Perinatal programming of female subfertility: the impact of neonatal immune activation on behaviour, ovarian development, and the brain

The early life environment prescribes long-term health and disease outcomes. Accumulating evidence suggests that female reproductive health is shaped by perinatal factors, such as immune status. The fundamentals of female reproductive success and longevity are established in early life, where the dynamics of ovarian development are co-regulated via immune pathways to establish the ovarian reserve. Additionally, the immune system is known to be especially sensitive to perinatal stressors. This suggests that the early life environment plays an important role in sustained ovarian health and female fertility. Thus, inflammatory stressors during this critical period may permanently modify female ovarian development and immune-drive reproductive functioning, altering sexual behaviour and leading to a suboptimal female phenotype. Using a rat model, we have previously demonstrated that neonatal immune activation (NIA) with bacterial mimetic lipopolysaccharide (LPS) is associated with; altered immune milieu, hypothalamic-pituitary-adrenal axis dysfunction, adult stress vulnerability, and an anxiety-like phenotype in males. The current thesis aimed to examine both the acute and long-term alterations in reproductive parameters in female rats exposed to an intraperitoneal injection of saline (control) or LPS (0.05mg/kg) to induce NIA on postnatal days 3 and 5. Firstly, the behavioural phenotype of females in this model was examined in order to confirm and refine previous findings pertaining to female mating behaviour deficits, and establish if these alterations were driven by altered motivational states. The results of this study indicate that NIA leads to impairments in proceptive and receptive mating behaviours and an altered reproductive developmental trajectory. Secondly, the acute effects of NIA on female rats was analysed, where by NIA treatment was demonstrated to significantly deplete early ovarian follicle populations and increase ovarian inflammation, suggesting that immune-mediated development of the ovary is perturbed by NIA in the female rat. Thirdly, the long term ramifications of neonatal bacterial exposure was examined in the adult female rat, demonstrating that NIA led to significantly advanced puberty onset, sustained ovarian reserve depletion, exaggerated peripheral inflammatory responses to stress, and increased ovarian inflammatory pathway gene expression. Lastly, the central gene expression of mediators associated with inflammation, stress regulation, and reproductive function were examined to elucidate on potential central mechanisms that may contribute to behavioural alterations and ovarian inflammation and reserve depletion. Furthermore, prospective mechanisms are suggested and data is presented demonstrating the potential of these for investigation in a female rat model of subfertility. The findings presented in this thesis suggest that NIA has the potential to perinatally program long-term central and ovarian immune functioning to a proinflammatory bias. This may detrimentally affect female reproductive fitness, fecundity, and stress responsivity, and as such, have implications for both physiological and psychological female health.