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The experiments reported in this thesis examined the long-term effects of chronic maternal-separation on the mother and her future offspring. Adult female rats were bred and were then repeatedly separated from their pups (maternal separation; MS) or remained with their pups (standard rearing; SR). After those pups were weaned, females were bred again with all pups from the subsequent litters being standard reared. Hence, these subsequent litter pups had mothers that were either previously separated (MSSUB) or not (SRSUB) from their prior litter. Infant offspring of the subsequent litter and their mothers were the focus of the research reported in this thesis. In the first series of experiments (Chapter 2), those infants were examined for anxiety-like behaviour, as well as whether they use maternal cues to regulate their responses to aversive situations, a process referred to as maternal buffering. It was found that MSSUB infants did not exhibit more anxiety-like behaviour compared to standard-reared controls. However, these infants exhibited impaired maternal buffering in response to aversive stimulation. The second series of experiments (Chapter 3) examined whether alterations in mother-infant attachment might underlie the atypical learned fear behaviour that has been previously demonstrated in MSSUB infants (Kan et al., 2016) and the impaired maternal buffering observed in Chapter 2. It was found that mothers with a stress history do not behave differently towards their future offspring when they are undisturbed in the nest. However, under more challenging situations (i.e., when briefly separated from her offspring), mothers that were previously-stressed retrieve their offspring significantly faster, compared to non-stressed mothers. The third and final series of experiment (Chapter 4) examined behavioural and biological factors in the mother following previous exposure to stress. While previously-stressed mothers did not differ from controls on biological measures, such as serum levels of corticosterone, these mothers exhibited behavioural differences on measures of cognition. Specifically, previously-stressed mothers showed poorer spatial learning, compared to non-stressed mothers. These findings are discussed in terms of broader clinical implications for targeting the mother to prevent the intergenerational transmission of stress effects.

The adverse effects of early-life stress are pervasive, with well-established mental and physical health consequences for exposed individuals. The impact of early adverse experiences is also highly persistent, with documented increases in risk for mental illness across the life span that are accompanied by stable alterations in neural function and hormonal responses to stress. Here, we review some of these 'stress phenotypes', with a focus on intermediary factors that may signal risk for long-term mental health outcomes, such as altered development of the fear regulation system. Intriguingly, recent research suggests that such stress phenotypes may persist even beyond the life span of the individuals, with consequences for their offspring and grand-offspring. Phenotypic characteristics may be transmitted to future generations via either the matriline or the patriline, a phenomenon that has been demonstrated in both human and animal studies. In this review, we highlight behavioral and epigenetic factors that may contribute to this multigenerational transmission and discuss the potential of various treatment approaches that may halt the cycle of stress phenotypes.