Abstract
Subchronic gestational stress leads to permanent modifications in the hippocampus-hypothalamus-pituitary-adrenal axis of offspring probably due to the increase in circulating glucocorticoids known to affect prenatal programming. The aim of this study was to investigate whether cell turnover is affected in the hippocampus-hypothalamus-pituitary axis by subchronic prenatal stress and the intracellular mechanisms involved. Restraint stress was performed in pregnant rats during the last week of gestation (45 minutes; 3 times/day). Only male offspring were used for this study and were sacrificed at 6 months of age. In prenatally stressed adults a decrease in markers of cell death and proliferation was observed in the hippocampus, hypothalamus and pituitary. This was associated with an increase in insulin-like growth factor-I mRNA levels, phosphorylation of CREB and calpastatin levels and inhibition of calpain -2 and caspase -8 activation. Levels of the anti-apoptotic protein Bcl-2 were increased and levels of the pro-apoptotic factor p53 were reduced. In conclusion, prenatal restraint stress induces a long-term decrease in cell turnover in the hippocampus-hypothalamus-pituitary axis that might be at least partly mediated by an autocrine-paracrine IGF-I effect. These changes could condition the response of this axis to future physiological and pathophysiological situations.
Highlights
Prenatal restraint stress in rats is a common experimental model of early stress known to have long-term behavioral and neurobiological consequences [1,2,3,4]
Relative levels of cell death were assayed by ELISA and proliferating cell nuclear antigen (PCNA) levels were measured by Western blotting in the hippocampus, hypothalamus and pituitary of control rats and prenatally stressed rats (PS)
We show that prenatal stress decreases proliferation markers in the hypothalamus of adult male rats, in agreement with our previous report [13], and that a similar phenomenon occurs in the hippocampus and pituitary
Summary
Prenatal restraint stress in rats is a common experimental model of early stress known to have long-term behavioral and neurobiological consequences [1,2,3,4]. The duration and/or intensity of the stress, different effects on the central nervous system occur resulting in alterations in neurochemical systems, including activation of neurotransmission of serotonin and norepinephrine, among others [1,10], changes in synaptic organization with atrophy of dendrites in the hippocampus [9] and reduction in the number of hippocampal synapses [11,12], cerebral asymmetry and anomalies in the morphology of the brain [1,13], as well as inhibition of cell death and neurogenesis [12,13,14,15,16] These changes may condition the brain’s response to future physiological and pathophysiological situations
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