Prenatal Hypoxia-Induced Adverse Reaction to Mild Stress is Associated with Depressive-Like Changes in the Glucocorticoid System of Rats

The effects of prenatal hypoxia on neurodevelopment are predominantly associated with impaired maternal glucocorticoid stimulation of the fetus, which is "imprinted" in altered sensitivity of glucocorticoid reception in brain structures of offspring and can affect brain plasticity during lifespan. This study aimed to investigate response of the brain glucocorticoid system to mild stress (MS) in adult rats that survived prenatal severe hypoxia (PSH) on embryonic days 14-16. In response to MS the control (but not PSH) rats demonstrate increased corticosterone levels, a decrease in exploratory activity and increased anxiety. In the raphe nuclei of adult PSH rats the expression of glucocorticoid receptors (GR) is increased without changes in serotonin levels in comparison with the control. MS induces a decrease in GR expression accompanied by up-regulation of tryptophan hydroxylase 2 (tph2) and down-regulation of monoamine oxidase A (maoa) transcription in the raphe nuclei of both control and PSH groups. PSH also causes significant deviations in GR expression and GR-dependent transcription in the hippocampus, the medial prefrontal cortex, but not in the amygdala of rats. However, in response to MS, PSH rats demonstrate mild changes in their activity, while in control animals the MS-induced activity of the glucocorticoid system in these brain structures is similar to intact PSH animals. Impaired activity of the glucocorticoid system in the extrahypothalamic brain structures of PSH rats is accompanied by increase in the hypothalamic corticotropin-releasing hormone (CRH) levels in comparison with the control regardless of MS. Synthesis of proopiomelanocortin (POMC) and release of adrenocorticotropic hormone (ACTH) into the blood are decreased in response to MS in the pituitary of control rats, which demonstrates a negative glucocorticoid feedback mechanism. Meanwhile, in the pituitary of PSH rats reduced POMC levels were found regardless of MS. Thus, prenatal hypoxia causes depression-like patterns in the brain glucocorticoid system with adverse reaction to mild stressors.