Prenatal food restriction induces neurobehavioral abnormalities in adult female offspring rats and alters intrauterine programming

Abstract

The higher risk of adult neuropsychiatric diseases in individuals with low fetal birth weight may be related to brain-derived neurotrophic factor (BDNF) signaling pathway inhibition. Here, we investigated whether prenatal food restriction (PFR) induces neurobehavioral alterations in adult female offspring and explored the underlying intrauterine programming mechanism. Pregnant Wistar rats in the PFR group were fed 50% of the daily food intake of control rats from gestational day (GD) 11 to 20; some pregnant rats were sacrificed at GD20, and the remaining female pups had normal delivery and were fed a post-weaning high-fat diet (HFD) and half of them were exposed to an unpredictable chronic stress (UCS) from postnatal week (PW) 21. All adult female offspring were sacrificed at PW24. At GD20, PFR altered fetal hippocampal structure and function, increased glucocorticoid receptor (GR) expression, and decreased mineralocorticoid receptor (MR), BDNF and synaptic plasticity-related gene expressions. At PW24, PFR induced depression-like behavioral abnormalities in adult rat offspring fed an HFD. These rats exhibited depression- and anxiety-like behavioral changes after HFD/UCS. Furthermore, the hippocampal morphology of the PFR group showed abnormal changes in adult offspring fed an HFD and more serious damage after HFD/UCS. These changes were accompanied by increased serum corticosterone levels, elevated GR expression, and reduced expression of the BDNF signaling pathway and synaptic plasticity-related genes in the hippocampus. In conclusion, PFR may induce neurobehavioral abnormalities in adult offspring, especially those exposed to UCS, through high levels of glucocorticoids, which increase hippocampal GR expression and decrease BDNF expression.

Fig. 1. Schematic procedure for animal treatment from gestational day 0 to postnatal week 24.

Fig. 2. Effects of prenatal food restriction (PFR) on the hippocampal morphology in female fetal rats on gestational day 20. A: Morphological changes in the fetal hippocampus, including the whole hippocampus (HE ×100), the pyramidal cells of the cornu ammonis 1 (CA1) and cornu ammonis 3 (CA3) regions and the granule cells of the dentate gyrus (DG) region (HE ×400). B: Ultrastructural changes in the fetal hippocampus (transmission electron microscopy, ×10 000).

Fig. 3. Effects of prenatal food restriction (PFR) on the expression of corticoid receptors, brain-derived neurotrophic factor (BDNF) pathway, synaptic plasticity and cytoskeleton-related genes in female fetal rats. A: Serum CORT levels; B: hippocampal mineralocorticoid receptor (MR), glucocorticoid receptor (GR), cAMP-responsive element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), glutamate receptor, ionotropic, N-methyl d-aspartate 1 (NR1), glutamate receptor, ionotropic, N-methyl d-aspartate 2A (NR2A), synapsin I (Syn1), synaptosomal-associated protein 25 (SNAP25), ras homolog gene family, member A (RhoA), ras-related C3 botulinum toxin substrate 1 (Rac1) mRNA expression. Multigene expression was detected using a GenomeLab GeXP Genetic Analysis System. Mean ± S.E.M., n = 8 pups from 8 pregnant rats. ^*P < 0.05, ^**P < 0.01 vs. the control.

Fig. 4. Effects of prenatal food restriction (PFR) on the body weights and body weight gain rates of female offspring fed a high-fat diet (HFD) without/with unpredictable chronic stress (UCS). A: Body weights in the offspring rats without UCS from gestational day (GD) 20 to postnatal week (PW) 24; B: body weight gain rates in the offspring rats without UCS from PW4 to PW24; C: body weights in offspring rats with UCS from GD20 to PW24; D: body weight gain rates in the offspring rats with UCS from PW4 to PW24. Mean ± S.E.M., n = 8 offspring rats from 8 pregnant rats. ^*P < 0.05, ^**P < 0.01 vs. the control.

Fig. 5. Effects of prenatal food restriction (PFR) on the hippocampal morphology in female adult offspring fed a high-fat diet (HFD) without/with unpredictable chronic stress (UCS). A, B: Hippocampal morphological changes in offspring rats without/with UCS, including the whole hippocampus (HE ×100), the pyramidal cells of the cornu ammonis 1 (CA1) and cornu ammonis 3 (CA3) regions, and the granule cells of the dentate gyrus (DG) region (HE ×400).

Fig. 6. Effects of prenatal food restriction (PFR) on the serum corticosterone (CORT) level and expression of hippocampal functional genes in female adult offspring rats fed a high-fat diet (HFD) with/without unpredictable chronic stress (UCS). A: Serum CORT level; B–J: hippocampal mineralocorticoid receptor (MR), glucocorticoid receptor (GR), cAMP-responsive element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), glutamate receptor, ionotropic, N-methyl d-aspartate 1 (NR1), glutamate receptor, ionotropic, N-methyl d-aspartate 2A (NR2A), synapsin I (Syn1), and synaptosomal-associated protein 25 (SNAP25) mRNA expression. Mean ± S.E.M., n = 8 adult offspring rats from 8 pregnant rats. ^*P < 0.05, ^**P < 0.01 vs. control.

Fig. 7. Proposed intrauterine programming mechanisms for the effect of prenatal food restriction (PFR) on neurobehavioral abnormalities in female adult offspring fed a high-fat diet (HFD) with and without unpredictable chronic stress (UCS). GCs, glucocorticoids; IUGR, intrauterine growth retardation; BDNF, brain-derived neurotrophic factor.