Impact of Maternal Separation on Dopamine System and its Association with Parkinson's Disease

Abstract

As a type of stress, maternal separation (MS) has been one of the most widely used models in neuropsychiatric research. An increasing number of studies has found that MS not only affects the function of the hypothalamic–pituitary–adrenal axis and hippocampal 5-hydroxytryptamine system, but also causes dysfunction of the central dopamine (DA) system and increases the susceptibility of dopaminergic neurons to pathogenic factors of Parkinson's disease (PD), for instance, 6-hydroxydopamine, thus impairing motor function. We reviewed the impact of MS on the DA system and its correlation with PD and found the following: (1) discrepant effects of MS on the DA system have been reported; (2) MS is a good model to study the impact of stress on the occurrence and development of PD, however, unified modeling criteria of MS are required; (3) correlation between MS and PD may involve the impact of MS on the DA system, which however is not the only connection; (4) intervening measures can block pathways between MS and PD, which provides reference for the prevention of PD in specific populations such as left-behind children.

This is a preview of subscription content, access via your institution.

Fig. 1

Abbreviations

DA:

Dopamine

DANs:

Dopaminergic neurons

DAT:

Dopamine transporter

ELS:

Early life stress

MS:

Maternal separation

PD:

Parkinson's disease

6-OHDA:

6-Hydroxydopamine

TH:

Tyrosine hydroxylase

References

  1. Akers, K. G., Nakazawa, M., Romeo, R. D., Connor, J. A., McEwen, B. S., & Tang, A. C. (2006). Early life modulators and predictors of adult synaptic plasticity. The European Journal of Neuroscience, 24(2), 547–554. https://doi.org/10.1111/j.1460-9568.2006.04921.x.

    Article  PubMed  Google Scholar 

  2. Anier, K., Malinovskaja, K., Pruus, K., Aonurm-Helm, A., Zharkovsky, A., & Kalda, A. (2014). Maternal separation is associated with DNA methylation and behavioural changes in adult rats. European Neuropsychopharmacology, 24(3), 459–468. https://doi.org/10.1016/j.euroneuro.2013.07.012.

    CAS  Article  PubMed  Google Scholar 

  3. Braun, K., Lange, E., Metzger, M., & Poeggel, G. (2000). Maternal separation followed by early social deprivation affects the development of monoaminergic fiber systems in the medial prefrontal cortex of octodon degus. Neuroscience, 95(1), 309–318. https://doi.org/10.1016/s0306-4522(99)00420-0.

    CAS  Article  PubMed  Google Scholar 

  4. Brenhouse, H. C., Lukkes, J. L., & Andersen, S. L. (2013). Early life adversity alters the developmental profiles of addiction-related prefrontal cortex circuitry. Brain Sciences, 3(1), 143–158. https://doi.org/10.3390/brainsci3010143.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chen, L., & Jackson, T. (2016). Early maternal separation and responsiveness to thermal nociception in rodent offspring: A meta-analytic review. Behavioral and Brain Sciences, 299, 42–50. https://doi.org/10.1016/j.bbr.2015.11.022.

    Article  Google Scholar 

  6. Chen, X., Zeng, C., Gong, C., Zhang, L., Wan, Y., Tao, F., et al. (2019). Associations between early life parent-child separation and shortened telomere length and psychopathological outcomes during adolescence. Psychoneuroendocrinology, 103, 195–202. https://doi.org/10.1016/j.psyneuen.2019.01.021.

    Article  PubMed  Google Scholar 

  7. Chocyk, A., Dudys, D., Przyborowska, A., Mackowiak, M., & Wedzony, K. (2010). Impact of maternal separation on neural cell adhesion molecules expression in dopaminergic brain regions of juvenile, adolescent and adult rats. Pharmacological Reports, 62(6), 1218–1224. https://doi.org/10.1016/s1734-1140(10)70385-6.

    CAS  Article  PubMed  Google Scholar 

  8. Chocyk, A., Przyborowska, A., Dudys, D., Majcher, I., Mackowiak, M., & Wedzony, K. (2011). The impact of maternal separation on the number of tyrosine hydroxylase-expressing midbrain neurons during different stages of ontogenesis. Neuroscience, 182, 43–61. https://doi.org/10.1016/j.neuroscience.2011.03.008.

    CAS  Article  PubMed  Google Scholar 

  9. Dalle, E., & Mabandla, M. V. (2018). Early life stress, depression and Parkinson's disease: A new approach. Molecular Brain, 11(1), 18. https://doi.org/10.1186/s13041-018-0356-9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Dalle, E., Daniels, W. M. U., & Mabandla, M. V. (2016). Anti-parkinsonian effects of fluvoxamine maleate in maternally separated rats. International Journal of Developmental Neuroscience, 53, 26–34. https://doi.org/10.1016/j.ijdevneu.2016.06.004.

    CAS  Article  PubMed  Google Scholar 

  11. Dalle, E., Daniels, W. M., & Mabandla, M. V. (2017a). Fluvoxamine maleate normalizes striatal neuronal inflammatory cytokine activity in a Parkinsonian rat model associated with depression. Behavioral and Brain Sciences, 316, 189–196. https://doi.org/10.1016/j.bbr.2016.08.005.

    CAS  Article  Google Scholar 

  12. Dalle, E., Daniels, W. M. U., & Mabandla, M. V. (2017b). Fluvoxamine maleate effects on dopamine signaling in the prefrontal cortex of stressed Parkinsonian rats: Implications for learning and memory. Brain Research Bulletin, 132, 75–81. https://doi.org/10.1016/j.brainresbull.2017.05.014.

    CAS  Article  PubMed  Google Scholar 

  13. Daskalakis, N. P., Bagot, R. C., Parker, K. J., Vinkers, C. H., & de Kloet, E. R. (2013). The three-hit concept of vulnerability and resilience: Toward understanding adaptation to early-life adversity outcome. Psychoneuroendocrinology, 38(9), 1858–1873. https://doi.org/10.1016/j.psyneuen.2013.06.008.

    Article  PubMed  PubMed Central  Google Scholar 

  14. de Souza, J. A., da Silva, M. C., de Matos, R. J. B., do Amaral Almeida, L. C., Beltrao, L. C., de Souza, F. L., et al. (2018). Pre-weaning maternal separation increases eating later in life in male and female offspring, but increases brainstem dopamine receptor 1a and 2a only in males. Appetite, 123, 114–119. https://doi.org/10.1016/j.appet.2017.12.004.

    Article  PubMed  Google Scholar 

  15. Dimatelis, J. J., Hendricks, S., Hsieh, J., Vlok, N. M., Bugarith, K., Daniels, W. M., et al. (2013). Exercise partly reverses the effect of maternal separation on hippocampal proteins in 6-hydroxydopamine-lesioned rat brain. Experimental Physiology, 98(1), 233–244. https://doi.org/10.1113/expphysiol.2012.066720.

    CAS  Article  PubMed  Google Scholar 

  16. Djamshidian, A., & Lees, A. J. (2014). Can stress trigger Parkinson's disease? Journal of Neurology, Neurosurgery, and Psychiatry, 85(8), 878–881. https://doi.org/10.1136/jnnp-2013-305911.

    Article  PubMed  Google Scholar 

  17. Faure, J., Stein, D. J., & Daniels, W. (2009). Maternal separation fails to render animals more susceptible to methamphetamine-induced conditioned place preference. Metabolic Brain Disease, 24(4), 541–559. https://doi.org/10.1007/s11011-009-9158-1.

    CAS  Article  PubMed  Google Scholar 

  18. Gracia-Rubio, I., Martinez-Laorden, E., Moscoso-Castro, M., Milanes, M. V., Laorden, M. L., & Valverde, O. (2016). Maternal separation impairs cocaine-induced behavioural sensitization in adolescent mice. PLoS ONE, 11(12), e0167483. https://doi.org/10.1371/journal.pone.0167483.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Hall, F. S., Wilkinson, L. S., Humby, T., & Robbins, T. W. (1999). Maternal deprivation of neonatal rats produces enduring changes in dopamine function. Synapse (New York, N. Y.), 32(1), 37–43. https://doi.org/10.1002/(SICI)1098-2396(199904)32:1%3c37:AID-SYN5%3e3.0.CO;2-4.

    CAS  Article  Google Scholar 

  20. Hemmerle, A. M., & OhioLINK Electronic Theses and Dissertations Center. (2011). Effects of stress-induced depression on parkinson’s disease symptomatology (p. 243). Cincinnati, Ohio: University of Cincinnati. Retrieved July 3, 2019 from https://etd.ohiolink.edu/.

  21. Hemmerle, A. M., Herman, J. P., & Seroogy, K. B. (2012). Stress, depression and Parkinson's disease. Experimental Neurology, 233(1), 79–86. https://doi.org/10.1016/j.expneurol.2011.09.035.

    CAS  Article  PubMed  Google Scholar 

  22. Hendricks, S., Ojuka, E., Kellaway, L. A., Mabandla, M. V., & Russell, V. A. (2012). Effect of maternal separation on mitochondrial function and role of exercise in a rat model of Parkinson's disease. Metabolic Brain Disease, 27(3), 387–392. https://doi.org/10.1007/s11011-012-9305-y.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Hoeijmakers, L., Lesuis, S. L., Krugers, H., Lucassen, P. J., & Korosi, A. (2018). A preclinical perspective on the enhanced vulnerability to Alzheimer's disease after early-life stress. Neurobiology of Stress, 8, 172–185. https://doi.org/10.1016/j.ynstr.2018.02.003.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hulshoff Pol, H. E., Hoek, H. W., Susser, E., Brown, A. S., Dingemans, A., Schnack, H. G., et al. (2000). Prenatal exposure to famine and brain morphology in schizophrenia. The American Journal of Psychiatry, 157(7), 1170–1172. https://doi.org/10.1176/appi.ajp.157.7.1170.

    CAS  Article  PubMed  Google Scholar 

  25. Johnson, M. E., Stecher, B., Labrie, V., Brundin, L., & Brundin, P. (2019). Triggers, facilitators, and aggravators: Redefining Parkinson's disease pathogenesis. Trends in Neurosciences, 42(1), 4–13. https://doi.org/10.1016/j.tins.2018.09.007.

    CAS  Article  PubMed  Google Scholar 

  26. Kawakami, S. E., Quadros, I. M., Machado, R. B., & Suchecki, D. (2013). Sex-dependent effects of maternal separation on plasma corticosterone and brain monoamines in response to chronic ethanol administration. Neuroscience, 253, 55–66. https://doi.org/10.1016/j.neuroscience.2013.08.031.

    CAS  Article  PubMed  Google Scholar 

  27. Li, M., Xue, X., Shao, S., Shao, F., & Wang, W. (2013). Cognitive, emotional and neurochemical effects of repeated maternal separation in adolescent rats. Brain Research, 1518, 82–90. https://doi.org/10.1016/j.brainres.2013.04.026.

    CAS  Article  PubMed  Google Scholar 

  28. Liu, B., Gao, H. M., & Hong, J. S. (2003). Parkinson's disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: Role of neuroinflammation. Environmental Health Perspectives, 111(8), 1065–1073. https://doi.org/10.1289/ehp.6361.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Lukkes, J. L., Meda, S., Thompson, B. S., Freund, N., & Andersen, S. L. (2017). Early life stress and later peer distress on depressive behavior in adolescent female rats: Effects of a novel intervention on GABA and D2 receptors. Behavioural Brain Research, 330, 37–45. https://doi.org/10.1016/j.bbr.2017.04.053.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Mabandla, M. V., & Russell, V. A. (2010). Voluntary exercise reduces the neurotoxic effects of 6-hydroxydopamine in maternally separated rats. Behavioural Brain Research, 211(1), 16–22. https://doi.org/10.1016/j.bbr.2010.02.045.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Majcher-Maslanka, I., Solarz, A., Wedzony, K., & Chocyk, A. (2017). The effects of early-life stress on dopamine system function in adolescent female rats. International Journal of Developmental Neuroscience, 57, 24–33. https://doi.org/10.1016/j.ijdevneu.2017.01.001.

    CAS  Article  PubMed  Google Scholar 

  32. Meaney, M. J., Brake, W., & Gratton, A. (2002). Environmental regulation of the development of mesolimbic dopamine systems: A neurobiological mechanism for vulnerability to drug abuse? Psychoneuroendocrinology, 27(1–2), 127–138. https://doi.org/10.1016/s0306-4530(01)00040-3.

    CAS  Article  PubMed  Google Scholar 

  33. Miller, D. B., & O'Callaghan, J. P. (2008). Do early-life insults contribute to the late-life development of Parkinson and Alzheimer diseases? Metabolism, 57(Suppl 2), S44–49. https://doi.org/10.1016/j.metabol.2008.07.011.

    CAS  Article  PubMed  Google Scholar 

  34. Mirescu, C., Peters, J. D., & Gould, E. (2004). Early life experience alters response of adult neurogenesis to stress. Nature Neuroscience, 7(8), 841–846. https://doi.org/10.1038/nn1290.

    CAS  Article  PubMed  Google Scholar 

  35. Mpofana, T., Daniels, W. M., & Mabandla, M. V. (2016). Exposure to early life stress results in epigenetic changes in neurotrophic factor gene expression in a Parkinsonian rat model. Parkinson’s Disease, 2016, 6438783. https://doi.org/10.1155/2016/6438783.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Niu, H., Shen, L., Li, T., Ren, C., Ding, S., Wang, L., et al. (2018). Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson's disease. Translational Neurodegeneration, 7, 25. https://doi.org/10.1186/s40035-018-0128-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Niwa, M., Matsumoto, Y., Mouri, A., Ozaki, N., & Nabeshima, T. (2011). Vulnerability in early life to changes in the rearing environment plays a crucial role in the aetiopathology of psychiatric disorders. The International Journal of Neuropsychopharmacology, 14(4), 459–477. https://doi.org/10.1017/S1461145710001239.

    Article  PubMed  Google Scholar 

  38. O'Mahony, S. M., Hyland, N. P., Dinan, T. G., & Cryan, J. F. (2011). Maternal separation as a model of brain-gut axis dysfunction. Psychopharmacology (Berlin), 214(1), 71–88. https://doi.org/10.1007/s00213-010-2010-9.

    CAS  Article  Google Scholar 

  39. Pienaar, I. S., Kellaway, L. A., Russell, V. A., Smith, A. D., Stein, D. J., Zigmond, M. J., et al. (2008). Maternal separation exaggerates the toxic effects of 6-hydroxydopamine in rats: Implications for neurodegenerative disorders. Stress, 11(6), 448–456. https://doi.org/10.1080/10253890801890721.

    CAS  Article  PubMed  Google Scholar 

  40. Ploj, K., Roman, E., & Nylander, I. (2003). Long-term effects of maternal separation on ethanol intake and brain opioid and dopamine receptors in male Wistar rats. Neuroscience, 121(3), 787–799. https://doi.org/10.1016/s0306-4522(03)00499-8.

    CAS  Article  PubMed  Google Scholar 

  41. Pruessner, J. C., Champagne, F., Meaney, M. J., & Dagher, A. (2004). Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: A positron emission tomography study using [11C]raclopride. Journal of Neuroscience, 24(11), 2825–2831. https://doi.org/10.1523/JNEUROSCI.3422-03.2004.

    CAS  Article  PubMed  Google Scholar 

  42. Recamier-Carballo, S., Estrada-Camarena, E., & Lopez-Rubalcava, C. (2017). Maternal separation induces long-term effects on monoamines and brain-derived neurotrophic factor levels on the frontal cortex, amygdala, and hippocampus: Differential effects after a stress challenge. Behavioural Pharmacology, 28(7), 545–557. https://doi.org/10.1097/FBP.0000000000000324.

    CAS  Article  PubMed  Google Scholar 

  43. Ren, C., Yin, P., Ren, N., Wang, Z., Wang, J., Zhang, C., et al. (2018). Cerebrospinal fluid-stem cell interactions may pave the path for cell-based therapy in neurological diseases. Stem Cell Research & Therapy, 9(1), 66. https://doi.org/10.1186/s13287-018-0807-3.

    CAS  Article  Google Scholar 

  44. Roceri, M., Hendriks, W., Racagni, G., Ellenbroek, B. A., & Riva, M. A. (2002). Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Molecular Psychiatry, 7(6), 609–616. https://doi.org/10.1038/sj.mp.4001036.

    CAS  Article  PubMed  Google Scholar 

  45. Romano-Lopez, A., Mendez-Diaz, M., Garcia, F. G., Regalado-Santiago, C., Ruiz-Contreras, A. E., & Prospero-Garcia, O. (2016). Maternal separation and early stress cause long-lasting effects on dopaminergic and endocannabinergic systems and alters dendritic morphology in the nucleus accumbens and frontal cortex in rats. Developmental Neurobiology, 76(8), 819–831. https://doi.org/10.1002/dneu.22361.

    CAS  Article  PubMed  Google Scholar 

  46. Rots, N. Y., de Jong, J., Workel, J. O., Levine, S., Cools, A. R., & De Kloet, E. R. (1996). Neonatal maternally deprived rats have as adults elevated basal pituitary-adrenal activity and enhanced susceptibility to apomorphine. Journal of Neuroendocrinology, 8(7), 501–506. https://doi.org/10.1046/j.1365-2826.1996.04843.x.

    CAS  Article  PubMed  Google Scholar 

  47. Smith, A. D., Castro, S. L., & Zigmond, M. J. (2002). Stress-induced Parkinson's disease: A working hypothesis. Physiology & Behavior, 77(4–5), 527–531. https://doi.org/10.1016/s0031-9384(02)00939-3.

    CAS  Article  Google Scholar 

  48. Sugama, S., Sekiyama, K., Kodama, T., Takamatsu, Y., Takenouchi, T., Hashimoto, M., et al. (2016). Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson's disease. Brain, Behavior, and Immunity, 51, 39–46. https://doi.org/10.1016/j.bbi.2015.08.015.

    CAS  Article  PubMed  Google Scholar 

  49. Sun, H., Zhu, X., Dong, W., Chen, L., Feng, Z., Lei, X., et al. (2011). The effect and its mechanism of neonate-mother separation on the behavior change in adult rats. Maternal and Child Health Care of China, 26(19), 2984–2986. Retrieved July 3, 2019 from https://kns.cnki.net/kcms/detail/detail.aspx?FileName=ZFYB201119047&DbName=CJFQ2011.

  50. Tractenberg, S. G., Levandowski, M. L., de Azeredo, L. A., Orso, R., Roithmann, L. G., Hoffmann, E. S., et al. (2016). An overview of maternal separation effects on behavioural outcomes in mice: Evidence from a four-stage methodological systematic review. Neuroscience and Biobehavioral Reviews, 68, 489–503. https://doi.org/10.1016/j.neubiorev.2016.06.021.

    Article  PubMed  Google Scholar 

  51. Tugyan, K., Uysal, N., Ozdemir, D., Sonmez, U., Pekcetin, C., Erbil, G., et al. (2006). Protective effect of melatonin against maternal deprivation-induced acute hippocampal damage in infant rats. Neuroscience Letters, 398(1–2), 145–150. https://doi.org/10.1016/j.neulet.2005.12.090.

    CAS  Article  PubMed  Google Scholar 

  52. Zhu, X., Peng, S., Ma, X., & Li, T. (2010). Effect of maternal deprivation on emotion and expression of dopamine transporter in adult rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 35(1), 32–37. https://doi.org/10.3969/j.issn.1672-7347.2010.01.005.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all their past and present team members and collaborators who have contributed to the data discussed in the review. We would like to express our gratitude to Professor Chun-feng Liu of Soochow University for his cordial support, valuable information, and guidance, which helped us in completing this review.

Funding

This study was supported by the Science Technology Development and Guidance Foundation of Suzhou (SYSD2017089) and Postgraduate Research & Practice Innovation Program of Jiangsu Province.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Chao Ren or Fen Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

He, Kj., Zhang, Yt., Wei, Sz. et al. Impact of Maternal Separation on Dopamine System and its Association with Parkinson's Disease. Neuromol Med 22, 335–340 (2020). https://doi.org/10.1007/s12017-019-08587-x

Download citation

Keywords

  • Parkinson’s disease
  • Maternal separation
  • Stress
  • Dopamine
  • Left-behind children