Impact of intrauterine hypoxia on adolescent and adult cognitive function in rat offspring: sexual differences and the effects of spermidine intervention.

Intrauterine hypoxia (IUH) affects the growth and development of offspring. It remains unclear that how long the impact of IUH on cognitive function lasts and whether sexual differences exist. Spermidine (SPD) has shown to improve cognition, but its effect on the cognitive function of IUH offspring remains unknown. In the present study we investigated the influence of IUH on body weight and neurological, motor and cognitive function and the expression of APP, BACE1 and Tau5 proteins in brain tissues in 2- and 4-month-old IUH rat offspring, as well as the effects of SPD intervention on these parameters. IUH rat model was established by treating pregnant rats with intermittent hypoxia on gestational days 15-21, meanwhile pregnant rats were administered SPD (5 mg·kg·d;ip) for 7 days. Neurological deficits were assessed in the Longa scoring test; motor and cognitive functions were evaluated in coat hanger test and active avoidance test, respectively. We found that IUH decreased the body weight of rats in both sexes but merely impaired motor and cognitive function in female rats without changing neurological function in the rat offspring of either sex at 2 months of age. For 4-month-old offspring, IUH decreased body weight in males and impaired neurological function and increased cognitive function in both sexes. IUH did not affect APP, BACE1 or Tau5 protein expression in either the hippocampus or cortex of all offspring; however, it increased the cortical Tau5 level in 2-month-old female offspring. Surprisingly, SPD intervention prevented weight loss. SPD intervention reversed the motor and cognitive decline caused by IUH in 2-month-old female rat offspring. Taken together, IUH-induced cognitive decline in rat offspring is sex-dependent during puberty and can be recovered in adult rats. SPD intervention improves IUH-induced cognitive and neural function decline.