Angela L. Cumberland

Intrauterine growth restriction (IUGR) is a pregnancy complication impairing fetal growth and development. The compromised development is often attributed to disruptions of oxygen and nutrient supply from the placenta, resulting in a number of unfavourable physiological outcomes with impaired brain and organ growth. IUGR is associated with compromised development of both grey and white matter, predisposing the infant to adverse neurodevelopmental outcomes, including long‐lasting cognitive and motor difficulties. Cerebral thyroid hormone (TH) signalling, which plays a crucial role in regulating white and grey matter development, is dysregulated in IUGR, potentially contributing to the neurodevelopmental delays associated with this condition. Notably, one of the major TH transporters, monocarboxylate transporter‐8 (MCT8), is deficient in the fetal IUGR brain. Currently, no effective treatment to prevent or reverse IUGR exists. Management strategies involve close antenatal monitoring, management of maternal risk factors if present and early delivery if IUGR is found to be severe or worsening in utero. The overall goal is to determine the most appropriate time for delivery, balancing the risks of preterm birth with further fetal compromise due to IUGR. Drug candidates have shown either adverse effects or little to no benefits in this vulnerable population, urging further preclinical and clinical investigation to establish effective therapies. In this review, we discuss the major neuropathology of IUGR driven by uteroplacental insufficiency and the concomitant long‐term neurobehavioural impairments in individuals born IUGR. Importantly, we review the existing clinical and preclinical literature on cerebral TH signalling deficits, particularly the impaired expression of MCT8 and their correlation with IUGR. Lastly, we discuss the current evidence on MCT8‐independent TH analogues which mimic the brain actions of THs by being metabolised in a similar manner as promising, albeit underappreciated approaches to promote grey and white matter development and improve the neurobehavioural outcomes following IUGR. image

Neurodevelopmental disorders such as schizophrenia and autism are thought to involve an imbalance of excitatory and inhibitory signaling in the brain. Intrauterine growth restriction (IUGR) is a risk factor for these disorders, with IUGR onset occurring during critical periods of neurodevelopment. The aim of this study was to determine the impact of IUGR on excitatory and inhibitory neurons of the fetal neocortex and hippocampus. Fetal brains (n = 2) were first collected from an unoperated pregnant guinea pig at mid‐gestation (32 days of gestation [dg]; term ∼67 dg) to visualize excitatory (Ctip2) and inhibitory (calretinin [CR] and somatostatin [SST]) neurons via immunohistochemistry. Chronic placental insufficiency (CPI) was then induced via radial artery ablation at 30 dg in another cohort of pregnant guinea pigs (n = 8) to generate IUGR fetuses (52 dg; n = 8); control fetuses (52 dg; n = 7) were from sham surgeries with no radial artery ablation. At 32 dg, Ctip2‐ and CR‐immunoreactive (IR) cells had populated the cerebral cortex, whereas SST‐IR cells had not, suggesting these neurons were yet to complete migration. At 52 dg, in IUGR versus control fetuses, there was a reduction in SST‐IR cell density in the cerebral cortex (p = .0175) and hilus of the dentate gyrus (p = .0035) but not the striatum (p > .05). There was no difference between groups in the density of Ctip2‐IR (cortex) or CR‐IR (cortex, hippocampus) neurons (p > 0.05). Thus, we propose that an imbalance in inhibitory (SST‐IR) and excitatory (Ctip2‐IR) neurons in the IUGR fetal guinea pig brain could lead to excitatory/inhibitory dysfunction commonly seen in neurodevelopmental disorders such as autism and schizophrenia.

Dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEAS) are dynamically regulated before birth and the onset of puberty. Yet, the origins and purpose of increasing DHEA[S] in postnatal development remain elusive. Here, we draw attention to this pre-pubertal surge from the adrenal gland—the adrenarche—and discuss whether this is the result of intra-adrenal gene expression specifically affecting the zona reticularis (ZR), if the ZR is influenced by the hypothalamic-pituitary axis, and the possible role of spino-sympathetic innervation in prompting increased ZR activity. We also discuss whether neural DHEA[S] synthesis is coordinately regulated with the developing adrenal gland. We propose that DHEA[S] is crucial in the brain maturation of humans prior to and during puberty, and suggest that the function of the adrenarche is to modulate, adapt and rewire the pre-adolescent brain for new and ever-changing social challenges. The etiology of DHEA[S] synthesis, neurodevelopment and recently described 11-keto and 11-oxygenated androgens are difficult to investigate in humans owing to: (i) ethical restrictions on mechanistic studies, (ii) the inability to predict which individuals will develop specific mental characteristics, and (iii) the difficulty of conducting retrospective studies based on perinatal complications. We discuss new opportunities for animal studies to overcome these important issues.

Intrauterine growth restriction (IUGR) is associated with hippocampal alterations that can increase the risk of short‐term memory impairments later in life. Despite the role of hippocampal neurogenesis in learning and memory, research into the long‐lasting impact of IUGR on these processes is limited. We aimed to determine the effects of IUGR on neuronal proliferation, differentiation and morphology, and on memory function at adolescent equivalent age. At embryonic day (E) 18 (term ∼E22), placental insufficiency was induced in pregnant Wistar rats via bilateral uterine vessel ligation to generate IUGR offspring (n = 10); control offspring (n = 11) were generated via sham surgery. From postnatal day (P) 36–44, spontaneous location recognition (SLR), novel object location and recognition (NOL, NOR), and open field tests were performed. Brains were collected at P45 to assess neurogenesis (immunohistochemistry), dendritic morphology (Golgi staining), and brain‐derived neurotrophic factor expression (BDNF; Western blot analysis). In IUGR versus control rats there was no difference in object preference in the NOL or NOR, the similar and dissimilar condition of the SLR task, or in locomotion and anxiety‐like behavior in the open field. There was a significant increase in the linear density of immature neurons (DCX+) in the subgranular zone (SGZ) of the dentate gyrus (DG), but no difference in the linear density of proliferating cells (Ki67+) in the SGZ, nor in areal density of mature neurons (NeuN+) or microglia (Iba‐1+) in the DG in IUGR rats compared to controls. Dendritic morphology of dentate granule cells did not differ between groups. Protein expression of the BDNF precursor (pro‐BDNF), but not mature BDNF, was increased in the hippocampus of IUGR compared with control rats. These findings highlight that while the long‐lasting prenatal hypoxic environment may impact brain development, it may not impact hippocampal‐dependent learning and memory in adolescence.

Intrauterine growth restriction (IUGR) and maternal stress during pregnancy are two compromises that negatively impact neurodevelopment and increase the risk of developing later life neuropsychiatric disorders such as schizophrenia, depression and behavioural disorders. Neurosteroids, particularly allopregnanolone, are important in protecting the developing brain and promoting many essential neurodevelopmental processes. Individually, IUGR and prenatal stress (PS) reduce myelination and neurogenesis within affected fetal brains, however less information is available on the combined effects of these two disorders on the term fetal brain. This study aimed to investigate how IUGR and PS impairs the neurosteroid pathway when combined using a guinea pig model, and how these then disrupt the neurodevelopment of the fetus. Uterine artery blood flow restriction was performed at GA30-35 to induce growth restriction, whilst PS was induced by exposure of the dam to a strobe light during gestation commencing GA40 and repeated every 5 days. Exposure in this model caused reductions in hippocampal CA1 MBP immunostaining of male fetuses in both IUGR alone and IUGR+PS paradigms but only by IUGR in the subcortical white mater, compared with control males. Plasma allopregnanolone was reduced by both stressors irrespective of sex, whereas GFAP or MAP2 expression were not affected by either stressor. Female neurodevelopment, as assessed by these markers, was unimpeded by these compromises. The addition of prenatal stress did not further compound these deficits.

Neurosteroids are essential for aiding proper fetal neurodevelopment. Pregnancy compromises such as preterm birth, prenatal stress and intrauterine growth restriction are associated with an increased risk of developing behavioural and mood disorders, particularly during adolescence. These pathologies involve the premature loss or alteration of trophic steroid hormones reaching the fetus leading to impaired neurodevelopment. While the specific programming mechanisms are yet to be fully elucidated, in adult life, dysfunctions of allopregnanolone action are prevalent in individuals with depression, post‐traumatic stress disorder and anxiety disorders. The objective of this study was to assess if changes in concentrations of the neurosteroid, allopregnanolone, may be a fetal programming factor in priming the brain towards a negative behavioural phenotype during the childhood to adolescent period using a guinea pig model. Pregnant guinea pigs received either vehicle (45% (2‐hydroxypropyl)‐β‐cyclodextrin) or the 5α‐reductase inhibitor, finasteride (25 mg/kg maternal weight) from gestational age 60 until spontaneous delivery (∼71 days gestation). Male and female offspring from vehicle and finasteride treated dams were tested at postnatal day 20 (juvenile‐equivalence) in an open field arena, and hippocampus and amygdala subsequently assessed for neurological changes in markers of development and GABA production pathways 24 h later. Females with reduced allopregnanolone exposure in utero displayed increased neophobic‐like responses to a change in their environment compared to female controls. There were no differences in the neurodevelopmental markers assessed; MAP2, NeuN, MBP, GFAP or GAD67 between intrauterine finasteride or vehicle exposure, in either the hippocampus or amygdala whereas GAT1 staining was decreased. This study indicates that an intrauterine reduction in the supply of allopregnanolone programs vulnerability of female offspring to anxiety‐like disorders in juvenility without impacting long term allopregnanolone concentrations.

Elevated gestational concentrations of allopregnanolone are essential for the development and neuroprotection of the foetal brain. Preterm birth deprives the foetus of these high levels of allopregnanolone, which may contribute to the associated adverse effects on cerebellar development. Preterm birth alters expression of GABA_A receptor subunit composition, which may further limit neurosteroid action. The objective of this study was to determine the effects of suppression of allopregnanolone levels on the markers of development and functional outcome. Pregnant guinea pigs were treated with finasteride at a dose (25 mg/kg maternal weight) shown to suppress allopregnanolone between 60 days of gestation until delivery (term ∼71 days). The cerebella from neonates, whose mothers were treated with finasteride or vehicle during pregnancy, were collected at postnatal age 8. Pups that received finasteride displayed significantly greater glial fibrillary acid protein area coverage and reduced GABA_A receptor α₆-subunit messenger RNA within the cerebellum than pups that were exposed to vehicle. These findings indicate that loss of neurosteroid action on the foetal brain in late gestation produces prolonged astrocyte activation and reductions in GABA_A receptor α₆-subunit expression. These changes may contribute to the long-term changes in function associated with preterm birth.