Prenatal stress induces vulnerability to stress together with the disruption of central serotonin neurons in mice

A growing body of evidence suggests that prenatal stress increases the vulnerability to neuropsychiatric disorders. On the other hand, the ability to adapt to stress is an important defensive function of a living body, and disturbance of this stress adaptability may be related, at least in part, to the pathophysiology of stress-related psychiatric disorders. The aim of the present study was to clarify the relationship between exposure to prenatal stress and the ability to adapt to stress in mice. Naive and prenatally stressed mice were exposed to repeated restraint stress for 60. min/day for 7 days. After the final exposure to restraint stress, the emotionality of mice was evaluated in terms of exploratory activity, i.e., total distance moved as well as the number and duration of rearing and head-dipping behaviors, using an automatic hole-board apparatus. A single exposure to restraint stress for 60. min induced a decrease in head-dipping behavior in the hole-board test. This acute emotional stress response disappeared in naive mice that had been exposed to repeated restraint stress for 60. min/day for 7 days, which confirmed the development of stress adaptation. In contrast, prenatally stressed mice did not develop this stress adaptation, and still showed a decrease in head-dipping behavior after the repeated exposure to restraint stress. Biochemical studies showed that the rate-limiting enzyme in 5-HT synthesis, tryptophan hydroxylase, was increased in raphe obtained from stress-adapted mice. In contrast, a decrease in tryptophan hydroxylase was observed in stress-maladaptive mice. In addition, the transcription factor Lmx1b, which is essential for differentiation and the maintenance of normal functions in central 5-HT neurons, was decreased in the embryonic hindbrain and adult raphe of prenatally stressed mice. These findings suggest that exposure to excessive prenatal stress may induce a vulnerability to stress and disrupt the development of 5-HT neurons.