Maternal care, hippocampal synaptogenesis and cognitive development in rats

Abstract

We report that variations in maternal care in the rat promote hippocampal synaptogenesis and spatial learning and memory through systems known to mediate experience-dependent neural development. Thus, the offspring of mothers that show high levels of pup licking and grooming and arched-back nursing showed increased expression of NMDA receptor subunit and brain-derived neurotrophic factor (BDNF) mRNA, increased cholinergic innervation of the hippocampus and enhanced spatial learning and memory. A cross-fostering study provided evidence for a direct relationship between maternal behavior and hippocampal development, although not all neonates were equally sensitive to variations in maternal care.

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 behavior of high and low LG-ABN mothers.
Figure 2: Spatial learning/memory and hippocampal synaptogenesis in the adult offspring of high compared with low LG-ABN mothers.
Figure 3: Cross-fostering reverses differences in spatial learning and hippocampal synaptogenesis in the offspring of low, but not high LG-ABN mothers.
Figure 4: The adult offspring of high and low LG-ABN mothers differ in hippocampal cholinergic innervation.
Figure 5: Brain-derived neurotrophic factor (BDNF) gene expression.
Figure 6: NMDA receptor subunit gene expression.
Figure 7: NMDA receptor subunit gene expression in newborn offspring of high and low LG-ABN mothers.

References

  1. 1

    Ainsworth, M. S. & Bowlby, J. An ethological approach to personality development. Am. Psychol. 46 , 333–341 (1991).

    Article  Google Scholar 

  2. 2

    Suomi, S. J. Early determinants of behaviour: evidence from primate studies. Br. Med. Bull. 53, 170–184 (1997).

    CAS  Article  Google Scholar 

  3. 3

    Trickett, P. K. & McBride-Chang, C. The developmental impact of different forms of child abuse and neglect. Dev. Rev. 15, 311–337 ( 1995).

    Article  Google Scholar 

  4. 4

    Ammerman, R. T., Cassisi, J. E., Hersen, M. & van Hasselt, V. B. Consequences of physical abuse and neglect in children. Clin. Psychol. Rev. 6, 291–310 ( 1986).

    Article  Google Scholar 

  5. 5

    Cogill, S. R., Caplan, H. L., Alexandra, H., Robson, K. M. & Kumar, R. Impact of maternal postnatal depression on cognitive development of young children. Br. Med. J. 292, 1165–1167 (1986).

    CAS  Article  Google Scholar 

  6. 6

    Alberts, J. R. & Cramer, C. P. in Handbook of Behavioral Neurobiology , Vol. 9. 1–39 (ed. Blass, E. M.) (Plenum, New York, 1989).

    Google Scholar 

  7. 7

    Stern, J. M. Offspring-induced nurturance: animal-human parallels. Dev. Psychobiol. 31, 19–37 ( 1997).

    CAS  Article  Google Scholar 

  8. 8

    Liu, D. et al. Maternal care, hippocampal glucocorticoid receptor expression and hypothalamic-pituitary-adrenal responses to stress. Science 277, 1659–1662 (1997).

    CAS  Article  Google Scholar 

  9. 9

    Francis, D. D., Diorio, J., Liu, D. & Meaney, M. J. Nongenomic transmission across generations in maternal behavior and stress responses in the rat. Science 286, 1155–1158 ( 1999).

    CAS  Article  Google Scholar 

  10. 10

    Morris, R. G. M., Garrard, P., Rawlins, J. N. P. & O'Keefe, J. Place navigation is impaired in rats with hippocampal lesions. Nature 297, 681–683 ( 1982).

    CAS  Article  Google Scholar 

  11. 11

    Whishaw, I. Q. Place learning in hippocampal rats and the path integration hypothesis. Neurosci. Biobehav. Rev. 22, 209–220 (1998).

    CAS  Article  Google Scholar 

  12. 12

    Wood, E. R., Dudchenko, P. A. & Eichenbaum, H. The global record of memory in hippocampal neuronal activity. Nature 397, 561– 563 (1999).

    Article  Google Scholar 

  13. 13

    Milner, B., Squire, L. R. & Kandel, E. R. Cognitive neuroscience and the study of memory. Neuron 20, 445–468 ( 1998).

    CAS  Article  Google Scholar 

  14. 14

    Fields, R. D. & Itoh, K. Neural cell adhesion molecules in activity-dependent development and synaptic plasticity. Trends Neurosci. 19, 473–480 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Maccari, S., Piazza, P. V., Kabbaj, M., Barbazanges, A., Simon, H. & Le Moal, M. Adoption reverses the long-term impairments in glucocorticoid feedback induced by prenatal stress. J. Neurosci. 15 , 110–116 (1994).

    Article  Google Scholar 

  16. 16

    McCarty, R. & Lee, J. H. Maternal influences on adult blood pressure of SHRs: a single pup cross-fostering study. Physiol. Behav. 59, 71–75 ( 1996).

    CAS  Article  Google Scholar 

  17. 17

    Quirion, R. et al. Facilitation of acetylcholine release and cognitive performance by an M2 muscarinic receptor antagonist in aged memory-impaired rats. J. Neurosci. 15, 1455– 1462 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Gage, F. H. & Bjorklund, A. Cholinergic speptal grafts into hippocampal formation improve spatial learning and memory in aged rat by an atropine-sensitive mechanism. J. Neurosci. 6, 2837–2847 (1986).

    CAS  Article  Google Scholar 

  19. 19

    Thoenen, H. Neurotrophins and neuronal plasticity. Science 270, 593–598 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Alderson, R. F., Alterman, A. L., Barde, Y.-A. & Lindsay, R. M. Brain-derived neurotrophic factor increases survival and differentiated functions of rat spetal cholinergic neurons in culture. Neuron 5, 297–306 (1990).

    CAS  Article  Google Scholar 

  21. 21

    Friedman, B. et al. BDNF and NT-4/5 exert neurotrophic influences on injured spinal motor neurons. J. Neurosci. 15, 1044– 1056 (1995).

    CAS  Article  Google Scholar 

  22. 22

    Marini, A. M., Rabin, S. J., Lipsky, R. H. & Mocchetti, I. Activity-dependent release of brain-derived neurotrophic factor underlies the neuroprotective effect of N-methyl-D-aspartate. Proc. Natl. Acad. Sci. USA 273, 29394–29399 (1998).

    CAS  Google Scholar 

  23. 23

    Constatine-Paton, M., Cline, H. T. & Debski, E. Patterned activity, synaptic convergence, and the NMDA receptor in developing visual pathways. Annu. Rev. Neurosci. 13, 129–154 (1990).

    Article  Google Scholar 

  24. 24

    Schatz, C. J. Impulse activity and the patterning of connections during CNS development . Neuron 5, 745–756 (1990).

    Article  Google Scholar 

  25. 25

    Diamond, M. E., Armstrong-James, M. & Ebner, F. F. Experience-dependent plasticity in adult rat barrel cortex. Proc. Natl. Acad. Sci. USA 90, 2082 –2086 (1993).

    CAS  Article  Google Scholar 

  26. 26

    Kirkwood, A., Dudek, S. M., Gold, J. T., Aizenman, C. D. & Bear, M. F. Common forms of synaptic plasticity in the hippocampus and neocortex in vitro. Science 260, 1518–1521 (1993).

    CAS  Article  Google Scholar 

  27. 27

    Schanberg, S. M. & Field, T. M. Sensory deprivation stress and supplemental stimulation in the rat pup and preterm human neonate . Child. Dev. 58, 1431– 1447 (1987).

    CAS  Article  Google Scholar 

  28. 28

    Levine, S. Maternal behavior as a mediator of pup adrenocortical function. Ann. NY Acad. Sci. 746, 260–275 (1994).

    Article  Google Scholar 

  29. 29

    van Oers, H. J., de Kloet, E. R. & Levine, S. Maternal deprivation effect on the infant's neural stress markers is reversed by tactile stimulation and feeding but not by suppressing corticosterone. J. Neurosci. 18, 10171– 10179 (1998).

    CAS  Article  Google Scholar 

  30. 30

    Chao, H. M., Sakai, R. R., Ma, L. Y. & McEwen, B. S. Adrenal steroid regulation of neurotrophic factor expression in the rat hippocampus. Endocrinology 139, 3112–3118 (1998).

    CAS  Article  Google Scholar 

  31. 31

    Anisman, H., Zaharia, M. D., Meaney, M. J. & Merali, Z. Do early life events permanently alter behavioral and hormonal responses to stressors? Int. J. Dev. Neurosci. 16, 149 –164 (1998).

    CAS  Article  Google Scholar 

  32. 32

    Quinlan, E. M., Philpot, B. D., Huganir, R. L. & Bear, M. F. Rapid, experience-dependent expression of synaptic NMDA receptors in visual cortex in vivo. Nat. Neurosci. 2, 352–357 (1999).

    CAS  Article  Google Scholar 

  33. 33

    Jablonska, B., Kossut, M. & Skangiel-Kramska, J. Transitent increase of AMPA and NMDA receptor binding in the barrel cortex of mice after tactile stimulation. Neurobol. Learn. Mem. 66, 36–43 ( 1996).

    CAS  Article  Google Scholar 

  34. 34

    Morris, R. G. M., Anderson, E., Lynch, G. S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774–776 (1986).

    CAS  Article  Google Scholar 

  35. 35

    Bailey, C. H., Bartsch, D. & Kandel, E. R. Toward a molecular definition of long-term memory storage. Proc. Natl. Acad. Sci. USA 93, 13445–13452 (1996).

    CAS  Article  Google Scholar 

  36. 36

    Bliss, T. V. P. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 ( 1993).

    CAS  Article  Google Scholar 

  37. 37

    McHugh, T. J., Blum, K. I., Tsien, J. Z., Tonegawa, S. & Wilson, M. A. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice Cell 87, 1339–1349 (1996).

    CAS  Article  Google Scholar 

  38. 38

    Calabresi, P., Centonze, D., Gubellini, P., Pisani, A. & Bernardi, G Blockade of M2-like muscarinic receptors enahnces long-term potentiation at corticostriatal synapses. Eur. J. Neurosci. 10, 3020–3023 (1998).

    CAS  Article  Google Scholar 

  39. 39

    Tang, Y. P. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 ( 1999).

    CAS  Article  Google Scholar 

  40. 40

    West, M. J. Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci. 22, 51–61 (1999).

    CAS  Article  Google Scholar 

  41. 41

    Araujo, D. M., Lapchak, P. A., Robitaille, Y., Gauthier, S. & Quirio, R. Differential alterations of various cholinergic markers in cortical and subcortical regions of human brain in Alzheimer's disease. J. Neurochem. 50, 1914 –1923 (1988).

    CAS  Article  Google Scholar 

  42. 42

    Bradford, M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein using the principle of protein-dye binding. Anal. Biochem. 72, 248–254 ( 1976).

    CAS  Article  Google Scholar 

  43. 43

    Mesulam, M. M. in Tracing Neural Connections With Horseradish Peroxydase (ed. Mesulam, M. M.) 1–52 (Wiley, Chichester, UK, 1982).

    Google Scholar 

  44. 44

    Towbin, H., Staehlin, T. & Gordon, J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc. Natl. Acad. Sci. USA 76, 4350– 4354 (1979).

    CAS  Article  Google Scholar 

  45. 45

    Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B. & Seeburg, P. H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540 ( 1994).

    CAS  Article  Google Scholar 

  46. 46

    Ernfors, P., Wetmore, C., Olson, L. & Persson, H. Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family. Neuron 5, 511–526 (1990).

    CAS  Article  Google Scholar 

  47. 47

    Ernfors, P., Ibanez, C. F., Ebendal, T., Olson, L. & Persson, H. Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: Developmental and topographical expression in the brain. Proc. Natl. Acad. Sci. USA 87, 5454–5458 (1990).

    CAS  Article  Google Scholar 

  48. 48

    Whittemore, S. R. et al. Rat β-nerve growth factor sequence and site of synthesis in the adult hippocampus. J. Neurosci. Res. 20, 403–410 (1988).

    CAS  Article  Google Scholar 

  49. 49

    Kuchel, G. A., Hellendall, R. & Blum, M. Transynaptic regulation of low-affinity p75 nerve growth factor receptor mRNA precedes and accompanies lesion-induced collateral neuronal sprouting. Exp. Neurol. 118, 73– 84 (1992).

    CAS  Article  Google Scholar 

  50. 50

    Williams, K., Hanna, J. L. & Molinoff, P. B. Developmental changes in the sensitivity of the N-methyl-D-aspartate receptor to polyamines. Mol. Pharmacol. 40, 774–782 (1991).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the laboratory of R. Quirion, Douglas Hospital Research Centre, for advice on the acetylcholine studies and G. Kuchel for advice on the NGF mRNA in situ protocol. This research was supported by a grant from the Natural Sciences & Engineering Research Council of Canada (to M.J.M.). D.L. holds a Graduate Fellowship, J.D. a Post-Doctoral Fellowship and M.J.M. a Senior Scientist award from the Medical Research Council of Canada.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Michael J. Meaney.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, D., Diorio, J., Day, J. et al. Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat Neurosci 3, 799–806 (2000). https://doi.org/10.1038/77702

Download citation

Further reading