The Impact of Maternal Weaning on Behavioural Development in Rats: Exploring the Role of the Gut-Brain Axis.

The complex mechanisms by which early life factors can impact the developing mammalian system remain largely unclear. Animal studies have led to the identification of neurotransmitter systems that are influenced through manipulation of early life conditions. In addition, evidence suggests that early life events can influence signaling through the gut-brain axis to modulate brain function and behaviour. Specifically, the functions of the host gut microbiota and metabolism have been highlighted. Weaning and stress have both been shown to influence the development of central neurotransmitters implicated in emotional regulation. This thesis applied a multidisciplinary approach to investigate the effect of delayed weaning and its modulation by stress upon host development at multiple tiers of biological organisation. These included behavioural, neurochemical, gut microbial and metabonomic studies. Animal behavioural studies demonstrated that a lack of weaning at the standard age of 21 days in rats, leads to a marked ‘depressive-like’ phenotype. Furthermore, receptor autoradiography revealed non-weaned animals to exhibit altered oxytocin receptor binding in the amygdala and different stress coping mechanisms. Fluorescence in situ hybridisation studies exposed significant weaning and stress-induced effects upon gut microbiota composition. In addition, NMR-based metabonomic studies illuminated fluctuations in a number of endogenous and host-microbial co-metabolites known to be implicated in mood and stress-related disorders. Collectively, the results show that early life factors such as weaning and stress are able to have a marked influence on behavioural development. The findings highlight that signaling through the gut-brain axis may modulate behavioural development possibly through the production of neuroactive metabolites at critical stages of development and open new areas of investigation. The findings identify novel targets for interventions in the pathogenesis of paediatric neuropsychiatric disorders