Abstract
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.
Highlights
Childhood adversity has repeatedly been identified as a risk factor for mental and physical illness[1]
Summary The present study demonstrates that pre-pubertal stress (PPS) has a profound effect on the structure and function of the adult male hippocampus
We found that PPS decreased production but enhanced survival of newborn neurons in the ventral dentate gyrus, and impaired pattern separation and trace fear conditioning—behaviours that depend on neurogenesis
Summary
Childhood adversity has repeatedly been identified as a risk factor for mental and physical illness[1]. Stressful experiences activate the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the release of corticosteroid hormones These hormones traverse the blood–brain barrier, providing a pathway through which stress can alter brain development and leave individuals susceptible to a range of psychiatric disorders later in life. Stress in utero can lead to impaired hippocampal synaptic plasticity, and stress in the first 2–3 weeks of life reduces adult hippocampal neurogenesis (AHN) in the dentate gyrus and brain-derived neurotrophic factor expression[11,12,13]. Studies to date have revealed that pre-pubertal stress (PPS) impairs synaptic plasticity in the dorsal hippocampus, alters the expression of corticosteroid receptors and impairs performance in a hippocampal-dependent contextual fear task in males[15,16,17]
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