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Prenatal dexamethasone exposure on neuroanatomical and functional characterisation of gonadotropin-releasing hormone neurons

posted on 2017-02-16, 23:57 authored by Lim, Wei Ling
The gonadotropin-releasing hormone (GnRH) neuronal system regulates fertility across vertebrates. Thus, migration and positioning of GnRH neurons in the preoptic area (POA) is crucial for proper development and maturation of the GnRH system. However, prenatal stress and glucocorticoid exposure alters reproductive function and behaviour in the adult offsprings. Furthermore, prenatal glucocorticoid exposure during late gestational stages coincides with the early development of GnRH neurons in the brain, thus renders this system vulnerable to this effect. Whether prenatal glucocorticoid exposure alters the GnRH system linked with adult reproductive dysfunction in the offspring has not been shown. This study thus determined the effect of prenatal dexamethasone (DEX, a synthetic glucocorticoid agonist) exposure on the early postnatal GnRH neurons using transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of GnRH promoter. We first tested the hypothesis that prenatal DEX administration disrupts the number, distribution and dendritic development of GnRH neurons in the brain of early postnatal day 0 (P0) male offsprings. Prenatal DEX exposure decreased the total number of GnRH neurons in the brain of P0 males, observed within the medial septum (MS), organum vasculosom of the lamina terminalis (OVLT) and anterior hypothalamic area (AHA). GnRH promoter activity in P0 males, expressed indirectly as EGFP-GnRH/IF-GnRH neuronal ratio, was not affected by DEX exposure. However, decreased percentage of GnRH neurons with branched dendritic structure was observed in the OVLT/POA of DEX-P0 males. Morphological observations in Chapter 2 thus demonstrated that prenatal DEX exposure disrupts the early establishment of GnRH neuronal system in the brain of the P0 male offspring. We further determined the effect of prenatal DEX exposure on the characteristic cellular movement of early postnatal GnRH neurons within the brain of male offsprings in vitro. Time-lapse image analysis demonstrated that the neuronal movement of maternally DEX-administered P0 GnRH neurons localised within the POA was decreased at 60 hr in vitro. The altered motility of DEX-P0 GnRH neurons is possibly linked with the decrease F-actin expression seen by phalloidin staining in DEX-P0 GnRH neurons at 60 hr time point. Taken together in Chapter 3, prenatal DEX exposure possibly alters the fine-tuning movement for the positioning of GnRH neurons in the brain during the early postnatal stage. The effect of prenatal DEX administration on functional characterisation of GnRH neuronal plasticity and synaptic inputs were further determined in P0 male offspring. Prenatal DEX exposure did not alter the spine density in GnRH neurons of DEX-P0 males. The number of synaptic cluster inputs in areas surrounding the GnRH neurons was decreased within the OVLT of DEX-P0 males. The number of synaptic cluster inputs in close apposition with the GnRH neurons was decreased within the OVLT and AHA region. These results in Chapter 4 further demonstrate that the synaptic inputs of neural afferents to the GnRH neurons are altered by prenatal DEX exposure in the P0 male offsprings. Collectively, the body of work presented in this thesis provides morphological evidences that prenatal DEX exposure during late gestational stages alters GnRH neurons and function in the early postnatal stage of the male offsprings. Early disruption of establishment and development of GnRH neurons in the POA by prenatal DEX in males suggests long-term consequences of adult reproductive dysfunction and altered sexual behaviour, mediated by early-life stress and prenatal glucocorticoid exposure.


Principal supervisor

Ishwar Parhar

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Jeffrey Cheah School of Medicine and Health Sciences (Monash University Malaysia)

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Doctor of Philosophy

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Faculty of Medicine Nursing and Health Sciences

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