Effect of prenatal stress exposure on cognitive function in later life in rats
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Prenatal stress exposure (PNS) has detrimental effects on the offspring’s brain and behaviour and has been identified as an etiological factor in inducing cognitive function deficits in rodents and humans. The neural mechanisms are unclear, however reprogramming of the neuroendocrine stress axis, the hypothalamo-pituitary- adrenal (HPA) axis is hypothesised. A psychosocial stressor (residentintruder paradigm) was used to generate PNS rat offspring, making these studies clinically compatible. The hippocampus and the medial prefrontal cortex (mPFC) are critical in regulating cognitive function and also contribute to the negative feedback control of the HPA axis via corticosteroid receptors, including the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Here the Barnes maze was used to assess spatial learning and memory in male and female PNS offspring during adulthood under different scenarios, including basal and acute and chronic stress conditions. Under basal conditions, PNS was associated with reduced GR and MR mRNA expression in the medial prefrontal cortex (mPFC) and the hippocampus, respectively; suggesting inhibitory feedback control of the HPA axis may be compromised in PNS rats. Moreover, impaired spatial learning was observed in male PNS rats following acute restraint stress. Bilateral lesions of the prelimbic cortex and central administration of an MR antagonist in control rats suggested acute stress-induced learning deficits in PNS males were a result of impaired hippocampus-mediated inhibitory feedback control of the HPA axis. Conversely, a one-week variable stress regimen facilitated spatial learning in PNS rats and this was associated with elevated MR mRNA expression in the dentate gyrus. Moreover, facilitated learning in the PNS rats exposed to chronic stress could be blocked by central administration of an MR antagonist, indicating a facilitatory role of hippocampal MR in spatial learning. In summary, opposite effects of PNS on spatial learning were observed under acute and chronic stress conditions, in which hippocampal MR played a key role in regulating behavioural performance. The effect of age was also examined in PNS rats, and the findings from middle-aged (10-11 months old) rats indicated PNS may accelerate cognitive decline. Sex differences were also studied, with control females’ out-performing males under basal conditions in terms of spatial learning and behavioural flexibility; however following prenatal or chronic stress these sex differences were no longer detected. Furthermore, acute stress impaired spatial learning to a greater extent in females, and this might be attributed to greater HPA axis responses to stress in females compared with males. In conclusion, prenatal stress alters later cognitive performance, in a sex- and stress context-dependent manner. Hippocampal MR plays a critical role in mediating spatial learning, particularly during stress conditions.