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Brain-Derived Neurotrophic Factor in the Nucleus Accumbens Mediates Individual Differences in Behavioral Responses to a Natural, Social Reward

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Abstract

BDNF-oxytocin interactions in the brain are implicated in mammalian maternal behavior. We found that BDNF gene expression is increased in the hippocampus of rat mothers that show increased pup licking/grooming (high LG mothers) compared to low LG mothers. High LG mothers also showed increased BDNF protein levels in the nucleus accumbens (nAcc). Immunoneutralization of BDNF in the nAcc eliminated the differences in pup LG between high and low LG mothers. Oxytocin antagonist in the ventral hippocampus significantly decreased the frequency of maternal LG behavior. Oxytocin antagonist significantly prevented the oxytocin-induced BDNF gene expression in primary hippocampal cell cultures. We suggest that oxytocin-induced regulation of BDNF in the nAcc provides a neuroendocrine basis for both individual differences in maternal behavior and resilience to the stress of reproduction in female mammals.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

B2M:

Beta-2 microglobulin

FBS:

Fetal bovine serum

LG:

Licking/grooming

nAcc:

Nucleus accumbens

OT:

Oxytocin

OTA:

[β-Mercapto-β,β cyclopentamethylenepropionyl1, O-Me-Tyr2, Orn8]- Oxytocin

PBS:

Phosphate buffer saline

SD:

Standard deviation

SEM:

Standard error of the mean

Veh:

Vehicle

References

  1. Repetti RL, Taylor SE, Seeman TE (2002) Risky families: family social environments and the mental and physical health of offspring. Psychol Bull 128:330–366

    PubMed  Google Scholar 

  2. Belsky J, de Haan M (2011) Annual research review: parenting and children’s brain development: the end of the beginning. J Child Psychol Psychiatry 52:409–428

    PubMed  Google Scholar 

  3. Fischer D, Patchev VK, Hellbach S, Hassan AH, Almeida OF (1995) Lactation as a model for naturally reversible hypercorticalism plasticity in the mechanisms governing hypothalamo-pituitary- adrenocortical activity in rats. J Clin Invest 96:1208–1215

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Walker CD, Lightman SL, Steele MK, Dallman MF (1992) Suckling is a persistent stimulus to the adrenocortical system of the rat. Endocrinology 130:115–125

    CAS  PubMed  Google Scholar 

  5. Neumann ID (2009) The advantage of social living: brain neuropeptides mediate the beneficial consequences of sex and motherhood. Front Neuroendocrinol 30:483–496

    CAS  PubMed  Google Scholar 

  6. Numan M, Stolzenberg DS (2009) Medial preoptic area interactions with dopamine neural systems in the control of the onset and maintenance of maternal behavior in rats. Front Neuroendocrinol 30:46–64

    CAS  PubMed  Google Scholar 

  7. Barrett J, Fleming AS (2011) Annual research review: all mothers are not created equal: neural and psychobiological perspectives on mothering and the importance of individual differences. J Child Psychol Psychiatry 52:368–397

    PubMed  Google Scholar 

  8. Ferris CF, Kulkarni P, Sullivan JM Jr et al (2005) Pup suckling is more rewarding than cocaine: evidence from functional magnetic resonance imaging and three-dimensional computational analysis. J Neurosci 25:149–156

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Pereira M, Morrell JI (2011) Functional mapping of the neural circuitry of rat maternal motivation: effects of site-specific transient neural inactivation. J Neuroendocrinol 23:1020–1035

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Swain JE (2011) The human parental brain: in vivo neuroimaging. Prog Neuro-Psychopharmacol Biol Psychiatry 35:1242–1254

    Google Scholar 

  11. Mileva-Seitz V, Fleming AS, Meaney MJ, Mastroianni A, Sinnwell JP, Steiner M, Atkinson L, Levitan RD et al (2012) Dopamine receptors D1 and D2 are related to observed maternal behavior. Genes Brain Behav 11:684–694

    CAS  PubMed  Google Scholar 

  12. Hansen S, Bergvall AH, Nyiredi S (1993) Interaction with pups enhances dopamine release in the ventral striatum of maternal rats: a microdialysis study. Pharmacol Biochem Behav 45:673–676

    CAS  PubMed  Google Scholar 

  13. Champagne FA (2004) Variations in nucleus accumbens dopamine associated with individual differences in maternal behavior in the rat. J Neurosci 24:4113–4123

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Shahrokh DK, Zhang T-Y, Diorio J, Gratton A, Meaney MJ (2010) Oxytocin-dopamine interactions mediate variations in maternal behavior in the rat. Endocrinology 151:2276–2286

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Pedersen CA (1997) Oxytocin control of maternal behavior. Regulation by sex steroids and offspring stimuli. Ann N Y Acad Sci 807:126–145

    CAS  PubMed  Google Scholar 

  16. Sarnyai Z (1999) Oxytocin and neuroadaptation to cocaine. Prog Brain Res 119:449–466

  17. Insel TR (2003) Is social attachment an addictive disorder? Physiol Behav 79:351–357

    CAS  PubMed  Google Scholar 

  18. Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 16:223–244

    CAS  PubMed  Google Scholar 

  19. Thomas MJ, Kalivas PW, Shaham Y (2008) Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br J Pharmacol 154:327–342

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Pu L, Liu Q-S, Poo M-M (2006) BDNF-dependent synaptic sensitization in midbrain dopamine neurons after cocaine withdrawal. Nat Neurosci 9:605–607

    CAS  PubMed  Google Scholar 

  21. Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P (2001) BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411:86–89

    CAS  PubMed  Google Scholar 

  22. Ghitza UE, Zhai H, Wu P, Airavaara M, Shaham Y, Lu L (2010) Role of BDNF and GDNF in drug reward and relapse: a review. Neurosci Biobehav Rev 35:157–171

    CAS  PubMed  Google Scholar 

  23. Bahi A, Boyer F, Dreyer J-L (2008) Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in rats. Psychopharmacology 199:169–182

    CAS  PubMed  Google Scholar 

  24. Hall FS, Drgonova J, Goeb M, Uhl GR (2003) Reduced behavioral effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice. Neuropsychopharmacology 28:1485–1490

    CAS  PubMed  Google Scholar 

  25. Horger BA, Iyasere CA, Berhow MT, Messer CJ, Nestler EJ, Taylor JR (1999) Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J Neurosci 19:4110–4122

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Graham DL, Edwards S, Bachtell RK, DiLeone RJ, Rios M, Self DW (2007) Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat Neurosci 10:1029–1037

    CAS  PubMed  Google Scholar 

  27. Cordeira JW, Frank L, Sena-Esteves M, Pothos EN, Rios M (2010) Brain-derived neurotrophic factor regulates hedonic feeding by acting on the mesolimbic dopamine system. J Neurosci 30:2533–2541

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Maynard KR, Hobbs JW, Phan BN, et al (2018) BDNF-TrkB signaling in oxytocin neurons contributes to maternal behavior. Elife 7. doi https://doi.org/10.7554/eLife.33676

  29. Havranek T, Zatkova M, Lestanova Z, Bacova Z, Mravec B, Hodosy J, Strbak V, Bakos J (2015) Intracerebroventricular oxytocin administration in rats enhances object recognition and increases expression of neurotrophins, microtubule-associated protein 2, and synapsin I. J Neurosci Res 93:893–901

    CAS  PubMed  Google Scholar 

  30. Barrett J, Wonch KE, Gonzalez A, Ali N, Steiner M, Hall GB, Fleming AS (2012) Maternal affect and quality of parenting experiences are related to amygdala response to infant faces. Soc Neurosci 7:252–268

    PubMed  Google Scholar 

  31. Altar CA, Cai N, Bliven T, Juhasz M, Conner JM, Acheson AL, Lindsay RM, Wiegand SJ (1997) Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389:856–860

    CAS  PubMed  Google Scholar 

  32. Hansen N, Manahan-Vaughan D (2014) Dopamine D1/D5 receptors mediate informational saliency that promotes persistent hippocampal long-term plasticity. Cereb Cortex 24:845–858

    PubMed  Google Scholar 

  33. Greisen MH, Altar CA, Bolwig TG, Whitehead R, Wörtwein G (2005) Increased adult hippocampal brain-derived neurotrophic factor and normal levels of neurogenesis in maternal separation rats. J Neurosci Res 79:772–778

    CAS  PubMed  Google Scholar 

  34. Champagne FA, Francis DD, Mar A, Meaney MJ (2003) Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol Behav 79:359–371

    CAS  PubMed  Google Scholar 

  35. Vaccari C, Lolait SJ, Ostrowski NL (1998) Comparative distribution of vasopressin V1b and oxytocin receptor messenger ribonucleic acids in brain. Endocrinology 139:5015–5033

    CAS  PubMed  Google Scholar 

  36. Tomizawa K, Iga N, Lu Y-F, Moriwaki A, Matsushita M, Li ST, Miyamoto O, Itano T et al (2003) Oxytocin improves long-lasting spatial memory during motherhood through MAP kinase cascade. Nat Neurosci 6:384–390

    CAS  PubMed  Google Scholar 

  37. Berridge KC, Robinson TE (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev 28:309–369

    CAS  PubMed  Google Scholar 

  38. Wise RA, Rompre PP (1989) Brain dopamine and reward. Annu Rev Psychol 40:191–225

    CAS  PubMed  Google Scholar 

  39. Ross HE, Young LJ (2009) Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Front Neuroendocrinol 30:534–547

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Neumann I, Landgraf R (1989) Septal and hippocampal release of oxytocin, but not vasopressin, in the conscious lactating rat during suckling. J Neuroendocrinol 1:305–308

    CAS  PubMed  Google Scholar 

  41. Mühlethaler M, Sawyer WH, Manning MM, Dreifuss JJ (1983) Characterization of a uterine-type oxytocin receptor in the rat hippocampus. Proc Natl Acad Sci U S A 80:6713–6717

    PubMed  PubMed Central  Google Scholar 

  42. Goto Y, Grace AA (2008) Limbic and cortical information processing in the nucleus accumbens. Trends Neurosci 31:552–558

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Graham DL, Krishnan V, Larson EB, Graham A, Edwards S, Bachtell RK, Simmons D, Gent LM et al (2009) Tropomyosin-related kinase B in the mesolimbic dopamine system: region-specific effects on cocaine reward. Biol Psychiatry 65:696–701

    CAS  PubMed  Google Scholar 

  44. Yan Q, Matheson C, Sun J, Radeke MJ, Feinstein SC, Miller JA (1994) Distribution of intracerebral ventricularly administered neurotrophins in rat brain and its correlation with Trk receptor expression. Exp Neurol 127:23–36

    CAS  PubMed  Google Scholar 

  45. Do T, Kerr B, Kuzhikandathil EV (2007) Brain-derived neurotrophic factor regulates the expression of D1 dopamine receptors. J Neurochem 100:416–428

    CAS  PubMed  Google Scholar 

  46. Champagne F, Diorio J, Sharma S, Meaney MJ (2001) Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors. Proc Natl Acad Sci 98:12736–12741

    CAS  PubMed  Google Scholar 

  47. Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM et al (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868

    CAS  Google Scholar 

  48. Eisch AJ, Bolaños CA, de Wit J, Simonak RD, Pudiak CM, Barrot M, Verhaagen J, Nestler EJ (2003) Brain-derived neurotrophic factor in the ventral midbrain–nucleus accumbens pathway: a role in depression. Biol Psychiatry 54:994–1005

    CAS  PubMed  Google Scholar 

  49. Krishnan V, Han M-H, Graham DL, Berton O, Renthal W, Russo SJ, LaPlant Q, Graham A et al (2007) Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131:391–404

    CAS  PubMed  Google Scholar 

  50. Walsh JJ, Friedman AK, Sun H et al (2013) Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nat Neurosci 17:27–29

    PubMed  PubMed Central  Google Scholar 

  51. Shirayama Y, Chen AC-H, Nakagawa S, Russell DS, Duman RS (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22:3251–3261

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Deltheil T, Tanaka K, Reperant C, Hen R, David DJ, Gardier AM (2009) Synergistic neurochemical and behavioural effects of acute intrahippocampal injection of brain-derived neurotrophic factor and antidepressants in adult mice. Int J Neuropsychopharmacol 12:905–915

    CAS  PubMed  Google Scholar 

  53. Taliaz D, Loya A, Gersner R, Haramati S, Chen A, Zangen A (2011) Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J Neurosci 31:4475–4483

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Mileva-Seitz V, Steiner M, Atkinson L, Meaney MJ, Levitan R, Kennedy JL, Sokolowski MB, Fleming AS (2013) Interaction between oxytocin genotypes and early experience predicts quality of mothering and postpartum mood. PLoS One 8:e61443

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Green CG, Babineau V, Jolicoeur-Martineau A, Bouvette-Turcot AA, Minde K, Sassi R, St-André M, Carrey N et al (2017) Prenatal maternal depression and child serotonin transporter linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4) genotype predict negative emotionality from 3 to 36 months. Dev Psychopathol 29:901–917

    PubMed  Google Scholar 

  56. Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates: hard cover edition. Elsevier, Amsterdam

    Google Scholar 

  57. Herman JP, Watson SJ (1987) The rat brain in stereotaxic coordinates (2nd edn). Trends Neurosci 10:439

    Google Scholar 

  58. Hellstrom IC, Dhir SK, Diorio JC, Meaney MJ (2012) Maternal licking regulates hippocampal glucocorticoid receptor transcription through a thyroid hormone-serotonin-NGFI-A signalling cascade. Philos Trans R Soc Lond Ser B Biol Sci 367:2495–2510

    CAS  Google Scholar 

  59. Reisert I, Lieb K, Beyer C, Pilgrim C (1996) Sex differentiation of rat hippocampal GABAergic neurons. Eur J Neurosci 8:1718–1724

    CAS  PubMed  Google Scholar 

  60. Mitchell JB, Rowe W, Boksa P, Meaney MJ (1990) Serotonin regulates type II corticosteroid receptor binding in hippocampal cell cultures. J Neurosci 10:1745–1752

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This research was supported by grants from the Hope for Depression Research Foundation and the Canadian Institutes for Health Research to MJM, by grants from Natural Sciences and Engineering Research Council of Canada to TYZ.

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Author notes

  1. Tie-Yuan Zhang and Dara Shahrokh contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, H4H1R3, Canada

    Tie-Yuan Zhang, Dara Shahrokh, Ian C. Hellstrom, Xianglan Wen, Josie Diorio, Lionel Breuillaud, Christian Caldji & Michael J Meaney

  2. Sackler Program for Epigenetics & Psychobiology at McGill University, Montreal, Quebec, H4H1R3, Canada

    Tie-Yuan Zhang, Xianglan Wen, Josie Diorio & Michael J Meaney

  3. Ludmer Centre for Neuroinformatics and Mental health, McGill University, Montreal, Quebec, H4H1R3, Canada

    Tie-Yuan Zhang & Michael J Meaney

  4. Singapore Institute for Clinical Sciences, Singapore, 117609, Singapore

    Michael J Meaney

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  1. Tie-Yuan Zhang
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  2. Dara Shahrokh
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Contributions

TYZ, DS, ICH, XLW, JD, and CC performed all experiments, which were designed by TYZ, DS, ICH, JD, and MJM. TYZ, DS, ICH, and MJM analyzed the data and prepared the manuscript.

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Correspondence to Tie-Yuan Zhang or Michael J Meaney.

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All procedures were performed according to the guidelines from the Canadian Council on Animal Care and approved by the McGill University Animal Care Committee.

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The authors declare that they have no conflicts of interest.

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Zhang, TY., Shahrokh, D., Hellstrom, I.C. et al. Brain-Derived Neurotrophic Factor in the Nucleus Accumbens Mediates Individual Differences in Behavioral Responses to a Natural, Social Reward. Mol Neurobiol 57, 290–301 (2020). https://doi.org/10.1007/s12035-019-01699-2

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