Altering the fetal programming of the HPA axis and the consequences in the adult auditory system

Sammanfattning: Prenatal glueocorticoid (GC) has been associated with a variety of alterations in the adult offspring. Hypothalamo-Pituitary-Adrenal (HPA) axis, which is the key regulator for almost all kind of neuroendocine function and behavior, is highly susceptible to prenatal exposure to excess GC during development. While GC is necessary for normal activity of HPA axis, prenatal exposure to excess endogenous or exogenous GC can adversely affects the stability of HPA axis. Like any other systems of the body, auditory system also sensitive to prenatal GC induced programming of the HPA axis. The main goal of this thesis is to determine the relationship between the programming effect of the HPA axis and auditory system by prenatal synthetic GC, dexamethasone (DEX) in the final week gestation, and responses to an audiogenic stressor in the adult offspring. DEX in the late gestation was shown to increase the susceptibility of the inner ear to acoustic trauma in the adult offspring. Acute auditory brainstem response thresholds were not different between the age-matched groups. However, when measured at 48h and 4 week postexposure, the DEX treated rats showed little or no recovery from the trauma. In addition, acoustic trauma resulted in a massive outer hair cell loss in the DEX rats compared to minor loss in the normal rats. To determine whether oxidative stress plays a role in the recovery phase of acoustic trauma, the free radical scavenger PBN (100 mg/kg) was administered before, during and several times after noise exposure. PBN treatment significantly reduced the physiological and morphological cochlear differences, which were observed between DEX and control rats after acoustic trauma. Prenatal synthetic GC was also involved in long-term effects on the adult offspring HPA function and persistent behavioral disorders. DEX in the final week of gestation and adult exposure to an acoustic trauma in the offspring was shown to alter the resposiveness of the HPA axis. Stereological quantification of neuronal protein expression (glucocorticoid receptor, GR) in the paraventricular nucleus (PVN) demonstrated gender-related differences in the basal protein expression, as well as its responsiveness to acoustic stress. Acoustic trauma caused a robust responsiveness of GR expression and nuclear translocation in DEX females. Gender-related behavioral difference was also evidenced in the offspring of prenatal DEX treated adults, DEX males exhibited increase level of anxiety in the elevatedplus maze. In conclusion, results from these studies imply that prenatal DEX can modify the developmental programme of the cochlea and gender-related altered regulation of the HPA axis to an acoustic trauma in the adult life. Key words: HPA axis, glucocorticoid receptor, dexamethasone, paraventricular nucleus, cochlea, acoustic trauma.