- Title
- Prenatal and postnatal stress on neurobehavioural outcomes: understanding mechanisms and preventative therapies
- Creator
- Crombie, Gabrielle Kate
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Stressful environments in the perinatal period significantly increase the risk of behavioural and mood disorders in childhood and adolescence. The exact mechanisms by which these adverse outcomes are programmed by elevated cortisol in early life are not fully understood. However, dysregulation in myelin processes are commonly linked to children with disorders such as attention deficit hyperactivity disorder (ADHD) and anxiety. In the fetal brain, the inhibitory GABAergic and excitatory glutamatergic pathways require tight regulation in order to promote the correct balance for neurogenesis, synaptogenesis, and myelination for optimal neurodevelopment. This period of critical maturational processes is therefore particularly vulnerable to perinatal compromise. Previously, prenatal stress has been shown to alter neurosteroid pathways in the fetus and disrupt the inhibitory tone at the GABAA receptor. In these studies, we propose that excitotoxic stress through elevated cortisol exposure in vulnerable periods of development along with disruption of the trophic neurosteroid environment deleteriously programs the perinatal brain. The studies examined the proposal that dysregulation of key neurodevelopmental pathways will cause long-lasting effects on behaviour and white matter structure, at an age equivalent to childhood. The work further examined the proposal that postnatal neurosteroid supplementation therapy will provide neuroprotective effects to reduce or ameliorate negative childhood outcomes. The studies showed that the fetal brain exposed to prenatal stress displays deficits in myelin production from as early as 0.7 of gestation when myelin begins being produced, and these deficits persist until late-childhood equivalence. We reported that myelination deficits may be attributed to dysregulation of mechanisms important for MBP translation. The GABAergic and glutamatergic pathways and other key components of neurodevelopment were substantially disrupted in the neonate, suggesting an arrest of maturation of these pathways. By late-childhood equivalence overcompensation mechanisms of these pathways were apparent, with marked disruptions to the inhibitory/excitatory balance still evident. Reduced mature myelin and GABA/glut disruptions at the childhood age were associated with sex-dependent adverse behavioural outcomes – anxious-like behaviour in female offspring exposed to prenatal stress and hyperactive-like behaviour in males. Interestingly, psychosocial stress in the postnatal period following a stressful prenatal environment offered advantage to the offspring and improved outcomes. The allopregnanolone analogue ganaxolone and the translocator protein ligand emapunil were both able to restore female behavioural phenotypes to control levels after prenatal stress exposure, however adverse male behaviour remained. Emapunil improved myelin deficits in both sexes, and ganaxolone improved excitatory imbalances in the female hippocampus. Placentae of male and female fetuses displayed sex-dependent developmental expression patterns and responses to prenatal stress. These current studies have demonstrated that marked disruptions that can occur in the fetal and juvenile brain following perinatal stressors, especially stress exposure in the mid-late gestation period. The work identified this gestational age as a period of particular vulnerability. The effects of perinatal stressors on neurodevelopment delineated through the current work, and the successful effects of postnatal manipulation to reverse these outcomes, offers important insights into the complex process of stress and neurodevelopment interactions. The work highlighted how multiple pathways act in concert to promote optimal outcomes, or are dysregulated to cause abnormal development. The placental sex-dependent response to stress, the sexually dimorphic childhood behavioural outcomes and the differing response to the therapeutics are intriguing. These findings demonstrate that sex-dependent treatment regimens are essential in treatment approaches for offspring exposed to stressful in utero environments.
- Subject
- perinatal stress; neurosteroids; behavioural disorders; postnatal stress
- Identifier
- http://hdl.handle.net/1959.13/1513764
- Identifier
- uon:56766
- Rights
- Copyright 2022 Gabrielle Kate Crombie
- Language
- eng
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