Chronic Unpredictable Stress Before Pregnancy Reduce the Expression of Brain-Derived Neurotrophic Factor and N-Methyl-D-Aspartate Receptor in Hippocampus of Offspring Rats Associated with Impairment of Memory

Abstract

To investigate the effect of stress before pregnancy on memory function and serum corticosterone (COR) levels, as well as the expression of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate (NMDA) 2A (NR2A) and 2B (NR2B) receptors in the hippocampus of the offspring rats when they were 2 months postnatally. Adult female Sprague-Dawley (SD) rats were divided randomly into two groups: control group (n = 8) and chronic unpredictable stress (CUS) group (n = 12). All rats were tested in the open field test and sucrose intake test before and after CUS. The memory function of their offspring were tested in the Morris water maze. Serum COR levels were determined by using a standard radioimmunoassay kit. The expression of BDNF, NR2A and NR2B in the hippocampus of the offspring rats were studied by immunoreactivity quantitative analysis and real-time RT-PCR. (1) Following CUS, reduced open field test activity and decreased sucrose consumption were observed relative to controls. (2) The Morris water maze task demonstrated increased escape latency in the offspring rats of CUS group relative to controls (P < 0.01). No-platform probe testing showed reduced crossings for offspring of CUS relative to controls (P < 0.05). (3) CUS induced a significant increase in serum COR levels of the offspring rats (P < 0.01), but no difference was observed in the body or brain weight between the offspring of the two groups. (4) Immunoreactivity quantitative analysis shows that BDNF and NR2B in the offspring of CUS group was decreased in the CA3 and DG regions of the hippocampus compared to the control group offspring, but NR2A levels were not altered between the offspring of the two groups. (5) Real-time RT-PCR demonstrated that BDNF and NR2B mRNAs were significantly decreased in the offspring of the CUS group compared with the control group (P < 0.01). No significant difference in the levels of NR2A mRNA was detected between offspring of CUS and offspring of control groups. In our study, pregestational stress can increase serum corticosterone levels and reduce the expression of BDNF and NR2B in the hippocampus of offspring. These alterations are associated with impairment of memory in the adult offspring. These data suggest that, stress before pregnancy might have a profound influence on brain development of offspring, that may persist into and be manifested in adulthood.

Altered emotionality, hippocampus-dependent performance and expression of NMDA receptor subunit mRNAs in chronically stressed mice

“…A limitation of our study, however, is the need for confirmation that the mRNA changes result in corresponding changes in subunit protein levels and in altered synaptic function in the hippocampus. In agreement with our data, separate studies have reported that molecular changes such as we found are associated with a disruption of long-term memory, but not short-term learning (Calabrese et al, 2012;Cui et al, 2013;Huang et al, 2010). In the present experiment, mRNA expression of NR2B and the NR1 in the hippocampus was not significantly changed by stress (Figure 3).…”

“…This study revealed stress-induced increases in the hippocampal expression of NR2A and the NR2A/NR2B ratio ( Figure 3A, C), which were previously shown to accompany elevated anxiety (Boyce-Rustay & Holmes, 2006;Calabrese et al, 2012;Gao et al, 2010), impulsivity and aggression (Bortolato et al, 2012;Meyer et al, 2004), home cage hyperactivity and a stress-induced increase in peripheral concentrations of corticosterone (Huang et al, 2010;Longordo et al, 2009) in various conditions. A limitation of our study, however, is the need for confirmation that the mRNA changes result in corresponding changes in subunit protein levels and in altered synaptic function in the hippocampus.…”

“…In the present experiment, mRNA expression of NR2B and the NR1 in the hippocampus was not significantly changed by stress (Figure 3). However, previous work has reported a significant decrease in NR2B expression in several brain areas during stress (Cull-Candy et al, 2001;Huang et al, 2010), aging (Dere et al, 2003) and compromised plasticity (Bortolato et al, 2012). Previous work has also reported a decrease in NR1 mRNA after stress (Cull-Candy et al, 2001;Schenberg et al, 2006).…”

Mechanisms of Neuroprotection from Hypoxia-Ischemia (HI) Brain Injury by Up-regulation of Cytoglobin (CYGB) in a Neonatal Rat Model

“…Morris Water Maze Test-Spatial learning and memory abilities were evaluated using the MWM test with P28 -P33 rats (n ϭ 8) (36). A circular pool (160-cm diameter ϫ 50-cm high) divided into four quadrants was filled with water (22 Ϯ 1°C), and a 12 ϫ 12-cm platform was positioned 1 cm below the water surface in the center of one of the quadrants.…”

Genetic regulatory network analysis reveals that low density lipoprotein receptor-related protein 11 is involved in stress responses in mice

“…In our experiment we modified the protocol of CUS according to Katz et al (1981) and Willner (1997); (Huang et al, 2010;Willner, 1992). The CUS protocol lasted 4 weeks and consisted of 10 different stressors.…”