Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior.
Gene-environment interactions impact the development of neuropsychiatric disorders, but the relative contributions are unclear. Here, we identify gut microbiota as sufficient to induce depressive-like behaviors in genetically distinct mouse strains. Daily gavage of vehicle (dH2O) in nonobese diabetic (NOD) mice induced a social avoidance behavior that was not observed in C57BL/6 mice. This was not observed in NOD animals with depleted microbiota via oral administration of antibiotics. Transfer of intestinal microbiota, including members of the Clostridiales, Lachnospiraceae and Ruminococcaceae, from vehicle-gavaged NOD donors to microbiota-depleted C57BL/6 recipients was sufficient to induce social avoidance and change gene expression and myelination in the prefrontal cortex. Metabolomic analysis identified increased cresol levels in these mice, and exposure of cultured oligodendrocytes to this metabolite prevented myelin gene expression and differentiation. Our results thus demonstrate that the gut microbiota modifies the synthesis of key metabolites affecting gene expression in the prefrontal cortex, thereby modulating social behavior.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States.
Mar
0000-0003-1583-1643
M
Gacias
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States.
Sevasti
S
Gaspari
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States.
Patricia-Mae G
PM
Santos
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
Sabrina
S
Tamburini
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
Monica
M
Andrade
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States.
Fan
F
Zhang
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
Nan
N
Shen
BERG, Framingham, United States.
Vladimir
V
Tolstikov
BERG, Framingham, United States.
Michael A
MA
Kiebish
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, United States.
Jeffrey L
JL
Dupree
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States.|Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, United States.
Venetia
V
Zachariou
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.|Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, United States.
Jose C
0000-0002-3970-9856
JC
Clemente
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
Patrizia
P
Casaccia
D000818:Animals; D001419:Bacteria / Q000378:metabolism*; D003408:Cresols / Q000032:analysis; D000069196:Gastrointestinal Microbiome; D005786:Gene Expression Regulation; D055432:Metabolomics; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D017397:Prefrontal Cortex / Q000502:physiology*; D012919:Social Behavior; D014158:Transcription, Genetic
D003408:Cresols; C077977:cresol
behavior; brain; gut; microbiome; mouse; myelin; neuroscience; psychiatry