Environmental enrichment rescues survival and function of adult-born neurons following early life stress.

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 pre-pubertal 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 PND 35 to early adulthood, when behavioural testing and assessment of AHN took place. PPS enhanced fear reactions to a conditioned stimulus (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.

Sex specific effects of pre-pubertal stress on hippocampal neurogenesis and behaviour.

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.