Age-associated gut microbiota impairs hippocampus-dependent memory in a vagus-dependent manner
Damien Rei, Soham Saha, Marianne Haddad, Anna Haider Rubio, Blanca Liliana Perlaza, Marion Berard, Marie-Noelle Ungeheuer, Harry Sokol, Pierre-Marie Lledo
Damien Rei, Soham Saha, Marianne Haddad, Anna Haider Rubio, Blanca Liliana Perlaza, Marion Berard, Marie-Noelle Ungeheuer, Harry Sokol, Pierre-Marie Lledo
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Research Article Aging Neuroscience

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

Abstract

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.

Authors

Damien Rei, Soham Saha, Marianne Haddad, Anna Haider Rubio, Blanca Liliana Perlaza, Marion Berard, Marie-Noelle Ungeheuer, Harry Sokol, Pierre-Marie Lledo

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Figure 3

Decrease in VN signaling is necessary and sufficient for the age-associated GM’s negative impact on memory.

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Decrease in VN signaling is necessary and sufficient for the age-associa...
(A) Representative image of an adeno-associated virus (AAV) mCherry transduced left nodose ganglia (L-NG) and of the corresponding ascending mCherry+ fibers at the level of the left and right nucleus tractus solitarius (L-NTS and R-NTS, respectively). (B) Timeline of the L-NG pharmacogenetic inhibition experiment. Young (Y) mice received a coinjection in the L-NG of a Cre-expressing virus with either a Cre-dependent inhibitory hM4D(Gi) DREADD (Y hM4D[Gi]) or a Cre-dependent mCherry (mCh) control virus (Y mCh). Three weeks after the L-NG injection of viral vectors, animals were i.p. injected with clozapine N-oxide (CNO) 30 minutes prior to the isotropic-novel object location (ISO-NOL) task and novelty exposure (nov. expo.) assay. The 2 tests were performed 24 hours apart. (C and D) Effect of a L-NG DREADD inhibition on the memory ability in the ISO-NOL task (n = 8 and 6) (C) and the increase in the number of dorsal hippocampal CA1 C-FOS+ cells (D) after the exposure to novelty (n = 4, 5 and 4 per group), in Y hM4D(Gi) versus Y mCh control mice. (E) The timeline and procedure of the L-NG pharmacogenetic activation in AinY mice experiment and assessment of its effect in the ISO-NOL and novelty exposure assay was identical to the previous inhibitory DREADD experiment but with the usage of the activatory hM3D(Gq) DREADD in place of the inhibitory version. L-NG injection of viral vectors were directly followed by an age-associated FMT to generate L-NG transduced/FMT animals (AinY hM3D[Gq], YinY hM3D[Gq], AinY mCh, and YinY mCh). (F and G) Effect of the pharmacogenetic vagal activation in AinY mice on the memory abilities in the ISO-NOL task (n = 6, 7, 5 and 8) (F) and the increase in the number of dorsal hippocampal CA1 C-FOS+ cells (G) after the exposure to novelty in YinY and AinY mCh– versus AinY hM3D(Gq)–expressing mice (n = 7, 4, and 5 per group). Schematics (B and E) depict the experimental group color codes used for the associated quantifications. (C) One-tailed unpaired t test. (D, F, and G) One-way ANOVA. Data are shown as mean ± SD. *P < 0.05; **P > 0.01; ***P > 0.001. Scale bars: 100 μm. DIO, double-inverted opsin.