Experience of traumatic events in childhood is linked to an elevated risk of developing psychiatric disorders in adulthood. The neurobiological mechanisms underlying this phenomenon are not fully understood. The limbic system, particularly the hippocampus, is significantly impacted by childhood trauma. In particular, it has been hypothesised that childhood stress may impact adult hippocampal neurogenesis (AHN) and related behaviours, conferring increased risk for later mental illness. Stress in utero can lead to impaired hippocampal synaptic plasticity, and stress in the first 2–3 weeks of life reduces AHN in animal models. Less is known about the effects of stress in the post-weaning, pre-pubertal phase, a developmental time-point more akin to human childhood. Therefore, we investigated persistent effects of pre-pubertal stress (PPS) on functional and molecular aspects of the hippocampus. AHN was altered following PPS in male rats only. Specifically males showed reduced production of new neurons following PPS, but increased survival in the ventral dentate gyrus. In adult males, but not females, pattern separation and trace fear conditioning, behaviours that rely heavily on AHN, were also impaired after PPS. PPS also increased the expression of parvalbumin-positive GABAergic interneurons in the ventral dentate gyrus and increased glutamic acid decarboxylase 67 expression in the ventral hilus, in males only. Our results demonstrate the lasting effects of PPS on the hippocampus in a sex- and time-dependent manner, provide a potential mechanistic link between PPS and later behavioural impairments, and highlight sex differences in vulnerability to neuropsychiatric conditions after early-life stress.

Impaired social function is a core feature of many psychiatric illnesses. Adverse experiences during childhood increase risk for mental illness, however it is currently unclear whether stress early in life plays a direct role in the development of social difficulties. Using a rat model of pre-pubertal stress (PPS), we investigated effects on social behaviour, oxytocin and arginine vasopressin (AVP) in the periphery (plasma) and centrally in the paraventricular and supraoptic hypothalamic nuclei. We also explored social performance and AVP expression (plasma) in participants with borderline personality disorder (BPD) who experienced a high incidence of childhood stress. Social behaviour was impaired and AVP expression increased in animals experiencing PPS and participants with BPD. Behavioural deficits in animals were rescued through administration of the AVPR1a antagonist Relcovaptan (SR49059). AVP levels and recognition of negative emotions were significantly correlated in BPD participants only. In conclusion, early life stress plays a role in the precipitation of social dysfunction, and AVP mediates at least part of this effect.

Adverse experiences early in life are associated with the development of psychiatric illnesses. The hippocampus is likely to play pivotal role in generating these effects: it undergoes significant development during childhood and is extremely reactive to stress. In rodent models, stress in the prepubertal period impairs adult hippocampal neurogenesis (AHN) and behaviours which rely on this process. In normal adult animals, environmental enrichment (EE) is a potent promoter of AHN and hippocampal function. Whether exposure to EE during adolescence can restore normal hippocampal function and AHN following pre-pubertal stress (PPS) is unknown. We investigated EE as a treatment for reduced AHN and hippocampal function following PPS in a rodent model. Stress was administered between post-natal days (PND) 25-27, EE from PND35 to early adulthood, when behavioural testing and assessment of AHN took place. PPS enhanced fear reactions to a CS following a trace fear protocol and reduced the survival of 4-week-old adult-born neurons throughout the adult hippocampus. Furthermore, we show that fewer adult-born neurons were active during recall of the CS stimulus following PPS. All effects were reversed by EE. Our results demonstrate lasting effects of PPS on the hippocampus and highlight the utility of EE during adolescence for restoring normal hippocampal function. EE during adolescence is a promising method of enhancing impaired hippocampal function resulting from early life stress, and due to multiple benefits (low cost, few side effects, widespread availability), should be more thoroughly explored as a treatment option in human sufferers of childhood adversity.

28Impaired social function is a core feature of many psychiatric illnesses. Adverse experiences during 29 childhood increase risk for mental illness, however it is currently unclear whether stress early in life 30 plays a direct role in the development of social difficulties. Using an animal model of pre-pubertal 31 stress (PPS), we investigated effects on social behaviour, oxytocin and arginine vasopressin (AVP). We 32 also explored social performance and AVP expression in participants with borderline personality 33 disorder (BPD) who experienced a high incidence of childhood stress. Social behaviour was impaired 34 and AVP expression increased in animals experiencing PPS and participants with BPD. Behavioural 35 deficits in animals were rescued through administration of the AVP receptor 1a antagonist 36 Relcovaptan (SR49059). AVP levels and recognition of negative emotions were significantly correlated 37 in BPD participants only. In conclusion, early life stress plays a profound role in the precipitation of 38 social dysfunction, and AVP mediates at least part of this effect. 39 40