Paternal recognition of adult offspring mediated by newly generated CNS neurons

Journal name:
Nature Neuroscience
Volume:
13,
Pages:
753–758
Year published:
DOI:
doi:10.1038/nn.2550
Received
Accepted
Published online

Abstract

In mammals, olfaction is often used to distinguish individuals on the basis of their unique odor types (genetically programmed body odors). Parental-offspring recognition behavior is mediated, in part, by learning and processing of different odor types and is crucial for reproductive success. Maternal recognition behavior and associated brain plasticity has been well characterized, but paternal recognition behavior and brain plasticity is poorly understood. We found that paternal-adult offspring recognition behavior in mice was dependent on postnatal offspring interaction and was associated with increased neurogenesis in the paternal olfactory bulb and hippocampus. Newly generated paternal olfactory interneurons were preferentially activated by adult offspring odors. Disrupting prolactin signaling abolished increased paternal neurogenesis and adult offspring recognition. Rescuing this neurogenesis restored recognition behavior. Thus, neurogenesis in the paternal brain may be involved in offspring recognition.

At a glance

Figures

  1. Maternal and paternal mice display adult offspring recognition behavior.
    Figure 1: Maternal and paternal mice display adult offspring recognition behavior.

    (a) Paternal males showed improved latency of pup retrieval over time (F4,30 = 12.60, P2–3 versus P4–6, *P < 0.01). (b) Maternal mice showed more investigation toward adult non-offspring (**P < 0.05, n = 12). Paternal mice removed from the nest the day pups were born and tested for adult offspring recognition 6 weeks later showed no difference in investigation duration (n = 7), but paternal males remaining in the nest (n = 10) for the same duration as their maternal females partners showed greater investigation toward adult non-offspring (F1,15 = 6.26, males remaining in nest, P < 0.05). (c) Males assessed for general social recognition behavior using cage and non-cage mates with the same task spent more time investigating the non-cage mate after short-term separation (n = 7); however, over long-term separation (n = 6), the duration of investigation between cage and non-cage mates was not different (F1,11 = 6.42, short-term separation,**P < 0.05).

  2. Offspring interaction stimulates cell proliferation in the paternal brain.
    Figure 2: Offspring interaction stimulates cell proliferation in the paternal brain.

    (ac) Fluorescence micrographs of the forebrain SVZ (a) and hippocampus dentate gyrus (DG) (b) and quantification (mean ± s.e.m.) revealed an increase in the number of BrdU-labeled cells in the SVZ and dentate gyrus (c) of males in the P2 with pups group (n = 6) as compared with males separated from their lactating female partner and pups for 2 d (P2 no pups, n = 6) and males only remaining with their lactating female partner and pups on the day of birth (P0, n = 6) (SVZ: F2,13 = 31.85, P2 with pups versus P0, *P < 0.01; P2 with pups versus P2 no pups, P < 0.01; dentate gyrus: F2,13 = 22.18, P2 with pups versus P0, P < 0.01; P2 with pups versus P2 no pups, P < 0.01). (dg) Physical interaction with one's own pups (pups, n = 4) increased the number of BrdU-labeled cells in the SVZ and dentate gyrus (mean ± s.e.m.), as seen in males in the P2 with pups group (n = 4), but not in males that were only exposed to their lactating female partner and pups odor (odor, n = 4), males that were only exposed to their lactating female partner (LactF, n = 4), males that were exposed to pups under a mesh barrier (mesh, n = 4), males that were exposed to novel pups (uPups, n = 4), males that were exposed to novel pups under a mesh barrier (uMesh, n = 4) and males in the P2 no pups group (n = 4) (d, F4,15 = 31.12, P2 with pups and pups versus P2 no pups, LactF and odor, *P < 0.01; e, F4,15 = 46.22, P2 with pups and pups versus P2 no pups, LactF and odor, *P < 0.01; f, F4,15 = 19.17, P2 with pups versus P2 no pups, Mesh, uMesh and uPups, *P < 0.01; g, F4,15 = 118.2, P2 with pups versus P2 no pups, Mesh, uMesh and uPups, *P < 0.01).

  3. Newly generated neurons in the paternal brain preferentially respond to adult offspring odors.
    Figure 3: Newly generated neurons in the paternal brain preferentially respond to adult offspring odors.

    (ac) Fluorescent micrographs of the olfactory bulb (OB) (a) and dentate gyrus (b) and quantification revealed an increase in the number of BrdU and NeuN double-labeled cells in males in the P2 with pups group (c) (mean ± s.e.m., olfactory bulb, P2 with pups versus P0 and P2 no pups, F2,18 = 10.36, *P < 0.01, n = 7 mice per group; dentate gyrus, P2 with pups versus P0 and P2 no pups, F2,9 = 6.919, **P < 0.05, n = 4 mice per group). Scale bars represent 50 μm. (d,e) P2 with pups males showed an increase in the number of BrdU-Egr1 double-labeled cells in the olfactory bulb (d) when exposed to odors of adult offspring versus non-offspring (e) (mean ± s.e.m., F1,26 = 22.54, P2 with pups, offspring odor versus non-offspring odor, **P < 0.05, n = 3 exposed to clean cage odor, n = 6 exposed to non-offspring odors, n = 7 exposed to offspring odors).

  4. Prolactin mediates offspring-stimulated neurogenesis in the paternal brain.
    Figure 4: Prolactin mediates offspring-stimulated neurogenesis in the paternal brain.

    (ac) Fluorescence micrographs of PRLR staining in the forebrain SVZ (a) and dentate gyrus (b). Scale bars represent 50 μm. RT-PCR and western blot analysis indicated that PRLR isoforms were present in the adult male SVZ/choroid plexus (SVZ) and hippocampus (HPC) (c) (full-length gels and blots are included in Supplementary Figs. 11 and 12, respectively). (d) Males that were given PRL infusions showed significantly more BrdU-labeled cells in the SVZ and dentate gyrus (mean ± s.e.m.) than males given the vehicle (Veh) control (PRL versus vehicle, *P < 0.05, n = 4 mice per group). (e) Infusions of antibody to PRL into paternal males (n = 7) attenuated increased cell proliferation in the SVZ and dentate gyrus, as compared with paternal males given phosphate-buffered saline (PBS, n = 5) and IgG (n = 3) control infusions (mean ± s.e.m.) (SVZ, PBS and IgG controls versus antibody to prolactin, F2,12 = 81.49, **P < 0.01; dentate gyrus, PBS and IgG controls versus PRL, F2,12 = 17.37, P < 0.05). (f,g) Quantifying (mean ± s.e.m.) the number of BrdU-labeled cells in the SVZ (f) and dentate gyrus (g) of Prlr+/+ and Prlr−/− males either placed in the P0 or P2 with pups groups, revealed that only Prlr+/+ males in the P2 with pups group had enhanced cell proliferation in the SVZ and dentate gyrus (SVZ, P2 with pups, Prlr+/+ versus Prlr−/−, F1,20 = 79.00 P < 0.01, n = 6 mice per group; dentate gyrus, P2 with pups, Prlr+/+ versus Prlr−/−, F1,20 = 51.86, P < 0.05, n = 6 mice per group).

  5. Newly generated neurons in the paternal brain may be involved in adult offspring recognition behavior.
    Figure 5: Newly generated neurons in the paternal brain may be involved in adult offspring recognition behavior.

    (a) Prlr+/+ males spent more time investigating non-offspring (n = 8) than Prlr−/− males (n = 8) (Prlr+/+, non-offspring versus offspring, F1,14 = 20.74, *P < 0.01). (b) When adult offspring and non-offspring were introduced into the home cage of paternal Prlr males, Prlr+/+ males spent a greater percentage of time investigating adult non-offspring (n = 7) than Prlr−/− males (n = 9) (Prlr+/+, non-offspring versus offspring, F1,14 = 14.76, *P < 0.01). (c) When adult offspring and non-offspring were introduced into the home cage of paternal Prlr males, Prlr+/+ males exhibited a greater number of attacks toward adult non-offspring (n = 7) than Prlr−/− males (n = 9) (Prlr+/+, non-offspring versus offspring, F1,14 = 21.42, *P < 0.01). (d) The number of BrdU-labeled cells in the SVZ and dentate gyrus of Prlr−/− males that were given luteinizing hormone (LH) during pup interaction was increased (luteinizing hormone versus Veh, **P < 0.05, n = 4 mice per group). (e) Prlr−/− males that were given luteinizing hormone during pup interaction (n = 12) significantly more time investigating non-offspring than offspring (F1,20 = 4.39, non-offspring versus offspring, **P < 0.05), whereas Prlr−/− males that were given vehicle during pup interaction (n = 10) investigated both sides equally. (f) Prlr−/− males that were given luteinizing hormone during pup interaction (n = 10) spent significantly more time investigating adult non-offspring (F1,14 = 8.18, non-offspring versus offspring, **P < 0.05), whereas Prlr−/− males that were given vehicle during pup interaction (n = 7) investigated adult non-offspring and offspring similarly. (g) Prlr−/− males that were given luteinizing hormone during pup interaction (n = 10) exhibited a greater number of attacks toward adult non-offspring home cage intruders than adult offspring intruders (F1,14 = 4.99, non-offspring versus offspring, **P < 0.05), whereas Prlr−/− males that were given vehicle during pup interaction did not display any differences in the number of attacks. Data are presented as mean ± s.e.m.

References

  1. Brennan, P.A. & Kendrick, K.M. Mammalian social odors: attraction and individual recognition. Phil. Trans. R. Soc. Lond. B 361, 20612078 (2006).
  2. Dewsbury, D.A. Kin discrimination and reproductive behavior in muroid rodents. Behav. Genet. 18, 525536 (1988).
  3. Pusey, A. & Wolf, M. Inbreeding avoidance in animals. Trends Ecol. Evol. 11, 201206 (1996).
  4. Sánchez-Andrade, G., James, B.M. & Kendrick, K.M. Neural encoding of olfactory recognition memory. J. Reprod. Dev. 51, 547558 (2005).
  5. Singh, P.B. Chemosensation and genetic individuality. Reproduction 121, 529539 (2001).
  6. Restrepo, D., Lin, W., Salcedo, E., Yamazaki, K. & Beauchamp, G. Odortypes and MHC peptides: complementary chemosignals of MHC haplotype? Trends Neurosci. 29, 604609 (2006).
  7. Yamazaki, K., Beauchamp, G.K., Curran, M., Bard, J. & Boyse, E.A. Parent-progeny recognition as a function of MHC odor type identity. Proc. Natl. Acad. Sci. USA 97, 1050010502 (2000).
  8. Manning, C.J., Wakeland, E.K. & Potts, W.K. Communal nesting patterns in mice implicate MHC genes in kin recognition. Nature 360, 581583 (1992).
  9. Woodroffe, R. & Vincent, A. Mother's little helpers: patterns of male care in mammals. Trends Ecol. Evol. 9, 294297 (1994).
  10. Makin, J.W. & Porter, R.H. Paternal behavior in the spiny mouse (Acomys cahirinus). Behav. Neural Biol. 41, 135151 (1984).
  11. Ostermeyer, M.C. & Elwood, R.W. Pup recognition in Mus musculus: parental discrimination between their own and alien young. Dev. Psychobiol. 16, 7582 (1983).
  12. Buchan, J.C., Alberts, S.C., Silk, J.B. & Altmann, J. True paternal care in a multi-male primate society. Nature 425, 179181 (2003).
  13. Dubas, J.S., Heijkoop, M. & van Aken, M.A.G. A preliminary investigation of parent-progeny olfactory recognition and parental investment. Hum. Nat. 20, 8092 (2009).
  14. Porter, R.H. Olfaction and human kin recognition. Genetica 104, 259263 (1998).
  15. Lledo, P.M., Gheusi, G. & Vincent, J.D. Information processing in the mammalian olfactory system. Physiol. Rev. 85, 281317 (2005).
  16. Ming, G.L. & Song, H. Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28, 223250 (2005).
  17. Mak, G.K. et al. Male pheromone–stimulated neurogenesis in the adult female brain: possible role in mating behavior. Nat. Neurosci. 10, 10031011 (2007).
  18. Lonstein, J.S. & De Vries, G.J. Sex differences in the parental behavior of rodents. Neurosci. Biobehav. Rev. 24, 669686 (2000).
  19. Lonstein, J.S. & Fleming, A.S. Parental behaviors in rats and mice. Curr. Protoc. Neurosci. 8, 8.15 (2002).
  20. Enwere, E. et al. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis and deficits in fine olfactory discrimination. J. Neurosci. 24, 83548365 (2004).
  21. Rochefort, C., Gheusi, G., Vincent, J.D. & Lledo, P.M. Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J. Neurosci. 22, 26792689 (2002).
  22. Rochefort, C. & Lledo, P.M. Short-term survival of newborn neurons in the adult olfactory bulb after exposure to a complex odor environment. Eur. J. Neurosci. 22, 28632870 (2005).
  23. Magavi, S.S., Mitchell, B.D., Szentirmai, O., Carter, B.S. & Macklis, J.D. Adult-born and pre-existing olfactory granule neurons undergo distinct experience-dependent modifications of their olfactory responses in vivo . J. Neurosci. 25, 1072910739 (2005).
  24. Shingo, T. et al. Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 299, 117120 (2003).
  25. Kelly, P.A., Binart, N., Lucas, B., Bouchard, B. & Goffin, V. Implications of multiple phenotypes observed in prolactin receptor knockout mice. Front. Neuroendocrinol. 22, 140145 (2001).
  26. Hurst, J.L., Thom, M.D., Nevison, C.M., Humphries, R.E. & Beynon, R.J. MHC odors are not required or sufficient for recognition of individual scent owners. Proc. Biol. Sci. 272, 715724 (2005).
  27. Pusey, A.E. Sex-biased dispersal and inbreeding avoidance in birds and mammals. Trends Ecol. Evol. 2, 295299 (1987).
  28. Jiménez, J.A., Hughes, K.A., Alaks, G., Graham, L. & Lacy, R.C. An experimental study of inbreeding depression in a natural habitat. Science 266, 271273 (1994).
  29. Pillay, N. Father-daughter recognition and inbreeding avoidance in the striped mouse, Rhabdomys pumilio . Mamm. Biol. 67, 212218 (2002).
  30. Ruscio, M.G. et al. Pup exposure elicits hippocampal cell proliferation in the prairie vole. Behav. Brain Res. 187, 916 (2008).
  31. Sherborne, A.L. et al. The genetic basis of inbreeding avoidance in house mice. Curr. Biol. 17, 20612066 (2007).
  32. Curtis, M.A. et al. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315, 12431249 (2007).
  33. Eriksson, P.S. et al. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 13131317 (1998).
  34. Ormandy, C.J., Binart, N. & Kelly, P.A. Mammary gland development in prolactin receptor knockout mice. J. Mammary Gland Biol. Neoplasia 2, 355364 (1997).
  35. Trinh, K. & Storm, D.R. Vomeronasal organ detects odorants in absence of signaling through main olfactory epithelium. Nat. Neurosci. 6, 519525 (2003).
  36. Ling, C. et al. Prolactin (PRL) receptor gene expression in mouse adipose tissue: increases during lactation and in PRL-transgenic mice. Endocrinology 141, 35643572 (2000).
  37. Gregg, C. et al. White matter plasticity and enhanced remyelination in the maternal CNS. J. Neurosci. 27, 18121823 (2007).

Download references

Author information

Affiliations

  1. Hotchkiss Brain Institute, Department of Cell Biology & Anatomy, University of Calgary, Faculty of Medicine, Calgary, Alberta, Canada.

    • Gloria K Mak &
    • Samuel Weiss

Contributions

G.K.M. designed the project, collected the data, performed the analysis and wrote the paper. S.W. supervised the project, contributed to the design of the project and wrote the paper.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Author details

Supplementary information

PDF files

  1. Supplementary Text and Figures (12M)

    Supplementary Figures 1–12

Additional data