Acknowledgements: The authors of this article are funded in part by a GSK Varsity Award (300034212), with core funding from the Medical Research Council (G1000183) and Wellcome Trust (093875/Z/10/Z) in support of the Behavioural and Clinical Neuroscience Institute at Cambridge University. EGD was supported by the Gates Cambridge Trust. ML was supported by a fellowship from the Medical Research Council (MR/S006257/1). MRC received support from the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, the NIHR Blood and Transplant Research Unit, a Medical Research Council New Investigator Research Grant (MR/N024907/1), an Arthritis Research UK Cure Challenge Research Grant (#21777), and an NIHR Research Professorship (RP-2017-08-ST2-002). ETB was supported by an NIHR Senior Investigator Award.Funder: EC | Erasmus+; doi: https://doi.org/10.13039/501100010790Early-life stress (ELS) or adversity, particularly in the form of childhood neglect and abuse, is associated with poor mental and physical health outcomes in adulthood. However, whether these relationships are mediated by the consequences of ELS itself or by other exposures that frequently co-occur with ELS is unclear. To address this question, we carried out a longitudinal study in rats to isolate the effects of ELS on regional brain volumes and behavioral phenotypes relevant to anxiety and depression. We used the repeated maternal separation (RMS) model of chronic ELS, and conducted behavioral measurements throughout adulthood, including of probabilistic reversal learning (PRL), responding on a progressive ratio task, sucrose preference, novelty preference, novelty reactivity, and putative anxiety-like behavior on the elevated plus maze. Our behavioral assessment was combined with magnetic resonance imaging (MRI) for quantitation of regional brain volumes at three time points: immediately following RMS, young adulthood without further stress, and late adulthood with further stress. We found that RMS caused long-lasting, sexually dimorphic biased responding to negative feedback on the PRL task. RMS also slowed response time on the PRL task, but without this directly impacting task performance. RMS animals were also uniquely sensitive to a second stressor, which disproportionately impaired their performance and slowed their responding on the PRL task. MRI at the time of the adult stress revealed a larger amygdala volume in RMS animals compared with controls. These behavioral and neurobiological effects persisted well into adulthood despite a lack of effects on conventional tests of 'depression-like' and 'anxiety-like' behavior, and a lack of any evidence of anhedonia. Our findings indicate that ELS has long-lasting cognitive and neurobehavioral effects that interact with stress in adulthood and may have relevance for understanding the etiology of anxiety and depression in humans
