Age-associated gut microbiota impair 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, 5, 6, 7) , Pierre-Marie Lledo (1)

1 Perception et Mémoire / Perception and Memory
2 ICAReB - Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources
3 C2RA - Animalerie Centrale (plateforme) - Central Animal Facility (platform)
4 CRSA - Centre de Recherche Saint-Antoine
5 MICALIS - MICrobiologie de l'ALImentation au Service de la Santé
6 FHU PaCeMM - Paris Center for Microbiome Medicine
7 CHU Saint-Antoine [AP-HP]

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain highly debated. Here, we show that fecal microbiota transplantation (FMT) from aged, but not young, animal donors into 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–related (VN-related) neuronal activity patterns and report that aged FMT 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 mouse FMT on hippocampal functions and had a promnesic effect in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.

Mots clés: Aging; Behavior; Mouse models; Neuroscience

Domaines: Sciences du Vivant [q-bio]; Neurosciences [q-bio.NC]; Neurobiologie

Damien Rei, Soham Saha, Marianne Haddad, Anna Haider Rubio, Blanca Liliana Perlaza, et al.. Age-associated gut microbiota impair hippocampus-dependent memory in a vagus-dependent manner. JCI Insight, 2022, 7 (15), pp.e147700. ⟨10.1172/jci.insight.147700⟩. ⟨pasteur-03888764⟩