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Juvenile social isolation affects maternal care in rats: involvement of allopregnanolone

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Abstract

Rationale

Social isolation of rats immediately after weaning is thought to represent an animal model of anxiety-like disorders. Socially isolated virgin females showed a significant decrease in allopregnanolone levels, associated with increased anxiety-related behavior compared with group-housed rats.

Objectives

The present study investigates whether post-weaning social isolation affects maternal behavior and assesses neuroactive steroid levels in adult female rats during pregnancy and postpartum.

Results

Socially isolated dams displayed a reduction in the frequency of arched back nursing (ABN) behavior compared to group-housed dams. In addition, both total and active nursing were lower in socially isolated dams compared to group-housed dams. Compared to virgin females, pregnancy increases allopregnanolone levels in group-housed as well as isolated dams and such increase was greater in the latter group. Compared to pregnancy levels, allopregnanolone levels decreased after delivery and this decrease was more pronounced in isolated than group-housed dams. Moreover, the fluctuations in plasma corticosterone levels that occur in late pregnancy and during lactation follow a different pattern in socially isolated vs. group-housed rats.

Conclusions

The present results show that social isolation in female rats decreases maternal behavior; this effect is associated with lower allopregnanolone concentrations at postpartum, which may account, at least in part, for the poor maternal care observed in socially isolated dams. In support of this conclusion is the finding that finasteride-treated dams, which display a decrease in plasma allopregnanolone levels, also showed a marked reduction in maternal care, suggesting that allopregnanolone may contribute to the quality of maternal care.

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References

  • Azzolina B, Ellsworth K, Andersson S, Geissler W, Bull HG, Harris GS (1997) Inhibition of rat alpha-reductases by finasteride: evidence for isozyme differences in the mechanism of inhibition. J Steroid Biochem Mol Biol 61:55–64

    Article  CAS  PubMed  Google Scholar 

  • Babb JA, Carini LM, Spears SL, Nephew BC (2014) Transgenerational effects of social stress on social behavior, corticosterone, oxytocin, and prolactin in rats. Horm Behav 65:386–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Backstrom T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Stromberg J, Timby E, van Broekhoven F, van Wingen G (2014) Allopregnanolone and mood disorders. Prog Neurobiol 113:88–94

    Article  CAS  PubMed  Google Scholar 

  • Bicíková M, Klak J, Hill M, Zizka Z, Hampl R, Calda P (2002) Two neuroactive steroids in midpregnancy as measured in maternal and fetal sera and in amniotic fluid. Steroids 67:399–402

    Article  PubMed  Google Scholar 

  • Bitran D, Hilvers RJ, Kellogg CK (1991) Anxiolytic effects of 3 alpha-hydroxy-5 alpha[beta]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Res 561:157–161

    Article  CAS  PubMed  Google Scholar 

  • Bitran D, Shiekh M, McLeod M (1995) Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol 7:171–177

    Article  CAS  PubMed  Google Scholar 

  • Bridges RS, Rosenblatt JS, Feder HH (1978) Stimulation of maternal responsiveness after pregnancy termination in rats: effect of time of onset of behavioral testing. Horm Behav 10:235–245

    Article  CAS  PubMed  Google Scholar 

  • Brummelte S, Galea LA (2010) Chronic corticosterone during pregnancy and postpartum affects maternal care, cell proliferation and depressive-like behavior in the dam. Horm Behav 58:769–779

    Article  CAS  PubMed  Google Scholar 

  • Brummelte S, Galea LA (2016) Postpartum depression: etiology, treatment and consequences for maternal care. Horm Behav 77:153–166

    Article  PubMed  Google Scholar 

  • Brummelte S, Pawluski JL, Galea LA (2006) High post-partum levels of corticosterone given to dams influence postnatal hippocampal cell proliferation and behavior of offspring: a model of post-partum stress and possible depression. Horm Behav 50:370–382

    Article  CAS  PubMed  Google Scholar 

  • Brunton PJ, Russell JA (2008) The expectant brain: adapting for motherhood. Nat Rev Neurosci 9:11–25

    Article  CAS  PubMed  Google Scholar 

  • Brunton PJ, Russell JA (2011) Allopregnanolone and suppressed hypothalamo-pituitary-adrenal axis stress responses in late pregnancy in the rat. Stress 14:6–12

    Article  CAS  PubMed  Google Scholar 

  • Brunton PJ, Russell JA, Hirst JJ (2014) Allopregnanolone in the brain: protecting pregnancy and birth outcomes. Prog Neurobiol 113:106–136

    Article  CAS  PubMed  Google Scholar 

  • Cahill S, Tuplin E, Holahan MR (2013) Circannual changes in stress and feeding hormones and their effect on food-seeking behaviors. Front Neurosci 7:140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky PM, Meaney MJ (1998) Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci U S a 95:5335–5340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carini LM, Nephew BC (2013) Effects of early life social stress on endocrinology, maternal behavior, and lactation in rats. Horm Behav 64:634–641

    Article  CAS  PubMed  Google Scholar 

  • Carter CS, Altemus M, Chrousos GP (2001) Neuroendocrine and emotional changes in the post-partum period. Prog Brain Res 133:241–249

    Article  CAS  PubMed  Google Scholar 

  • Champagne FA, Curley JP (2009) Epigenetic mechanisms mediating the long-term effects of maternal care on development. Neurosci Biobehav Rev 33:593–600

    Article  PubMed  Google Scholar 

  • Clinton SM, Vázquez DM, Kabbaj M, Kabbaj MH, Watson SJ, Akil H (2007) Individual differences in novelty-seeking and emotional reactivity correlate with variation in maternal behavior. Horm Behav 51:655–664

    Article  PubMed  PubMed Central  Google Scholar 

  • Concas A, Mostallino MC, Porcu P, Follesa P, Barbaccia ML, Trabucchi M, Purdy RH, Grisenti P, Biggio G (1998) Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type a receptor in rat brain during pregnancy and after delivery. Proc Natl Acad Sci U S A 95:13284–13289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Brito Guzzo SF, Rafael C, Matheus Fitipaldi B, Amarylis Garcia A, Vinícius Dias K, Luiz YJ, Fernando F, de Gonçalves Carneiro Spera T (2015) Impact of chronic stressors on the anxiety profile of pregnant rats. Physiol Behav 142:137–145

    Article  PubMed  Google Scholar 

  • Essex MJ, Shirtcliff EA, Burk LR, Ruttle PL, Klein MH, Slattery MJ, Kalin NH, Armstrong JM (2011) Influence of early life stress on later hypothalamic-pituitary-adrenal axis functioning and its covariation with mental health symptoms: a study of the allostatic process from childhood into adolescence. Dev Psychopathol 23:1039–1058

    Article  PubMed  PubMed Central  Google Scholar 

  • Follesa P, Porcu P, Sogliano C, Cinus M, Biggio F, Mancuso L, Mostallino MC, Paoletti AM, Purdy RH, Biggio G, Concas A (2002) Changes in GABAA receptor γ2 subunit gene expression induced by long-term administration of oral contraceptives in rats. Neuropharmacology 42:325–336

    Article  CAS  PubMed  Google Scholar 

  • Fone KC, Porkess MV (2008) Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders. Neurosci Biobehav rev 32:1087–1102

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Genazzani AR, Petraglia F, Bernardi F, Casarosa E, Salvestroni C, Tonetti A, Nappi RE, Luisi S, Palumbo M, Purdy RH, Luisi M (1998) Circulating levels of allopregnanolone in humans: gender, age, and endocrine influences. J Clin Endocrinol Metab 83:2099–2103

    Article  CAS  PubMed  Google Scholar 

  • Girdler SS, Klatzkin R (2007) Neurosteroids in the context of stress: implications for depressive disorders. Pharmacol Ther 116:125–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Girdler SS, Lindgren M, Porcu P, Rubinow DR, Johnson JL, Morrow AL (2012) A history of depression in women is associated with an altered GABAergic neuroactive steroid profile. Psychoneuroendocrinology 37:543–553

    Article  CAS  PubMed  Google Scholar 

  • Goodman SH, Lusby CM, Thompson K, Newport DJ, Stowe ZN (2014) Maternal depression in association with fathers’ involvement with their infants: spillover or compensation/buffering? Infant Ment Health J 35:495–508

    Article  PubMed  Google Scholar 

  • Grobin AC, Morrow AL (2001) 3α-hydroxy-5α-pregnan-20-one levels and GABAA receptor-mediated 36Cl− flux across development in rat cerebral cortex. Brain Res Dev Brain Res 131:31–39

    Article  CAS  PubMed  Google Scholar 

  • Hawkley LC, Cole SW, Capitanio JP, Norman GJ, Cacioppo JT (2012) Effects of social isolation on glucocorticoid regulation in social mammals. Horm Behav 62:314–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herbison AE (2001) Physiological roles for the neurosteroid allopregnanolone in the modulation of brain function during pregnancy and parturition. Prog Brain Res 133:39–47

    Article  CAS  PubMed  Google Scholar 

  • Khisti RT, Chopde CT, Jain SP (2000) Antidepressant-like effect of the neurosteroid 3α-hydroxy-5α- pregnan-20-one in mice forced swim test. Pharmacol Biochem Behav 67:137–143

    Article  CAS  PubMed  Google Scholar 

  • Lambert JJ, Belelli D, Hill-Venning C, Peters JA (1995) Neurosteroids and GABAA receptor function. Trends Pharmacol Sci 16:295–303

    Article  CAS  PubMed  Google Scholar 

  • Lightman SL (1992) Alterations in hypothalamic-pituitary responsiveness during lactation. Ann N Y Acad Sci 652:340–346

    Article  CAS  PubMed  Google Scholar 

  • Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney MJ (1997) Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277(5332):1659–1662

    Article  CAS  PubMed  Google Scholar 

  • Maestripieri D, Badiani A, Puglisi-Allegra S (1991) Prepartal chronic stress increases anxiety and decreases aggression in lactating female mice. Behav Neurosci 105:663–668

    Article  CAS  PubMed  Google Scholar 

  • Majewska MD (1992) Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol 38:379–395

    Article  CAS  PubMed  Google Scholar 

  • Mann PE (2006) Finasteride delays the onset of maternal behavior in primigravid rats. Physiol Behav 88:333–338

    Article  CAS  PubMed  Google Scholar 

  • Meaney MJ (2001) Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu rev Neurosci 24:1161–1192

    Article  CAS  PubMed  Google Scholar 

  • Meaney MJ, Szyf M (2005) Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci 7:103–123

    PubMed  PubMed Central  Google Scholar 

  • Murgatroyd CA, Nephew BC (2013) Effects of early life social stress on maternal behavior and neuroendocrinology. Psychoneuroendocrinol 38:219–228

    Article  CAS  Google Scholar 

  • Myers MM, Brunelli SA, Squire JM, Shindeldecker RD, Hofer MA (1989) Maternal behavior of SHR rats and its relationship to offspring blood pressures. Dev Psychobiol 22:29–53

    Article  CAS  PubMed  Google Scholar 

  • Nappi RE, Petraglia F, Luisi S, Polatti F, Farina C, Genazzani AR (2001) Serum allopregnanolone in women with postpartum “blues”. Obstet Gynecol 97:77–80

    CAS  PubMed  Google Scholar 

  • Nephew BC, Bridges RS (2011) Effects of chronic social stress during lactation on maternal behavior and growth in rats. Stress 14:677–684

    Article  PubMed  PubMed Central  Google Scholar 

  • Numan M, Roach JK, del Cerro MC, Guillamón A, Segovia S, Sheehan TP, Numan MJ (1999) Expression of intracellular progesterone receptors in rat brain during different reproductive states, and involvement in maternal behavior. Brain res 830:358–371

    Article  CAS  PubMed  Google Scholar 

  • Otsuka T, Goto M, Kawai M, Togo Y, Sato K, Katoh K, Furuse M, Yasuo S (2012) Photoperiod regulates corticosterone rhythms by altered adrenal sensitivity via melatonin-independent mechanisms in Fischer 344 rats and C57BL/6J mice. PLoS One 7(6):e39090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paoletti AM, Romagnino S, Contu R, Orrù MM, Marotto MF, Zedda P, Lello S, Biggio G, Concas A, Melis GB (2006) Observational study on the stability of the psychological status during normal pregnancy and increased blood levels of neuroactive steroids with GABA-A receptor agonist activity. Psychoneuroendocrinology 31:485–492

    Article  CAS  PubMed  Google Scholar 

  • Pisu MG, Serra M (2004) Neurosteroids and neuroactive drugs in mental disorders. Life Sci 74:181–197

    Article  Google Scholar 

  • Pisu MG, Garau A, Olla P, Biggio F, Utzeri C, Dore R, Serra M (2013) Altered stress responsiveness and hypothalamic-pituitary-adrenal axis function in male rat offspring of socially isolated parents. J Neurochem 126:493–502

    Article  CAS  PubMed  Google Scholar 

  • Pisu MG, Garau A, Boero G, Biggio F, Pibiri V, Dore R, Locci V, Paci E, Porcu P, Serra M (2016) Sex differences in the outcome of juvenile social isolation on HPA axis function in rats. Neuroscience 320:172–182

    Article  CAS  PubMed  Google Scholar 

  • Popoola DO, Borrow AP, Sanders JE, Nizhnikov ME, Cameron NM (2015) Can low-level ethanol exposure during pregnancy influence maternal care? An investigation using two strains of rat across two generations. Physiol Behav 148:111–121

    Article  CAS  PubMed  Google Scholar 

  • Porcu P, Mostallino MC, Sogliano C, Santoru F, Berretti R, Concas A (2012) Long-term administration with levonorgestrel decreases allopregnanolone levels and alters GABA(a) receptor subunit expression and anxiety-like behavior. Pharmacol Biochem Behav 102:366–372

    Article  CAS  PubMed  Google Scholar 

  • Purdy RH, Moore PH Jr, Rao PN, Hagino N, Yamaguchi T, Schmidt P, Rubinow DR, Morrow AL, Paul SM (1990) Radioimmunoassay of 3-alpha-hydroxy-5 alpha-pregnan-20-one in rat and human plasma. Steroids 55:290–296

    Article  CAS  PubMed  Google Scholar 

  • Pyter LM, Adelson JD, Nelson RJ (2007) Short days increase hypothalamic-pituitary-adrenal axis responsiveness. Endocrinology 148(7):3402–3409

    Article  CAS  PubMed  Google Scholar 

  • Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F, Usala L, Purdy RH, Biggio G (2000) Social isolation-induced decreases in both the abundance of neuroactive steroids and GABAA receptor function in rat brain. J Neurochem 75:732–740

    Article  CAS  PubMed  Google Scholar 

  • Serra M, Pisu MG, Floris I, Biggio G (2005) Social isolation–induced changes in the hypothalamic-pituitary-adrenal axis in the rat. Stress 8:259–264

    Article  CAS  PubMed  Google Scholar 

  • Shen H, Gong QH, Aoki C, Yuan M, Ruderman Y, Dattilo M, Williams K, Smith SS (2007) Reversal of neurosteroid effects at α4β2δ GABAA receptors triggers anxiety at puberty. Nat Neurosci 10:469–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith SS, Gong QH, Li X, Moran MH, Bitran D, Frye CA, Hsu FC (1998) Withdrawal from 3α-OH-5α-pregnan-20-one using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor α4 subunit in association with increased anxiety. J Neurosci 18:5275–5284

    CAS  PubMed  Google Scholar 

  • Smith JW, Seckl JR, Evans AT, Costall B, Smythe JW (2004) Gestational stress induces post-partum depression-like behaviour and alters maternal care in rats. Psychoneuroendocrinology 29(2):227–244

    Article  CAS  PubMed  Google Scholar 

  • Stern JM, Johnson SK (1990) Ventral somatosensory determinants of nursing behavior in Norway rats. I. Effects of variations in the quality and quantity of pup stimuli. Physiol Behav 47:993–1011

    Article  CAS  PubMed  Google Scholar 

  • Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854

    Article  CAS  PubMed  Google Scholar 

  • Zimmerberg B, Farley MJ (1993) Sex differences in anxiety behavior in rats: role of gonadal hormones. Physiol Behav 54:1119–1124

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the Sardinian Government (RAS, Grant CRP 25459) and the Fondazione Banco di Sardegna (Grant 2013.0259) to MS and by the University of Cagliari PRID 2015 grants to MS and FB.

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Correspondence to Maria Giuseppina Pisu.

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Pisu, M.G., Boero, G., Biggio, F. et al. Juvenile social isolation affects maternal care in rats: involvement of allopregnanolone. Psychopharmacology 234, 2587–2596 (2017). https://doi.org/10.1007/s00213-017-4661-2

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  • DOI: https://doi.org/10.1007/s00213-017-4661-2

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