Abstract
Prenatal Restraint Stress (PRS) in rats is a validated model of early stress resulting in permanent behavioral and neurobiological outcomes. Although sexual dimorphism in the effects of PRS has been hypothesized for more than 30 years, few studies in this long period have directly addressed the issue. Our group has uncovered a pronounced gender difference in the effects of PRS (stress delivered to the mothers 3 times per day during the last 10 days of pregnancy) on anxiety, spatial learning, and a series of neurobiological parameters classically associated with hippocampus-dependent behaviors. Adult male rats subjected to PRS (“PRS rats”) showed increased anxiety-like behavior in the elevated plus maze (EPM), a reduction in the survival of newborn cells in the dentate gyrus, a reduction in the activity of mGlu1/5 metabotropic glutamate receptors in the ventral hippocampus, and an increase in the levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF in the hippocampus. In contrast, female PRS rats displayed reduced anxiety in the EPM, improved learning in the Morris water maze, an increase in the activity of mGlu1/5 receptors in the ventral and dorsal hippocampus, and no changes in hippocampal neurogenesis or BDNF levels. The direction of the changes in neurogenesis, BDNF levels and mGlu receptor function in PRS animals was not consistent with the behavioral changes, suggesting that PRS perturbs the interdependency of these particular parameters and their relation to hippocampus-dependent behavior. Our data suggest that the epigenetic changes in hippocampal neuroplasticity induced by early environmental challenges are critically sex-dependent and that the behavioral outcome may diverge in males and females.
Highlights
Prenatal Restraint Stress (PRS) in rats is a validated model of early stress with permanent behavioral and neurobiological consequences [1,2]
There is evidence that the hypothalamic-pituitary adrenal (HPA) axis response to stress is greater in female than in male PRS rats [4,11], PRS can switch the female response to stress into a male pattern, reducing the increase in corticosterone secretion induced by stress [7]
Changes in hippocampal brain-derived neurotrophic factor (BDNF) levels and neurogenesis occur during learning and in response to stress, and are intimately associated with the pathophysiology of mood and anxiety disorders [23,24,25,26,27,28,29]. metabotropic glutamate (mGlu) receptors, BDNF levels and neurogenesis are tightly interconnected. mGlu receptors are expressed by neural stem cells, and regulate the proliferation, differentiation, and survival of these cells [30,31]; BDNF is required for basal neurogenesis and mediates the enhancement of neurogenesis in response to exercise, dietary restrictions and psychotropic drugs [32,33,34,35]; and distinct mGlu receptor subtypes regulate BDNF expression and BDNF receptor signaling in brain tissue [36,37,38,39,40]
Summary
Prenatal Restraint Stress (PRS) in rats is a validated model of early stress with permanent behavioral and neurobiological consequences [1,2]. Recent evidence indicates that male rats subjected to PRS (‘‘PRS rats’’) are more prone to developing learning impairments than female PRS rats [4] It is worthy noting, that data on PRS and cognitive impairment are not unequivocal with some authors reporting a reduction in the performance of juvenile and adult PRS male rats in the water maze [5,6], and others reporting no effect of PRS on spatial and working memory [7]. There are two reports of increased anxiety-like behavior in adult female, but not male, PRS rats [6,7]. We examined (i) the expression and activity of metabotropic glutamate (mGlu) receptors; (ii) levels of brain-derived neurotrophic factor (BDNF); and (iii) neurogenesis in the dentate gyrus. Changes in hippocampal BDNF levels and neurogenesis occur during learning and in response to stress, and are intimately associated with the pathophysiology of mood and anxiety disorders [23,24,25,26,27,28,29]. mGlu receptors, BDNF levels and neurogenesis are tightly interconnected. mGlu receptors are expressed by neural stem cells, and regulate the proliferation, differentiation, and survival of these cells [30,31]; BDNF is required for basal neurogenesis and mediates the enhancement of neurogenesis in response to exercise, dietary restrictions and psychotropic drugs [32,33,34,35]; and distinct mGlu receptor subtypes regulate BDNF expression and BDNF receptor signaling in brain tissue [36,37,38,39,40]
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