Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Maternal TNF deficit enhances cognitive functions in the offspring.
Figure 2: Hematopoietic system specific inactivation of the Tnf gene in the mother results in enhanced memory.
Figure 3: Increased proliferation in the developing dentate gyrus is linked to enhanced adult spatial memory in the offspring of TNF mutant mothers.
Figure 4: Genetic compensation of increased proliferation in the WT(H) offspring normalizes spatial memory.
Figure 5: Dendritic morphology changes in adult WT(H) granule cells.
Figure 6: The maternal effect on offspring phenotypes is postnatal.
Figure 7: Reduced milk chemokine levels in TNF-deficient mothers are responsible for the WT(H) phenotypes.

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. 1

    Pasparakis, M., Alexopoulou, L., Episkopou, V. & Kollias, G. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med. 184, 1397–1411 (1996).

    CAS  PubMed  Google Scholar 

  2. 2

    Kuprash, D.V. et al. Novel tumor necrosis factor-knockout mice that lack Peyer's patches. Eur. J. Immunol. 35, 1592–1600 (2005).

    CAS  PubMed  Google Scholar 

  3. 3

    Müller, N. & Ackenheil, M. Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 22, 1–33 (1998).

    PubMed  Google Scholar 

  4. 4

    Stellwagen, D. & Malenka, R.C. Synaptic scaling mediated by glial TNF-alpha. Nature 440, 1054–1059 (2006).

    CAS  Google Scholar 

  5. 5

    Golan, H., Levav, T., Mendelsohn, A. & Huleihel, M. Involvement of tumor necrosis factor alpha in hippocampal development and function. Cereb. Cortex 14, 97–105 (2004).

    CAS  PubMed  Google Scholar 

  6. 6

    Yamada, K. et al. Neurobehavioral alterations in mice with a targeted deletion of the tumor necrosis factor-alpha gene: implications for emotional behavior. J. Neuroimmunol. 111, 131–138 (2000).

    CAS  PubMed  Google Scholar 

  7. 7

    Gleason, G. et al. The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety. Proc. Natl. Acad. Sci. USA 107, 7592–7597 (2010).

    CAS  PubMed  Google Scholar 

  8. 8

    Neves, G., Cooke, S.F. & Bliss, T.V. Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat. Rev. Neurosci. 9, 65–75 (2008).

    CAS  PubMed  Google Scholar 

  9. 9

    Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    van Praag, H., Kempermann, G. & Gage, F.H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270 (1999).

    CAS  PubMed  Google Scholar 

  11. 11

    Seri, B., Garcia-Verdugo, J.M., Collado-Morente, L., McEwen, B.S. & Alvarez-Buylla, A. Cell types, lineage and architecture of the germinal zone in the adult dentate gyrus. J. Comp. Neurol. 478, 359–378 (2004).

    PubMed  Google Scholar 

  12. 12

    Hasselmo, M.E. The role of acetylcholine in learning and memory. Curr. Opin. Neurobiol. 16, 710–715 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Perry, D.C. et al. Measuring nicotinic receptors with characteristics of alpha4beta2, alpha3beta2 and alpha3beta4 subtypes in rat tissues by autoradiography. J. Neurochem. 82, 468–481 (2002).

    CAS  PubMed  Google Scholar 

  14. 14

    Winner, B. et al. Role of alpha-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus. J. Neurosci. 32, 16906–16916 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Kaneko, N., Okano, H. & Sawamoto, K. Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb. Genes Cells 11, 1145–1159 (2006).

    CAS  PubMed  Google Scholar 

  16. 16

    Baraban, S.C. & Tallent, M.K. Interneuron diversity series: Interneuronal neuropeptides–endogenous regulators of neuronal excitability. Trends Neurosci. 27, 135–142 (2004).

    CAS  PubMed  Google Scholar 

  17. 17

    Fiala, B.A., Joyce, J.N. & Greenough, W.T. Environmental complexity modulates growth of granule cell dendrites in developing but not adult hippocampus of rats. Exp. Neurol. 59, 372–383 (1978).

    CAS  PubMed  Google Scholar 

  18. 18

    Francis, D.D. & Meaney, M.J. Maternal care and the development of stress responses. Curr. Opin. Neurobiol. 9, 128–134 (1999).

    CAS  PubMed  Google Scholar 

  19. 19

    Knight, D.M. et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol. Immunol. 30, 1443–1453 (1993).

    CAS  PubMed  Google Scholar 

  20. 20

    Mohler, K.M. et al. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J. Immunol. 151, 1548–1561 (1993).

    CAS  PubMed  Google Scholar 

  21. 21

    Zalevsky, J. et al. Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. J. Immunol. 179, 1872–1883 (2007).

    CAS  PubMed  Google Scholar 

  22. 22

    Triantafillidis, J.K. et al. Favorable response to subcutaneous administration of infliximab in rats with experimental colitis. World J. Gastroenterol. 11, 6843–6847 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Grounds, M.D. et al. Silencing TNFalpha activity by using Remicade or Enbrel blocks inflammation in whole muscle grafts: an in vivo bioassay to assess the efficacy of anti-cytokine drugs in mice. Cell Tissue Res. 320, 509–515 (2005).

    CAS  PubMed  Google Scholar 

  24. 24

    Garrett, W.S. et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8, 292–300 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Majumder, S. et al. p48/STAT-1alpha-containing complexes play a predominant role in induction of IFN-gamma-inducible protein, 10 kDa (IP-10) by IFN-gamma alone or in synergy with TNF-alpha. J. Immunol. 161, 4736–4744 (1998).

    CAS  PubMed  Google Scholar 

  26. 26

    Murao, K. et al. TNF-alpha stimulation of MCP-1 expression is mediated by the Akt/PKB signal transduction pathway in vascular endothelial cells. Biochem. Biophys. Res. Commun. 276, 791–796 (2000).

    CAS  PubMed  Google Scholar 

  27. 27

    Blais, D.R., Harrold, J. & Altosaar, I. Killing the messenger in the nick of time: persistence of breast milk sCD14 in the neonatal gastrointestinal tract. Pediatr. Res. 59, 371–376 (2006).

    PubMed  Google Scholar 

  28. 28

    Krathwohl, M.D. & Kaiser, J.L. Chemokines promote quiescence and survival of human neural progenitor cells. Stem Cells 22, 109–118 (2004).

    CAS  PubMed  Google Scholar 

  29. 29

    Villeda, S.A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Moser, B., Wolf, M., Walz, A. & Loetscher, P. Chemokines: multiple levels of leukocyte migration control. Trends Immunol. 25, 75–84 (2004).

    CAS  PubMed  Google Scholar 

  31. 31

    Luther, S.A. & Cyster, J.G. Chemokines as regulators of T cell differentiation. Nat. Immunol. 2, 102–107 (2001).

    CAS  PubMed  Google Scholar 

  32. 32

    Kipnis, J., Gadani, S. & Derecki, N.C. Pro-cognitive properties of T cells. Nat. Rev. Immunol. 12, 663–669 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Kempermann, G., Kuhn, H.G. & Gage, F.H. More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495 (1997).

    CAS  PubMed  Google Scholar 

  34. 34

    Chen, Y. & Ghosh, A. Regulation of dendritic development by neuronal activity. J. Neurobiol. 64, 4–10 (2005).

    CAS  PubMed  Google Scholar 

  35. 35

    van Praag, H., Kempermann, G. & Gage, F.H. Neural consequences of environmental enrichment. Nat. Rev. Neurosci. 1, 191–198 (2000).

    CAS  PubMed  Google Scholar 

  36. 36

    Kipnis, J., Cohen, H., Cardon, M., Ziv, Y. & Schwartz, M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc. Natl. Acad. Sci. USA 101, 8180–8185 (2004).

    CAS  PubMed  Google Scholar 

  37. 37

    Tosun, M. et al. Maternal and umbilical serum levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in normal pregnancies and in pregnancies complicated by preeclampsia. J. Matern. Fetal Neonatal Med. 23, 880–886 (2010).

    CAS  PubMed  Google Scholar 

  38. 38

    Buka, S.L. et al. Maternal cytokine levels during pregnancy and adult psychosis. Brain Behav. Immun. 15, 411–420 (2001).

    CAS  PubMed  Google Scholar 

  39. 39

    DeRijk, R. et al. Exercise and circadian rhythm-induced variations in plasma cortisol differentially regulate interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) production in humans: high sensitivity of TNF alpha and resistance of IL-6. J. Clin. Endocrinol. Metab. 82, 2182–2191 (1997).

    CAS  PubMed  Google Scholar 

  40. 40

    O'Connor, T.M., O'Halloran, D.J. & Shanahan, F. The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia. QJM 93, 323–333 (2000).

    CAS  PubMed  Google Scholar 

  41. 41

    Sellers, T.L., Jaussi, A.W., Yang, H.T., Heninger, R.W. & Winder, W.W. Effect of the exercise-induced increase in glucocorticoids on endurance in the rat. J. Appl. Physiol. 65, 173–178 (1988).

    CAS  PubMed  Google Scholar 

  42. 42

    Steer, J.H., Kroeger, K.M., Abraham, L.J. & Joyce, D.A. Glucocorticoids suppress tumor necrosis factor-alpha expression by human monocytic THP-1 cells by suppressing transactivation through adjacent NF-kappa B and c-Jun-activating transcription factor-2 binding sites in the promoter. J. Biol. Chem. 275, 18432–18440 (2000).

    CAS  PubMed  Google Scholar 

  43. 43

    de Man, Y.A., Dolhain, R.J., van de Geijn, F.E., Willemsen, S.P. & Hazes, J.M. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. 59, 1241–1248 (2008).

    PubMed  Google Scholar 

  44. 44

    Brustolim, D., Ribeiro-dos-Santos, R., Kast, R.E., Altschuler, E.L. & Soares, M.B. A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice. Int. Immunopharmacol. 6, 903–907 (2006).

    CAS  PubMed  Google Scholar 

  45. 45

    Yu, B. et al. Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency. J. Pharmacol. Exp. Ther. 327, 316–323 (2008).

    CAS  PubMed  Google Scholar 

  46. 46

    Love, O.P. & Williams, T.D. The adaptive value of stress-induced phenotypes: effects of maternally derived corticosterone on sex-biased investment, cost of reproduction, and maternal fitness. Am. Nat. 172, E135–E149 (2008).

    PubMed  Google Scholar 

  47. 47

    Harris, A. & Seckl, J. Glucocorticoids, prenatal stress and the programming of disease. Horm. Behav. 59, 279–289 (2011).

    CAS  PubMed  Google Scholar 

  48. 48

    Bick-Sander, A., Steiner, B., Wolf, S.A., Babu, H. & Kempermann, G. Running in pregnancy transiently increases postnatal hippocampal neurogenesis in the offspring. Proc. Natl. Acad. Sci. USA 103, 3852–3857 (2006).

    CAS  PubMed  Google Scholar 

  49. 49

    Catalani, A. et al. Progeny of mothers drinking corticosterone during lactation has lower stress-induced corticosterone secretion and better cognitive performance. Brain Res. 624, 209–215 (1993).

    CAS  PubMed  Google Scholar 

  50. 50

    Garofalo, R. Cytokines in human milk. J. Pediatr. 156, S36–S40 (2010).

    CAS  PubMed  Google Scholar 

  51. 51

    Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat. Genet. 23, 99–103 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Kühn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995).

    PubMed  Google Scholar 

  53. 53

    Grivennikov, S.I. et al. Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity 22, 93–104 (2005).

    CAS  PubMed  Google Scholar 

  54. 54

    Saxe, M.D. et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl. Acad. Sci. USA 103, 17501–17506 (2006).

    CAS  PubMed  Google Scholar 

  55. 55

    DePeters, E.J. & Hovey, R.C. Methods for collecting milk from mice. J. Mammary Gland Biol. Neoplasia 14, 397–400 (2009).

    PubMed  PubMed Central  Google Scholar 

  56. 56

    Tatapudy, S., Bruening, S., Gleason, G. & Toth, M. Validation and use of a computer-assisted counting procedure to quantify BrdU-labeled proliferating cells in the early postnatal mouse hippocampus. J. Neurosci. Methods 172, 173–177 (2008).

    PubMed  PubMed Central  Google Scholar 

  57. 57

    Bailey, S.J. & Toth, M. Variability in the benzodiazepine response of serotonin 5-HT1A receptor null mice displaying anxiety-like phenotype: evidence for genetic modifiers in the 5-HT-mediated regulation of GABA(A) receptors. J. Neurosci. 24, 6343–6351 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Dumont, M. et al. Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer's disease. FASEB J. 23, 2459–2466 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Pattwell, S.S., Bath, K.G., Casey, B.J., Ninan, I. & Lee, F.S. Selective early-acquired fear memories undergo temporary suppression during adolescence. Proc. Natl. Acad. Sci. USA 108, 1182–1187 (2011).

    CAS  PubMed  Google Scholar 

  60. 60

    van Velzen, A. & Toth, M. Role of maternal 5-HT(1A) receptor in programming offspring emotional and physical development. Genes Brain Behav. 9, 877–885 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. Nedospasov (Lomonosov Moscow State University) for providing the TnfloxP/loxP mouse strain and for discussions on inducible knockout and TNF neutralization strategies. We thank D. Jing (Weill Cornell Medical College) for providing Golgi staining reagents and technical support. We would like to thank C. Dipace and K. Rosania for the ELISA-based assays of TNF, and C. Pang for counting BrdU+ cells. This work was supported by US National Institute of Mental Health grant 1RO1MH080194 to M.T.

Author information

Affiliations

Authors

Contributions

B.L., B.Z. and M.T. conceived, designed and analyzed the experiments. B.L., E.L., B.Z., G.G., M.B., S.K. and J.G.T. performed the experiments. M.T. wrote the manuscript.

Corresponding author

Correspondence to Miklos Toth.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Effect of maternal TNF deficit on offspring cognitive functions.

(a) Breeding strategy to generate TNF+/+ and TNF−/− mice born to and raised by TNF+/+ (WT), TNF+/− (H), TNF−/− (KO) parents. (b) Design of the MWM experiment to test the spatial reference memory of offspring of TNF mutant parents. (c) Second probe trial following extensive training in MWM. While a second round of training improved the recall of the platform location of WT(WT) mice in probe trial 2, offspring of mutant parents still spent more time in the NW target quadrant (quadrant F3,148=172.69, P<10-5; quadrant x group, F9,148=2.84, P=0.004; LSD posthoc; N= 8,11,12,13/group). (d) Design of the contextual and cued fear conditioning experiments with the offspring of TNF mutant parents.

Supplementary Figure 2 Hematopoietic system specific inactivation of the TNF gene in the mother.

(a) Generation of male WT offspring of mothers with hematopoietic (mx-cre) or brain (nestin-cre) specific TNF deletion. SP=spleen, BM=bone marrow. (b) Hematopoietic system specificity of mx-cre mediated recombination demonstrated by the cre-reporter Gt(ROSA)26Sortm1Sor/J strain. LacZ immunostaining in the macrophage rich white pulp (WP), including the marginal zone (MZ), and in the red blood cells and macrophages rich red pulp (RP) in mx-Cre/ Gt(ROSA)26Sortm1Sor/J mice indicates recombination. No apparent immunoreactivity in cortex (Ctx) and hippocampus (Hip). Bar represents 50 μm.

Supplementary Figure 3 Performance in the MWM and conditional fear test of the offspring born to conditional TNF−/− mothers.

(a) All offspring improved in finding the platform during the first (Repeated measures of ANOVA: session, F4,244=45.10, P<10-5, N=7,9/group and F4,324=28.63, P <10-5, N=9,13 for mx-cre and nestin-cre, respectively) and second training periods (F4,240=6.71, P<10-5 and F4,128=6.02, P <10-5). There was also a genotype effect in the mx-cre (F1,62=6.23, P=0.015 and F1,60=9.15, P=0.004 for the first and second training trial, respectively; LSD posthoc *P<0.05) but not in the nestin-cre group comparison. (b) Performance of the offspring born to mx-cre and nestin-cre mothers in probe trial 2 of MWM. A second period of 5 training sessions increased spatial memory in all groups in probe trial 2, eliminating the difference caused by the maternal hematopoietic deletion of TNF-α, seen in probe trial 1 (ANOVA: effect of quadrant for mx-cre and nestin-cre; F3,56=68.35, P<10-5, N=7,9 and F3,28=19.77, P<10-5, N=9,13; no group x location interaction). (c) PolyIC and the mx transgene do not confound the behavior in MWM. In WT mice, e.g. in the absence of floxed TNF alleles, poly IC and the mx-cre transgene in mothers have no effect on offspring learning and memory. The behavior of the offspring of mx-cre+ polyIC; TNF+/+ mothers is indistinguishable from the behavior of the control offspring of mx-cre-; TNFflox/flox mothers (control data are same as shown in Fig. 2c). (d) A temporal increase in freezing in the offspring of mx-cre+ but not nestin-cre+ mothers during tone-shock pairing (Repeated measures ANOVA; session effect F4,96=53.34, P<10-5, N=13,13/group and F4,60=23.80, P<10-5, N=7,10/group for mx-cre and nestin-cre, respectively; group effect F1,24=11.49, P=0.002 and F1,15=0.26, P=0.6; LSD posthoc. *P<0.05, **<0.005). The difference between the groups disappeared at the end of the training.

Supplementary Figure 4 Proliferation in the developing DG in the offspring of TNF mutant mothers.

(a) Total number of cells (F3,14=3.95, P=0.03, N=4,5,5,5; *p<0.05, #p=0.05-0.1), (b) correlation between total and BrdU positive cells, and (c) the fraction of BrdU positive cells in percent of all cells (F3,14=0.52, P=0.67, N=4,5,5,5) in the GCL at P14. (d,e) No change in proliferation in the d-hilus, SVZ, and RMS at P14 (N=4,5,5,5). (f) No significant effect of the maternal genotype on the number of surviving BrdU positive cells in the DG, 3 weeks after pulse labeling with BrdU at P14 (P>0.05, N=5,5,5,6).

Supplementary Figure 5 Characteristics of the developing DG in the offspring of TNF mutant mothers.

(a-h) No volumetric changes in neurogenic areas in the offspring of TNF deficient mothers. Volume of GCL (a, c, g, h), hilus (b, d), SVZ (e), RMS (f) at P5 (a and b), P14 (c-f) and adolescent/adult age (g,h). The maternal effect has no significant impact on the volume at any region and age (N=5 per group). (i-k) No significant effect of the maternal genotype on the number of GFAP+ astrogia and Iba1+ microglia, in the stratum moleculare (mol), stratum oriens (ori), and hilus of the hippocampus and in the cortex of P14 pups (P>0.05, N=4,6).

Supplementary Figure 6 Constraining postnatal hippocampal proliferation by GCV.

(a,b) Repeated GCV administration results in a cumulative dose dependent reduction in P14 proliferation (ANOVA and LSD postoc test: F6,112=6.85, P<10-3; N=4,4,6,8,4,5/per group; **P<0.005, ***P<0.0005). GCV administered at P5+6 is sufficient to reduce proliferation by approximately 30%. (c) Postnatal administration of GCV did not alter weigh gain, except in the P5+6+7+8 group at P14 (weight of animals in this group was not followed further) (Repeated measures ANOVA: F3,14=3.88, P=0.03, *P=0.013, N=7,7,4,7/group). (d,f) GCV (P5+6) reduces ANP proliferation in P14 DG (t test, p< 0.05, N=5/group). Box-whisker plots represent the first three quartiles (25%, median and 75%) and values 1.5× the interquartile range below the first quartile (lower horizontal line) and above the third quartile (upper horizontal line). Representative micrographs showing BrdU+/Tbr2+ ANPs in the DG of GCV treated TK+ and TK- mice. Bar=50μm. (e,g) GCV (P5+6) does not alter QNP proliferation in P14 DG. Representative confocal images with orthogonal views of SGZ showing BrdU-labeled Sox-2 and GFAP positive QNPs in the DG of GCV treated TK+ and TK- mice. Arrows indicate triple stained QNPs. Bar=20μm.

Supplementary Figure 7 No long term consequence of GCV administration on proliferation and reactive gliosis.

(a) GCV (P5+6) resulted in no change in adult DG proliferation. (b) GCV (P5+6) resulted in no change in GFAP positive cell number in the neocortex (Ctx), hilus and molecular layer (ML) of the DG in P14 animals. Representative confocal images with orthogonal views of cortex showing no obvious loss of GFAP positive cells in 2x GCV injected mice at P14. Bar=20μm.

Supplementary Figure 8 TNF deficiency does not alter maternal behavior.

(a) (a,b) Arched-back nursing (ABN) of TNF+/− mothers during the light and dark periods, respectively. Data show an effect of time (F4,73=3.13, P=0.02 and F4,78=4.58, P=0.02) but no group effect (n=7). (c,d) Licking/grooming (LG) of TNF+/− mothers during the light and dark periods, respectively. Effect of time only in the dark period (F4,77=34, p=0.013) but no group effect. (e) No difference between WT and TNF+/− mothers in the latency to pup retrieval. Effect of time (F2,24= 4.87 P=0.017). (f) No difference in nest quality between WT and TNF+/− mothers.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Tables 1–2 (PDF 4269 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, B., Zupan, B., Laird, E. et al. Maternal hematopoietic TNF, via milk chemokines, programs hippocampal development and memory. Nat Neurosci 17, 97–105 (2014). https://doi.org/10.1038/nn.3596

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing