMed | Google Scholar |

1Neurosciences, Institut Pasteur de Paris, Paris, France

2ICAREB, Institut Pasteur de Paris, Paris, France

3Animalerie Centrale, Institut Pasteur de Paris, Paris, France

4Centre de Recherche Saint-Antoine, Sorbonne Université, Paris, France

Find articles by Saha, S. in: JCI | PubMed | Google Scholar |

1Neurosciences, Institut Pasteur de Paris, Paris, France

2ICAREB, Institut Pasteur de Paris, Paris, France

3Animalerie Centrale, Institut Pasteur de Paris, Paris, France

4Centre de Recherche Saint-Antoine, Sorbonne Université, Paris, France

Find articles by Haddad, M. in: JCI | PubMed | Google Scholar

1Neurosciences, Institut Pasteur de Paris, Paris, France

2ICAREB, Institut Pasteur de Paris, Paris, France

3Animalerie Centrale, Institut Pasteur de Paris, Paris, France

4Centre de Recherche Saint-Antoine, Sorbonne Université, Paris, France

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1Neurosciences, Institut Pasteur de Paris, Paris, France

2ICAREB, Institut Pasteur de Paris, Paris, France

3Animalerie Centrale, Institut Pasteur de Paris, Paris, France

4Centre de Recherche Saint-Antoine, Sorbonne Université, Paris, France

Find articles by Perlaza, B. in: JCI | PubMed | Google Scholar

1Neurosciences, Institut Pasteur de Paris, Paris, France

2ICAREB, Institut Pasteur de Paris, Paris, France

3Animalerie Centrale, Institut Pasteur de Paris, Paris, France

4Centre de Recherche Saint-Antoine, Sorbonne Université, Paris, France

Find articles by Berard, M. in: JCI | PubMed | Google Scholar

1Neurosciences, Institut Pasteur de Paris, Paris, France

2ICAREB, Institut Pasteur de Paris, Paris, France

3Animalerie Centrale, Institut Pasteur de Paris, Paris, France

4Centre de Recherche Saint-Antoine, Sorbonne Université, Paris, France

Find articles by Ungeheuer, M. in: JCI | PubMed | Google Scholar

1Neurosciences, Institut Pasteur de Paris, Paris, France

2ICAREB, Institut Pasteur de Paris, Paris, France

3Animalerie Centrale, Institut Pasteur de Paris, Paris, France

4Centre de Recherche Saint-Antoine, Sorbonne Université, Paris, France

Find articles by Sokol, H. in: JCI | PubMed | Google Scholar

1Neurosciences, Institut Pasteur de Paris, Paris, France

2ICAREB, Institut Pasteur de Paris, Paris, France

3Animalerie Centrale, Institut Pasteur de Paris, Paris, France

4Centre de Recherche Saint-Antoine, Sorbonne Université, Paris, France

Find articles by Lledo, P. in: JCI | PubMed | Google Scholar

Published June 23, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.147700.
Copyright © 2022, Rei et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 23, 2022 - Version history
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Abstract

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain yet highly debated. Here we showed that fecal microbiota transplantation (FMT) from aged, but not young, animal donors in young mice is sufficient to trigger profound hippocampal alterations including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation and impairment in hippocampus-dependent memory. Furthermore, similar alterations were reported when mice were subjected to an FMT from aged human donors. To decipher the mechanisms involved in mediating these microbiota-induced effects on brain function, we mapped the vagus nerve (VN)-related neuronal activity patterns and report that aged-mice FM transplanted animals showed a reduction in neuronal activity in the ascending VN output brain structure, whether under basal condition or after VN stimulation. Targeted pharmacogenetic manipulation of VN-ascending neurons demonstrated that the decrease in vagal activity is detrimental to hippocampal functions. In contrast, increasing vagal ascending activity alleviated the adverse effects of aged mice FMT on hippocampal functions, and had a pro-mnesic effect in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.

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