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Review: Effects of Postnatal Care in Epigenetic Structure of Rodents

Updated: Nov 24, 2022


Writers: Muhammed Emir Akat, Siyar Ozmen

Diyarbakir Bahcesehir College Science and Technology High School. Sur, Diyarbakir. 21010


Abstract:

This review summarizes the results of the previous studies examining the effects of postnatal care in rodents. Rodents’ maternal care is based on licking and grooming (LG) and arched-back nursing (ABM). The alterations related to maternal care were observed in the rodents’ neurobiological, endocrine, and behavioral systems. The general results, in which High-LG pups grew up healthier, indicate that licking and grooming by the mother positively impact the offspring. Furthermore, it is proven by cross-fostering methods that licking and grooming frequency is not genetically inherited. Thus, understanding the importance of maternal care in rodents, like other mammalians, can draw us a route for humans. The primary purpose of this review paper is to depict the significant results of the want of maternal care in rodents and asserting the same importance in the same or different format for

humans from rodents.


Keywords: Rodentia, Maternal care, stress, licking, and grooming


Introduction:

We want to introduce our review with the terminology. Postnatal care, which is the main discussion of the paper, is the care given by the mother to the newborn baby immediately after the birth (the six weeks) of the member of the rodent. It is proven to affect the offspring psychologically and physiologically. As said in the abstract, maternal care in mice is based on the licking and grooming of the offspring by the mother. Offspring whose mothers engage less in licking-grooming (low-LG) show a higher tendency to stress compared with offspring whose mothers engage more in licking-grooming (high-LG). It is for the benefit to mention that high-LG mothers often engage in licking-grooming twice as much as the low-LG mothers, with this difference only persisting for the first week. (Cameranet al., 2008)


Additionally, it has come to light that maternal LG correlates with offspring’s intelligence and physical development. Studies show that low-LG offspring show decreased levels of neurophysiologic growth factors and impaired performance on spatial learning and memory tests. (Champagne, 2008)

Furthermore, we would like to introduce the methods used in the experiments to understand the topic better. Cross-fostering is the action of taking the offspring from their biological parents and giving them to surrogates. DNA methylation is the addition of a methyl group in position 5’ to a cytosine residue (5-mC). Especially when guanine is in pursuit of cytosine. (CpG dinucleotide) Poly (I: C) - Polyinosinic: polycytidylic acid – is an immunostimulant. It is considered a synthetic analog of double-stranded RNA, which stimulates the immune system for infections. The medial preoptic area in the hypothalamus regulates social behaviors and social rewards. Ovariectomy is the surgical removal of one or both ovaries.



Methodology, Results, and Discussion:

The effects of postnatal care can be examined with two different aspects: genetic effects and physiological effects. Keeping in mind that every result affects mental health, this distinction will better understand the topic.


Genetic Results:

Cross fostering was experimented with to see the heritability of maternal LG. Offspring of high-LG and low-LG mothers were crossed. When pups reached sexual maturity, their actions were examined. The results were that offspring of high-LG mothers whom low-LG mothers nursed showed little LG and arched-back nursing, while the offspring of low-LG but nursed by high-LG mothers showed high levels of LG and arched-back nursing. This experiment shows that maternal care is correlated with postnatal care rather than genetic or prenatal factors.


Another method used in this field was handling. In a series of experiments, handling was used as a manipulation where each pup was separated from the mother for up to 15 minutes for the first two weeks after the parturition. The results were that there was tenacious maternal care, high levels of LG, and arched-back nursing. (Branchi, 2009) During the first week of life, variations of maternal care can cause methylation in the genome and H3K9 acetylation of the NR3C1 promoter region in rats.

(McGowan et al., 2011)


The effects of postnatal care on the DNA of mice are not limited to those, of course. Low LG offspring display a severe transcription decrease in 20 Pcdh of 33 genes registered within the Pcdh gene cluster. (McGowan, 2011)

In order to understand the role of ovaries, offspring of low-LG mothers were ovariectomized and exposed to high levels of estrogen, and they did not have increased oxytocin receptor binding on the MPOA. (Champagne, 2008)

When the adult offspring of low LG-ABN maternal care is treated with TSA (Trichostatin A), the epigenetic marks on the GR exon 17 promoters is reversed; histone acetylation increased, the gene was demethylated, and there was increased occupancy of the promoter with the transcription factor NGFI-A, resulting in increased GR exon 17 promoter expression. At this point, a behavioral change accompanies the epigenetic reversal so that there were no distinctive features between the stress responses of the TSA-treated adult offspring of low LG-ABN and the offspring of LG-ABN.

One of the most significant proofs on the genetic alterations resulted from postnatal care can be the study conducted by McGowan in 2011 focused on the response to maternal care in high and low LG adult offspring. The increase and decrease of DNA methylation and H3K9 acetylation were detected throughout the entire epigenome with different distribution ratios. While clustered regions were showing strengthened responses, many sequences showed no reaction at all. A significant 1413 probes of DNA methylation and 713 probes of H3K9 acetylation were found out of 44000 probes. (McGowan, 2011)

McGowan carried out an additional study of epigenetic changes in the NR3C1 gene in the same year. He defines a “regional difference” in DNA methylation and H3K9 acetylation as a minimum of 1000 bp (at least a probe per 1000 bp) difference between high LG and low LG adult offspring. Throughout the whole gene 723 Rome, (Regional Difference methylation) 373 being hypermethylated and 350 being hypomethylated was identified in high LG adult offspring compared to low LG adult offspring. He also defined 471 RDac, (Regional Difference acetylation), 204 of them being hyperacetylated and 267 of them being hypo acetylated. He discovered that these epigenetic changes were significantly localized within the locus with distances over 100 Kb. (McGowan, 2011)




Physiological Results:

Offspring of high-LG mothers show increased hippocampal GR expression, which helps have more substantial negative feedback onto the hypothalamic-pituitary-adrenal axis (HPA axis). It causes

mainly decreased reactivity to stress. (Lutz, 2014)


Another experiment showed that poly (I: C) treatment at E12.5 alters maternal care behavior (MCB): The experiment focused on pup licking/grooming (LG), nest-building, nursing, and non-pup appropriate behavior, which were assessed for four h per day. The statistical analysis demonstrated a significant decrease in the time poly (I: C) treated mothers spent in LG behavior while more engaged in nest-building behavior. However, the nursing and non-pup-related behaviors showed no change.

The importance of stress can be significantly seen in this study. Upon gestational stress, high-LG mothers’ behavior reversed back to the low-LG mother level. (Lutz, 2014) Offspring reared by low-LG mothers show increased levels of ACTH, which has direct effects on reduced hippocampal glucocorticoid receptor (GR) mRNA. These are correlated hypothalamic corticotrophin-releasing hormones. The release of this hormone activates the HPA axis and causes a negative feedback interaction with hippocampal glucocorticoid receptors through the stress response. (Champagne, 2008., Lutz, 2014)


The hormonal changes should be discussed as well. Maternal care, a group of actions, is highly correlated with the endocrine biology during late gestation. Estrogen levels increase significantly following the decrease of progesterone during the last days of gestation. These events are necessary for the set out of maternal behavior. Critical for the expression of maternal care, the effects of estrogen at the level of the medial preoptic area (MPOA) are of importance. Central oxytocinergic systems affect the maternal behavior in rats via ovarian hormones. Estrogen increases oxytocin synthesis in the parvocellular neurons of the hypothalamus (PVN) that project to the MPOA and other brain regions that regulate maternal behavior. In the MPOA, estrogen increases oxytocin receptor gene expression and receptor binding, mediated through estrogen receptor alpha. Intracerebroventricular (ICV) administration of oxytocin rapidly stimulates maternal behavior in virgin rats, and MPOA plays a crucial role in this event.


The neurobiological Transgenerational effects of maternal immune activation (MIA) on depression-like behavior in the offspring brain, the modulated as targets of altered maternal care behavior (MCB) and relevant for the pathogenesis of depression were examined. The hippocampus was primarily chosen because of its prominent role in the neural circuitry of depression. mRNA expression of mineralocorticoid receptor (MCR) and glucocorticoid receptor (GCR), both relevant to the pathophysiology of depression, was a significant increase in the hippocampus of F1 MIA compared to the control group. This situation was blatantly and statistically correlated with the amount of LG behavior. These changes were also examined in the F2 generation. Statistical analysis showed a significantly increased expression of MCR but not of GCR.


The results of low LG can be scary, but are they stable for lifelong? Even though maternal care affects the epigenetic programming for a short period after birth, and those effects are highly stable and cause lifelong gene expression alteration, surprisingly, it is reversible. The reason for that is the definition of the steady-state methylation pattern by a dynamic equilibrium of methylation-demethylation reactions.


Discussion:

The results of previous experiments prove that licking/grooming (maternal care) in rodents can result in behavioral and physiological alterations. Each study gives another perspective for us to understand these significant changes.

The results of the cross-fostering experiment furtherly disprove the idea that genetic factors determine postnatal maternal care. Furthermore, it depicts that we are on the right way to examine the results accordingly the licking/grooming situation of mothers in their postnatal period.

The increase in hippocampal GR expression in high-LG mothers in the following study and decreased reactivity to stress shows how vital maternal care is for the stress activity in rodents. Furthermore, considering the significant increase in stress activity, we can understand how low maternal care damages pups.

The study including Poly (I: C) treatment is about altering maternal care behavior rather than the results of LG. The Poly (I:C) treatment in rodents resulted in decreased LG behavior and increased nest-building, demonstrating that treating rodents with Poly (I:C) (or increase in their Poly (I:C) synthesis in their body) results in increased result activity in the pups. In late gestation, the increase of estrogen and decrease of progesterone are essential factors in maternal behavior as given. Therefore, we can figure out that any abnormalities in the late gestation will result in abnormalities in maternal behavior in the postnatal period.

The maternal care effects are stable, yet as shown in the study, they are reversible. The process behind this was given, and it provides the harmful effects caused by methylation in rodents to be recovered.

These studies show numerous results for rodents; however, how can we interpret those data for humans? Although maternal cares are in a different version, humans do not lick/groom their babies, as in rodents. Maternal care results in significant results in humans, too. Because the alterations in stress-related behavior in rodents are caused by their physiological changes due to maternal care, the same physiological changes can also be seen in humans, even if not in other versions. The results show us the importance of maternal care in the postnatal area in rodents and humans, even if they have different physiology and behaviors.


Acknowledgments:

The authors thank Alaettin Kaya for his contribution to this review paper.


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