ReviewThe brain-placental axis: Therapeutic and pharmacological relevancy to pregnancy
Graphical abstract
Section snippets
Introduction and overview of placenta
Pregnancy establishment and success involve complex cellular, molecular and physiological processes. The fertilized egg divides and develops into a blastocyst which then adheres and nidates into the endometrium. For implantation to occur, an implantation competent blastocyst must be superimposed on a receptive endometrium. Then a precise orchestration of apposition and attachment processes ensues invasion of the trophoblast cells to penetrate the endometrial epithelium and invade into the
Placenta and maternal brain connection
During pregnancy, the maternal brain undergoes temporal changes at different level. Pregnancy changes the maternal brain for at least two years following birth, including enhancement of key hippocampal functions in human [12,13]. Study also suggests that changes in hormone levels during late pregnancy and early postpartum influence specific cognitive abilities in women [14]. During pregnancy, many women experience varying symptoms relating to brain, often referred to as ‘pregnancy brain’,
Placenta and the fetal brain connection
Signaling plays a key role in regulating placental function to the communication between mother and fetus. The classical insulin-like growth factor (IGF) system is a well-studied example of placental role in maternal-fetal communication [62]. Also, the placenta contains a unique microbiome [63] that may have functional roles in pregnancy outcomes. However, several studies have demonstrated that placental regulation of Igf2, Cortisol, Serotonin, and T4/T3 influences neurodevelopmental processes
Animal models and clinical studies
Since the advent of the Barker Hypothesis in 1990, which posits that the intrauterine environment has direct and long-lasting effects on the fetus [101], much attention has been directed towards researching the fetal origins of adult disease. In this pursuit, the brain-placental axis is being dissected to understand the association between the placenta and the fetal brain and more recently the association of the placenta with the maternal brain. Animal models have proven invaluable for studying
Future prospects and research avenues
Understanding the architecture and hormonal links between the placenta and brain requires innovative experiments using both top-down and bottom-up approaches. Though these approaches have been used in research relating to animal physiology and metabolism [127], not much research has been conducted using these methods in the field of neuroendocrinology. An example of the top-down approach will be the establishment of genetic alteration (such as conditional knockout models) or physiological
Concluding remarks
Our current state of knowledge in placental and fetal biology, in general, requires new paradigms to pursue. Though a great deal of achievement has been made in advancing the field, we have not yet succeeded in curing placental insufficiency, hypoxia, preterm birth and fetal brain defects and other birth defects. Research needs to incorporate concepts and techniques from diverse areas including reproductive biology, systems biology, pharmacology, neuroendocrinology and chemical biology to
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgements
This work was supported in parts by grant from the University of Missouri (Research Council Grant) to S.K.B and R21 HD076347 and R01 HD096266 from the Eunice Kennedy Shriver National Institute of Child Health and Development to T.E.S.
References (178)
- et al.
Placentation in different mammalian species
Ann. Endocrinol. (Paris)
(2016) - et al.
Growth and function of the normal human placenta
Thromb. Res.
(2004) - et al.
Experience-facilitated improvements in pup retrieval; evidence for an epigenetic effect
Horm. Behav.
(2012) Neuroendocrine control of maternal behavior in non-human and human mammals
Ann. Endocrinol. (Paris)
(2016)- et al.
Both oxytocin and vasopressin are mediators of maternal care and aggression in rodents: from central release to sites of action
Horm. Behav.
(2012) - et al.
Eph and ephrin expression in normal placental development and preeclampsia
Placenta
(2004) - et al.
Hormonal induction of leptin resistance during pregnancy
Physiol. Behav.
(2007) - et al.
Physiological and molecular determinants of embryo implantation
Mol. Asp. Med.
(2013) - et al.
Endometrial secretions: creating a stimulatory microenvironment within the human early placenta and implications for the aetiopathogenesis of preeclampsia
J. Reprod. Immunol.
(2011) - et al.
Human early placental development: potential roles of the endometrial glands
Placenta
(2007)
Neuroendocrinology of pregnancy and parturition
Handb. Clin. Neurol.
Giving a good start to a new life via maternal brain allostatic adaptations in pregnancy
Front. Neuroendocrinol.
Changes in anxiety and cognition due to reproductive experience: a review of data from rodent and human mothers
Neurosci. Biobehav. Rev.
Reproductive experience alters hippocampal neurogenesis during the postpartum period in the dam
Neuroscience
The placenta as a window to the brain: a review on the role of placental markers in prenatal programming of neurodevelopment
Int. J. Dev. Neurosci.
Cerebral cortical development in rodents and primates
Prog. Brain Res.
Pathogens and the placental fortress
Curr. Opin. Microbiol.
Diagnosis and management of clinical chorioamnionitis
Clin. Perinatol.
The role of the placenta in fetal and perinatal pathology. Highlights of an eight months’ study
Am. J. Obstet. Gynecol.
Adrenal-mediated rather than direct effects of nicotine as a basis of altered sex steroid synthesis in fetal and neonatal rat
Reprod. Toxicol.
Prenatal effects of drugs of abuse on brain development
Drug Alcohol Depend.
Implantation and establishment of pregnancy in human and nonhuman Primates
Adv. Anat. Embryol. Cell Biol.
Uterine glands: developmental biology and functional roles in pregnancy
Endocr. Rev.
Comparative implantation and placentation
Gynecol. Obstet. Invest.
Placental growth factor and pre-eclampsia
J. Hum. Hypertens.
Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism
Exp. Mol. Med.
Long-term potentiation—a decade of progress?
Science
Changes in the maternal hypothalamic-pituitary-adrenal axis in pregnancy and postpartum: influences on maternal and fetal outcomes
Neuroendocrinology
Resetting the dynamic range of hypothalamic-pituitary-adrenal axis stress responses through pregnancy
J. Neuroendocrinol.
Neuroendocrine mechanisms in pregnancy and parturition
Endocr. Rev.
Pregnancy leads to long-lasting changes in human brain structure
Nat. Neurosci.
Motherhood improves learning and memory
Nature
Hormones and cognitive functioning during late pregnancy and postpartum: a longitudinal study
Behav. Neurosci.
Memory in pregnancy. II: implicit, incidental, explicit, semantic, short-term, working and prospective memory in primigravid, multigravid and postpartum women
J. Psychosom. Obstet. Gynaecol.
Evidence for functional interactions between the placenta and brain in pregnant mice
FASEB J.
Placental Effects on Maternal Brain Revealed by Disrupted Placental Gene Expression in Mouse Hybrids
The role of placental hormones in mediating maternal adaptations to support pregnancy and lactation
Front. Physiol.
Neuronal serotonin in the regulation of maternal behavior in rodents
Neurotransmitter (Houst.)
Increase of thyrotropin response to thyrotropin-releasing hormone (TRH) and TRH release in rats during pregnancy
Chin. J. Physiol.
Brain-derived neurotrophic factor promotes implantation and subsequent placental development by stimulating trophoblast cell growth and survival
Endocrinology
The role of ephrins’ receptors and ephrins’ ligands in normal placental development and disease
Expert Opin. Ther. Targets
Regulation of placental efficiency for nutrient transport by imprinted genes
Placenta
Review: the placenta and developmental programming: balancing fetal nutrient demands with maternal resource allocation
Placenta
Placental-specific IGF-II is a major modulator of placental and fetal growth
Nature
Leptin resistance during pregnancy in the rat
J. Neuroendocrinol.
Altered mitochondrial apoptotic pathway in placentas from undernourished rat gestations
Am. J. Physiol. Regul. Integr. Comp. Physiol.
Maternal calorie restriction modulates placental mitochondrial biogenesis and bioenergetic efficiency: putative involvement in fetoplacental growth defects in rats
Am. J. Physiol. Endocrinol. Metab.
Mitochondrial gene expression profiles are associated with maternal psychosocial stress in pregnancy and infant temperament
PLoS One
Brain aging and neurodegeneration: from a mitochondrial point of view
J. Neurochem.
Maternal lifetime stress and prenatal psychological functioning and decreased placental mitochondrial DNA copy number in the PRISM study
Am. J. Epidemiol.
Cited by (31)
The maternal epigenome as a window into the in utero environment that the foetus experiences
2023, Medical HypothesesPrenatal psychological or metabolic stress increases the risk for psychiatric disorders: the “funnel effect” model
2022, Neuroscience and Biobehavioral ReviewsEndocrine hypertension—an overview
2022, Endocrine Hypertension: From Basic Science to Clinical PracticePotential roles of imprinted genes in the teratogenic effects of alcohol on the placenta, somatic growth, and the developing brain
2022, Experimental NeurologyCitation Excerpt :Given our findings that alcohol-related growth restriction is partially mediated by alcohol-related alterations in placental imprinted gene expression, we hypothesize that these teratogenic effects in the placenta may also play mechanistic roles in FASD neurobehavioral deficits. Due to its role in neuroendocrine regulation, the placenta has been coined the “third brain”; connecting the maternal brain with the developing fetal brain (Behura et al., 2019; Yen, 1994). Moreover, the epigenomic signatures of the placenta are thought to be remarkably similar to that of the fetal brain—more so than other tissues (Keverne, 2015; Lester and Marsit, 2018; Yen, 1994).