title: Maternal hematopoietic TNF, via milk chemokines, programs hippocampal development and memory.
abstract: Tumor necrosis factor α (TNF) is a proinflammatory cytokine with established roles in host defense and immune system organogenesis. We studied TNF function and found a previously unidentified physiological function that extends its effect beyond the host into the developing offspring. A partial or complete maternal TNF deficit, specifically in hematopoietic cells, resulted in reduced milk levels of the chemokines IP-10, MCP-1, MCP-3, MCP-5 and MIP-1β, which in turn augmented offspring postnatal hippocampal proliferation, leading to improved adult spatial memory in mice. These effects were reproduced by the postpartum administration of a clinically used anti-TNF agent. Chemokines, fed to suckling pups of TNF-deficient mothers, restored both postnatal proliferation and spatial memory to normal levels. Our results identify a TNF-dependent 'lactrocrine' pathway that programs offspring hippocampal development and memory. The level of ambient TNF is known to be downregulated by physical activity, exercise and adaptive stress. We propose that the maternal TNF-milk chemokine pathway evolved to promote offspring adaptation to post-weaning environmental challenges and competition.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Bingfang
authors.initials: B
authors.lastname: Liu
authors.affiliation: 1] Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. [2].
authors.forename: Bojana
authors.initials: B
authors.lastname: Zupan
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Laird
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Shifra
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Gleason
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Marjan
authors.initials: M
authors.lastname: Bozinoski
authors.affiliation: The Rockefeller University, New York, New York, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Gal Toth
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Miklos
authors.initials: M
authors.lastname: Toth
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000254:growth & development* / Q000648:ultrastructure; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008892:Milk / Q000737:chemistry*; D009154:Mutation / Q000235:genetics; D064231:Nestin / Q000235:genetics; D011247:Pregnancy; D012333:RNA, Messenger; D055748:SOXB1 Transcription Factors; D016622:Silver Staining; D020825:T-Box Domain Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; C491198:Eomes protein, mouse; D005904:Glial Fibrillary Acidic Protein; C577485:Nes protein, mouse; D064231:Nestin; D012333:RNA, Messenger; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D020825:T-Box Domain Proteins; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins