In rats, variations in the levels of neuromodulatory molecules and in the expression of their receptors are observed during pregnancy and postpartum. These changes may contribute to the development and management of maternal behavior. The frequency of licking the pups is used to evaluate maternal care, having mothers with low licking (LL) and high licking (HL) frequencies. Previously, we found that HL had increased levels of transcriptional expression of the receptors for serotonin (HTR1a, HTR1b), estrogen (Erα), dopamine (D1a), and prolactin (Prlr) than LL in the olfactory bulb (OB); however, the molecular mechanisms behind this phenomenon are unknown. Since evidences pointed out that epigenetic marks, which may alter gene expression, are modulated by environmental factors such as exercise, diet, maternal care, and xenobiotic exposure, our objective was to verify the acetylation levels of histone-H4 in the OB of LL and HL rats. Maternal behavior was studied for the first 7 postpartum days. LL (n = 4) and HL (n = 5) mothers were selected according to the behavior of licking their pups. Acetylation levels of histone-H4 were determined using the Global Histone-H4 Acetylation Assay Kit and expressed as ng/mg protein (mean ± SD). Analysis revealed that HL (278.36 ± 68.95) had increased H4 acetylation levels than LL (183.24 ± 73.05; p = 0.045). The enhanced expression of the previously studied receptors in the OB could be related, at least in part, to the hyperacetylation status of histone-H4 here observed. Afterward, the modulation of histone acetylation levels could exert a pivotal role through molecular mechanisms involved in the different patterns of maternal behavior.
This is a preview of subscription content, log in to check access
We thank PROAP/UFCSPA, CAPES and FAPERGS for financial support.
Compliance with Ethical Standards
Conflict of interest
The authors have no financial conflicts of interest.
All procedures performed in this study were in accordance with the ethical standards of CONCEA (Conselho Nacional de Controle de Experimentação Animal) and were approved by the Ethics Committee of UFCSPA (Protocol Number 788/09).
Bie B, Wang Y, Cai YQ, Zhang Z, Hou YY, Pan ZZ (2012) Upregulation of nerve growth factor in central amygdala increases sensitivity to opioid reward. Neuropsychopharmacol 37(13):2780–2788CrossRefGoogle Scholar
Bradford MM (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:218–254CrossRefGoogle Scholar
Bredy TW, Wu H, Crego C et al (2007) Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem 14(4):268–276CrossRefPubMedPubMedCentralGoogle Scholar
Caldji C, Tannenbaum B, Sharma S, Francis DD, 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 USA 95:5335–5340CrossRefPubMedPubMedCentralGoogle Scholar
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 USA 98:12736–12741CrossRefPubMedPubMedCentralGoogle Scholar
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 79:359–371CrossRefPubMedGoogle Scholar
Champagne FA, Weaver IC, Diorio J, Dymov S, Szyf M, Meaney MJ (2006) Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology 147(6):2909–2915CrossRefPubMedGoogle Scholar
Champagne DL, Bagot RC, Van Hasselt F, Ramakers G, Meaney MJ, Kloet ER (2008) Maternal care and hippocampal plasticity: evidence for experience- dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J Neurosci 28:6037–6045CrossRefPubMedGoogle Scholar
Chiu K, Lau WM, Lau HT, So KF, Chang RCC (2007) Micro-dissection of rat brain for RNA or protein extraction from specific brain region. J Vis Exp 7:269PubMedGoogle Scholar
De Moura AC, Lazzari VM, Becker RO, Gil MS, Ruthschilling CA, Agnes G, Almeida S, Da Veiga ABG, Lucion AB, Giovenardi M (2015) Gene expression in the CNS of lactating rats with different patterns of maternal behavior. Neurosci Res 99:8–15CrossRefPubMedGoogle Scholar
Elsner VR, Lovatel GA, Bertoldi K et al (2011) Effect of different exercise protocols on histone acetyltransferases and histone deacetylases activities in rat hippocampus. Neuroscience 192:580–587CrossRefPubMedGoogle Scholar
Francis DD, Diorio J, Liu D, Meaney MJ (1999) Nongenomic transmission across generations in maternal behavior and stress responses in the rat. Science 286:1155–1158CrossRefPubMedGoogle Scholar
Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DE, Truong HT, Russo SJ, Laplant Q, Sasaki TS, Whistler KN et al (2005) Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48:303–314CrossRefPubMedGoogle Scholar
Lenz KM, Sengelaub DR (2009) Maternal care effects on SNB motoneuron development: the mediating role of sensory afferent distribution and activity. Dev Neurobiol 69:603–615CrossRefPubMedPubMedCentralGoogle Scholar
Levenson JM, O’Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD (2004) Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 279:40545–40559CrossRefPubMedGoogle Scholar
Liu D, Tannenbaum B, Caldji C, Francis DD, Freedman A, Sharma S (1997) Maternal care, hippocampal glucocorticoid receptor gene expression and hypothalamic–pituitary–adrenal responses to stress. Science 277:1659–1662CrossRefPubMedGoogle Scholar
Maccari S, Krugers HJ, Morley-Fletcher S, Szyf M, Brunton PJ (2014) The consequences of early-life adversity: neurobiological, behavioural and epigenetic adaptations. J Neuroendocrinol 26:707–723CrossRefPubMedGoogle 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 22:29–53CrossRefPubMedGoogle Scholar
Parent CI, Meaney MJ (2008) The influence of natural variations of maternal care on play fighting in the rat. Dev Psychobiol 50:767–776CrossRefPubMedGoogle Scholar
Patisaul HB, Scordalakes EM, Young LJ, Rissman EF (2003) Oxytocin, but not oxytocin receptor, is regulated by oestrogen receptor beta in the female mouse hypothalamus. J Neuroendocrinol 15(8):787–793CrossRefPubMedGoogle Scholar
Peña CJ, Neugut YD, Calarco CA, Champagne FA (2014) Effects of maternal care on the development of midbrain dopamine pathways and reward-directed behavior in female offspring. Eur J Neurosci 39:946–956CrossRefPubMedGoogle Scholar
Ruthschilling CA, Albiero G, Lazzari VM, Becker RO, de Moura AC, Lucion AB (2012) Analysis of transcriptional levels of the oxytocin receptor in different areas of the central nervous system and behaviors in high and low licking rats. Behav Brain Res 228:176–184CrossRefPubMedGoogle Scholar
Sharma RP (2005) Schizophrenia, epigenetics and ligand-activated nuclear receptors: a framework for chromatin therapeutics. Schizophr Res 72:79–90CrossRefPubMedGoogle Scholar
Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525CrossRefPubMedGoogle Scholar
Veenema AH, Neumann ID (2009) Maternal separation enhances offensive play-fighting, basal corticosterone and hypothalamic vasopressin mRNA expression in juvenile male rats. Psychoneuroendocrinology 34:463–467CrossRefPubMedGoogle Scholar
Yamawaki Y, Fuchikami M, Morinobu S, Segawa M, Matsumoto T, Yamawaki S (2012) Antidepressant-like effect of sodium butyrate (HDAC inhibitor) and its molecular mechanism of action in the rat hippocampus. World J Biol Psychiatry 13(6):458–467CrossRefPubMedGoogle Scholar