Hormonal Influences

The female mammalian brain undergoes a variety of changes during pregnancy which allow for maintenance of the pregnancy, healthy fetal development, parturition, and most importantly, maternal behaviours[1]. Hormonal changes are also prevalent during pregnancy[1]; hence, it is beneficial to understand how hormonal fluctuations and structural changes in the maternal brain are linked. The existing literature suggests that various hormones can have both positive and negative effects on the brain during pregnancy, some of which can persist post-parturition[1]. Since the changes that take place are not restricted to regions of the brain associated with maternal behaviour (i.e. the cingulate cortex[2]), rather extending to regions involved in learning and memory as well[3], understanding how hormones cause these often long-lasting changes to the female brain is essential for preventative and treatment purposes, especially since pregnancy is experienced by such a large portion of the world's female population.

1. Positive Influences

1.1 Estrogen and Progesterone

Figure 1
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These photomicrographs show labelling for GFAP and bFGF in cingulate cortex area 2.
Both maternal and non-maternal rats with high levels of estrogen and progesterone demonstrate greater levels
of GFAP and bFGF than cycling controls; however,the maternal experience of the HP Maternal group significantly
increased expression of these proteins over the non-maternal group (i.e. HP Not group). [2]

High levels of estrogen and decreasing levels of progesterone towards the end of pregnancy have been associated with a dramatic upregulation of astrocytes in the cingulate cortex area 2 of rats, which plays a role in maternal responsiveness[2]. These changes in estrogen and progesterone increase levels of glial fibrillary acidic protein (GFAP) and astrocytic basic fibroblast growth factor (FGF-2 or bFGF) (Figure 1), allowing for the creation of new astrocytes[2]. It is important to note that although these changes are associated with hormonal influences, these changes are not produced by hormonal activity alone, rather maternal experience plays a significant role as well[2]. This upregulation of glial cells during pregnancy may work to either stabilize existing circuits within the cingulate cortex area 2, or to support the creation of new neurons[2]; hence, increasing the expression of appropriate maternal behaviour.

Previous studies have demonstrated that non-human mammals who have not experienced pregnancy find neonates aversive, suggesting that dramatic changes must occur in the brain of a female during pregnancy to allow for neonatal stimuli to be rewarding, and to elicit maternal behaviour[4]. As a result, Lahey and colleagues conducted a study in which they looked at the association between polymorphisms in the gene for estrogen receptor alpha and maternal behaviour in humans[4]. It was hypothesized that neural changes, initiated by binding of estrogen to estrogen receptors during the estrogen surge towards the end of pregnancy, are necessary to make previously aversive infant stimuli rewarding for the mothers4. These neural changes include influences on serotonergic and dopaminergic circuits, as well as, proliferation of oxytocin receptors in the brain[4]. The study found that polymorphisms in estrogen receptor alpha, namely the presence of two intronic SNPs associated with dysphoria in women, prevent these effects of estrogen in late pregnancy; hence, eliciting negative maternal behaviour[4]. Presence of these genetic variations in estrogen receptor alpha was associated with increased blood flow to regions of the brain correlated with negative parenting[4]. However, the findings of this study are preliminary (not conclusive) and require further investigation.

1.2 Prolactin

Prolactin is a peptide hormone that is released from the anterior pituitary in response to a variety of stimuli, and it is best known for its role in lactation[5]. Scientific literature suggests that prolactin is involved in a variety of mechanisms throughout the body, and has significant effects on the brain in pregnant women.

1.2a Neuronal Plasticity

Prolactin causes increased neurogenesis in the subventricular zone of the brain during pregnancy in rodents, specifically an increase in the number of olfactory interneurons[6]. In rodents, the resultant olfactory interneurons are required for the processing of pheromones that affect various brain regions associated with maternal behaviour[6]. Exposure to male pheromones in non-pregnant and post-partum female rodents for a time period equivalent to rodent pregnancy advanced maternal behaviour in the rats due to the actions of prolactin and ovarian steroid hormones (i.e. estrogen and progesterone) on olfactory neurogenesis in the subventricular zone[6]. In humans, similar changes may explain the increased sensitivity pregnant women experience to certain odours[7].

1.2b Glial Plasticity

Hormones Affect the Maternal Brain to Alleviate MS Symptoms
Researchers at UCLA found that high levels of estriol during pregnancy can reduce
the amount of demyelinating, inflammatory lesions in the brain in women with early stage Multiple Sclerosis[12]

New myelinating oligodendrocytes are continuously being produced in the adult central nervous system by oligodendrocytic precursor cells (OPCs) and neural stem cells (NSCs)[5]. Both OPCs and NSCs play an important role in regeneration of tissue in the brain following injury or insult, specifically when white matter damage is involved[5]. In mice, prolactin levels surge during the first half of pregnancy at least twice daily; however, they decrease in the second half of pregnancy[5]. This is followed by another surge of prolactin post-partum[5]. According to a study conducted by Gregg, these changes in prolactin levels coincide with OPC proliferation in the subventricular zone; hence, increasing the number of myelinated axons in the white matter tracts of the maternal brain[5]. Although these changes do not impact maternal behaviour, they are a unique hormonally influenced adaptation of the brain to pregnancy which may have implications for the treatment of Multiple Sclerosis (MS), since MS involves demyelinating lesions, and is more prevalent in females than males[5]. This will add to existing findings that suggest other hormones, such as estriol, as a possible treatment option for MS[12].

1.3 Oxytocin and Vasopressin

Injecting oxytocin into virgin female rats causes the spontaneous emergence of maternal behaviour[8]. Furthermore, increased availability of vasopressin in lactating rodents has been found to promote maternal care[8]. Blocking vasopressin receptors (V1A) in the maternal brain reduces maternal caring towards offspring in rodents[8]. Intranasal oxytocin administration results in a variety of behaviours such as greater social memory, improved eye gaze or facial recognition, and increased trust[9], all of which can help facilitate positive maternal behaviour by increasing responsiveness to infant cues. Activation of oxytocin receptors in the ventral striatum, an important part of the dopaminergic pathway, results in infant facial expressions becoming more rewarding for the female[9]; hence, resulting in caring and loving responses to the infant.

Another finding that suggests a role for oxytocin and vasopressin in the modulation of maternal behaviours is the presence of vasopressin secreting neurons, V1A receptors, and oxytocin receptors in the limbic bed nucleus of the stria terminalis, which, in combination with the medial preoptic area, is regarded as a core brain region for maternal behaviour[8].

Maternal adaptations such as protective behaviour towards young, retrieval of offspring, and care (i.e. ano-genital licking) in rats depends on the innate anxiety of the mother[8]. Brain oxytocin and vasopressin levels mediate this anxiety, resulting in either maternal care behaviours or aggressive behaviours[8]. The effect that vasopressin and oxytocin have depends on the region in which these two hormones or the relevant neurons and receptors are expressed[8]. For example: should oxytocin be released in the medial preoptic region, it will result in the expression of maternal care behaviours toward the offspring; however, should the oxytocin be released or act in the central nucleus of the amygdala (CeA), it results in the expression of aggression towards the offpsring[8]. The same can be said for vasopressin, which if expressed in the medial preoptic area, results in the expression of maternal care; however, when expressed in regions such as the limbic bed nucleus, causes maternal aggression[8]. Higher innate anxiety is associated with increased vasopressin and oxytocin release, as well as, better maternal behaviours in the form of faster pup retrieval and greater motivation, even when encountering obstacles (i.e. having to retrieve a pup from behind a chain curtain)[8].

Allopregnanolone
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Molecular structure of allopregnanolone[12]

1.4 Allopregnanolone

Allopregnanolone is a progesterone metabolite that has been implicated in the suppression of activity of the hypothalamic-pituitary-adrenal (HPA) axis in pregnant rats[10]. It is a potent positive modulator of synaptic and extra-synaptic GABA receptors[10]. It prolongs the time period over which activated GABA receptors remain open to chloride ions; neurotransmission to neurons responsible for the release of corticotrophin releasing hormone (CRH)[10]. As a result, allopregnanolone inhibits the stress response in pregnant rats[10], allowing for more positive maternal behaviours.

2. Negative Influences

2.1 Learning and Memory

Figure 2
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Higher estradiol levels and lower cortisol levels were
found in pregnant women with poorer verbal recall memory.[3]

The changes that take place as a result of hormonal influences on the brain during pregnancy are not restricted to promoting positive maternal behaviour, rather they extend to regions involved in learning and memory as well where they can have a negative effect. Glynn conducted a study, enrolling 254 pregnant women in their first trimester alongside non-pregnant controls, which focused on the effect of pregnancy on human memory[3]. The study followed the pregnant women through the duration of their gestational periods. Both groups of women participated in memory assessments such as a backward digit span test to assess working memory, facial recognition tasks to test recognition memory, and paired associate learning tasks to test verbal recall memory[3]. Blood samples were drawn from each of the participants and used to measure plasma cortisol levels and 17-beta estradiol levels[3]. Memory assessments and blood samples revealed a reduction in verbal recall memory, but not working or recognition memory, in pregnant women[3]. This reduction was associated with low levels of cortisol, beginning in the second trimester and continuing into the third, and high levels of 17-beta estradiol beginning early in the second trimester[3] (Figure 2). Furthermore, this effect was found to persist post-parturition[3]. Glynn presents this finding as a possible cost associated with the more beneficial changes that occur in the human female brain during pregnancy. This study is the largest longitudinal study in humans to demonstrate the impact that pregnancy and associated hormonal fluctuations have on memory function, as well as, to show that these effects persist post-partum[3].

2.2 Depression

Depression is another example of a negative effect of hormonal influences on the brain during pregnancy. A variety of hormones have been implicated in the onset of depression during pregnancy. Increasing concentrations of progesterone and estradiol during pregnancy are correlated with a higher prevalence of depressive episodes[1]. In fact, pregnant women with depression have been shown to have higher amounts of a progesterone metabolite called 5-alpha-dihydroprogesterone[1]. Furthermore, high levels of cortisol, especially during the third trimester when cortisol levels are comparable to those found in patients with Cushing's Syndrome[3], are also associated with depression during pregnancy[1]. Although there are many different hypotheses regarding what may cause the onset of depression in pregnant women, there is no conclusive answer[1].

Post-Partum Depression has been explained as a consequence of the actions of a variety of hormones such as cortisol, prolactin, and oxytocin[1]. For example: studies have suggested that reduced post-partum levels of prolactin result in depressive symptoms, or that low plasma oxytocin during the third trimester is a good predictor of Post-Partum Depression[1]. According to a study conducted by O'Keane and colleagues, the sudden reduction of placental CRH following the birth of the fetus forces the HPA axis to undergo some adjusment[11]. This re-equilibration takes time and may be the cause of Post-Partum Depression[11]. During the third trimester of pregnancy, women undergo drastic elevations in cortisol levels[11]. This increase is important to maintain homeostasis in the uterine environment3, and is associated with hyper secretion of CRH from the placenta[11]. This de-sensitizes the HPA axis to CRH, such that hypothalamic suppression of CRH is inhibited[11]. When CRH levels suddenly drop following birth as a result of expulsion of the placenta, the HPA axis must re-adjust[11]. During this time, impaired cortical feedback mechanisms can result in Post-Partum Depression[11]. Furthermore, lowered oestriol levels and CRH levels, found to coincide with Post-Partum Depression symptoms, may increase monoamine oxidase A binding capacity[11]; hence, removing monoamines from synapses more quickly, resulting in depressive symptoms.

Bibliography
1. Workman, J.L. et al. Endocrine substrates of cognitive and affective changes during pregnancy and postpartum. Behav Neurosci. 126, 54-72 (2012).
2. Salmaso, N., Nadeau, J., and Woodside, B. Steroid hormones and maternal experience interact to induce glial plasticity in the cingulate cortex. Behav Neurosci. 29, 786-794 (2009).
3. Glynn, L.M. Giving birth to a new brain: Hormone exposure of pregnancy influence human memory. Psychoneuroendocrino. 35, 1148-1155 (2010).
4. Lahey, B.B. et al. Preliminary genetic imaging study of the association between estrogen receptor-alpha gene polymorphisms and harsh human maternal parenting. Neurosci Lett. 525, 17-22 (2012).
5. Gregg, C. Pregnancy, prolactin and white matter regeneration. J Neurol Sci. 285, 22-27 (2009).
6. Larsen, C.M., Kokay, I.C., and Grattan, D.R. Male pheromones initiate prolactin-induced neurogenesis and advance maternal behaviour in female mice. Horm Behav. 53, 509-517 (2008).
7. Stadtlander, L. Memory and Perceptual Changes during Pregnancy. International Journal of Childbirth Education. 28.2, 49-53 (2013).
8. Bosch, O.J. Maternal nurturing is dependent on her innate anxiety: The behavioral roles of the brain oxytocin and vasopressin. Horm Behav. 59, 202-212 (2011).
9. Strathearn, L., Fonagy, P., Amico, J., and Montague, P.R. Adult Attachment Predicts Maternal Brain and Oxytocin Response to Infant Cues. Neuropsychopharmacol. 34, 2655-2666 (2009).
10. Brunton, P.J., and Russell, J.A. Endocrine induced changes in brain function during pregnancy. Brain Res. 1364, 198-215 (2010).
11. O'Keane, V. et al. Changes in the Maternal Hypothalamic-Pituitary-Adrenal Axis During the Early Puerperium may be Related to the Postpartum 'Blues'. J Neuroendocrinol. 23, 1149-1155 (2011)
12. Doheny, K. (2012, March 7). Hormone Helps Multiple Sclerosis [Video File]. Retrieved from http://www.everydayhealth.com/multiple-sclerosis/0307/pregnancy-may-protect-against-ms.aspx.
13. Allopregnanolone [Image]. Retrieved March 26, 2014 from http://en.wikipedia.org/wiki/Allopregnanolone.

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