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Role of neurosteroid (allopregnanolone) in the modulation of kisspeptin-gonadotropin releasing hormone pathway and mood disorders
thesisposted on 22.03.2017, 01:44 by Dalpatadu, Kosmapatabendige Sandun Lakmika
Kisspeptin, a neuropeptide encoded by the Kiss1 gene, is a regulator of reproduction. Neurosteroids play an important role in reproduction. As a gatekeeper of reproductive activity, kisspeptin may be regulated by neurosteroids. Neurosteroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one, THP) has been well characterized for its role in anxiety-like behaviour. However, the mechanisms through which THP regulate reproduction and reproductive behaviour needs further investigation. On the other hand, stress during young life is a critical factor that affects reproduction, which causes various reproductive dysfunctions. Whether neonatal stress affects THP mediated reproductive regulations remains unknown. Chapter 2 of this thesis hypothesised that THP regulates kisspeptin, the upstream regulator of gonadotropin-releasing hormone neurons in young adult (postnatal day [PN] 45-55) female mice. Indeed, THP regulated kisspeptin mRNA expression in the anteroventral periventricular area (AVPV) and not in the arcuate (Arc) nucleus. THP action target; GABA(A) receptor subunit expression in kisspeptin neurons in the AVPV was down-regulated by THP. The down-regulation of GABA(A) expression enhanced kisspeptin expression in the AVPV. Chapter 3 focuses on the effect of neonatal stress on reproductive maturation. Synthetic glucocorticoid (dexamethasone, DEX) exposure during neonatal stage reduced kisspeptin mRNA expression in the AVPV and the Arc nucleus, causing delayed reproductive maturation and irregular oestrous cycles. More salient finding of this study was, kisspeptin neurons did not express glucocorticoid receptor but corticotrophin releasing hormone (CRH) receptor type-1 and CRH neuronal projections were seen in close proximity to kisspeptin neurons. Therefore, kisspeptin neurons receive stress signals from CRH neurons. Data in Chapter 2 showed GABA(A) receptors regulate Kiss1 mRNA. GABA(A) subunit expression in kisspeptin neurons increased in the AVPV of neonatal DEX treated mice (Chapter 2). Increased GABA(A) function could have decreased kisspeptin function in the AVPV and caused reproductive irregularities. In chapter 4, the regulation of sexual discrimination behaviour by THP was investigated. Since, THP levels and function depends on the reproductive stage of rodents, two age groups were selected, young adult (PN 45-55) and adult (PN 77-84). Because neonatal DEX cause deregulation of reproductive behaviour at the adult stage, effect of neonatal DEX on THP mediated sexual discrimination was investigated. Interestingly, neither DEX nor THP treatment had any effect on sexual discrimination behaviour of mice. Therefore, regulation of sexual discrimination could occur independently of THP mediated regulation of kisspeptin function. Collectively the data in this thesis suggest that THP plays an important role in the regulation of reproduction at a molecular level through modulations of kisspeptin neurons in the AVPV. Neonatal exposure to glucocorticoids affects reproductive regulation, which shows the long-term effects of neonatal stress on reproductive physiology. However, neither DEX nor THP plays a significant role in regulating sexual discrimination behaviour in female mice. Understanding the regulation of kisspeptin by THP and neonatal stress provide insight into novel pathways regulating kisspeptin neurons. These results enhance our overall understanding of kisspeptin physiology in mice.