Tumor necrosis factor–α (TNFα) is a proinflammatory cytokine produced by various cell types, including glial cells in the brain. In characterizing the role of TNFα in the mouse brain, Liu et al. found that a maternal TNFα deficit enhanced memory and learning in offspring (see also Parylak et al.). TNFα-deficient mothers had lower concentrations of various TNF-inducible chemokines in their milk. Pups (wild-type, Tnf+/–, or Tnf–/–) raised by mothers with a partial or complete deficit of TNFα (Tnf+/– or Tnf–/–) had longer dendrites in distal hippocampal dentate gyrus granule cells compared with those raised by wild-type mothers. In addition, pups raised by Tnf+/– or Tnf–/– mothers performed better on spatial memory and contextual fear learning tests, which require hippocampal activity. Conditional knockout of TNFα in hematopoietic cells, but not in glia or neurons, in mother mice elicited the improved learning performance in pups, which suggested that factors in a mother’s immune system can affect the development of their offspring’s central nervous system. Labeling with 5-bromo-2′-deoxyuridine (BrdU) showed that neural progenitor proliferation was increased specifically in the dorsal dentate gyrus in 14-day-old mice but not in 5-day-old or adult mice. Selectively blocking this transient proliferation in neuronal precursors prevented the memory enhancement in offspring raised by TNFα-deficient mothers. Daily administration of TNFα-inducible chemokines to pups from postnatal day 1 to 21 that were raised by Tnf–/– mothers impaired hippocampal cell proliferation and memory performance, whereas injection of a TNF inhibitor in pups raised by wild-type mothers phenocopied the effects of being raised by TNFα-deficient mothers. The expression of genes encoding proteins in the cholinergic pathway (including nicotinic receptor subunits and choline acetyltransferase) was increased, whereas the expression of genes encoding inhibitory neuropeptides (such as galanin and somatostatin) was decreased in the hippocampal cells of adult mice raised by TNFα-deficient mothers. These findings suggested that these mice may be more sensitive to cholinergic neurotransmission, which promotes learning and memory. TNFα-deficient mothers did not show changes in maternal care behavior, which excludes a behavioral contribution to the improved cognitive function in offspring. The findings show that proteins in a mother’s milk influence development and long-term function of the CNS as well as the immune system.
B. Liu, B. Zupan, E. Laird, S. Klein, G. Gleason, M. Bozinoski, J. Gal Toth, M. Toth, Maternal hematopoietic TNF, via milk chemokines, programs hippocampal development and memory. Nat. Neurosci. 17, 97–105 (2014). [PubMed]
S. L. Parylak, W. Deng, F. H. Gage, Mother’s milk programs offspring’s cognition. Nat. Neurosci. 17, 8–9 (2014). [PubMed]