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Enhancing cognition after stress with gene therapy - PubMed

  • ️Sun Jan 01 2006

Comparative Study

Enhancing cognition after stress with gene therapy

Andrea Nicholas et al. J Neurosci. 2006.

Abstract

Hippocampal function is essential for the acquisition, consolidation, and retrieval of spatial memory. High circulating levels of glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, have been shown to impair both acquisition and retrieval and can either impair or enhance consolidation, depending on experimental conditions. In contrast, estrogen can enhance spatial memory performance and can block the deleterious effects of GCs on such performance. We therefore constructed a chimeric gene ("ER/GR") containing the hormone-binding domain of the GC receptor and the DNA binding domain of the estrogen receptor; as a result, ER/GR transduces deleterious GC signals into beneficial estrogenic ones. We show here that acute immobilization stress, before acquisition and retrieval phases, increases latencies for male rats in a hidden platform version of the Morris water maze. This impairment is blocked by hippocampal expression of the ER/GR transgene. ER/GR expression also blocks decreases in platform crossings caused by acute stress, either after acquisition or before retrieval. Three days of stress before acquisition produces an estrogen-like enhancement of performance in ER/GR-treated rats. Moreover, ER/GR blocks the suppressive effects of GCs on expression of brain-derived neurotrophic factor (BDNF), a growth factor central to hippocampal-dependent cognition and plasticity, instead producing an estrogenic increase in BDNF expression. Thus, ER/GR expression enhances spatial memory performance and blocks the impairing effects of GCs on such performance.

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Figures

Figure 1.
Figure 1.

Typical expression of the GFP-tagged ER/GR transgene in hippocampus 48 h after infusion. Robust expression was observed for GFP and ER/GR vectors throughout the dentate gyrus of the dorsal hippocampus, with the vast majority in the dorsal blade.

Figure 2.
Figure 2.

Learning curves for GFP- and ER/GR-expressing control rats and rats treated with stress before training, after training, and before retrieval are represented as latency to platform (n = 9–11 per group). There was an overall significant effect of block (p < 0.001) for all groups, with no difference between treatment groups. Mean ± SEM in all figures.

Figure 3.
Figure 3.

Platform crossing number during the immediate (A) and 24 h (B) probe trials of the MWM. A, Crossings for GFP and ER/GR rats stressed before training, after training, or before retrieval (n = 9–11 per group). An overall enhancing effect of ER/GR on performance was observed (p < 0.01). Post hoc analysis revealed a trend toward significance in “Stress before retrieval” groups (p = 0.09). B, An overall impairing effect of stress was observed (p < 0.0001) along with a significant interaction of vector and stress (p < 0.05). GFP rats stressed before retrieval made significantly fewer crossings than control rats (p < 0.05), whereas a similar trend was noted for GFP rats stressed after training (p = 0.05). ER/GR expression rescued the impairments in both treatment groups. Consequently, ER/GR rats made significantly more crossings when stressed after training (p < 0.01) and stressed before retrieval (p < 0.001) relative to GFP rats. A trend toward increased crossings for ER/GR rats was also observed for rats stressed after training (p = 0.09). Two-way ANOVA with post hoc analysis; *p < 0.01, **p < 0.001.

Figure 4.
Figure 4.

Latency to platform during the immediate (A) and 24 h (B) probe trials of the MWM. A, Latency to platform for GFP and ER/GR rats stressed before training, after training, or before retrieval (n = 9–11 per group). No significant group differences were observed. B, GFP rats stressed before retrieval in the 24 h probe trial displayed significantly longer latency to platform relative to all other GFP treatment groups (p < 0.01 relative to all groups). This stress-induced impairment was completely rescued by ER/GR expression (p < 0.001). Two-way ANOVA with post hoc analysis; **p < 0.01.

Figure 5.
Figure 5.

Learning curves (A) and platform crossing number during the immediate probe trial of the MWM for rats stressed for 3 d. A, Learning curves for GFP- and ER/GR-expressing rats exposed to 3 d of rotating stressors are represented as latency to platform (n = 9–11 per group). There was an overall significant effect of block (p < 0.001) for all groups, with no significant difference between treatment groups. B, Platform crossings for GFP and ER/GR rats in response to stress or 17b-estradiol (Est) treatment (n = 6 per group). Stress had no effect on GFP rats but boosted performance in ER/GR rats. Estradiol treatment also significantly boosted performance (p < 0.05). Consequently, stressed ER/GR animals differed from all groups (p < 0.05 in all cases) except estradiol. Two-way ANOVA with post hoc analysis; n.s., not significant. *p < 0.05, **p < 0.01.

Figure 6.
Figure 6.

Effects of ER/GR chimera on BDNF mRNA expression. A, RT-PCR analysis performed on RNA extracted from left and right hippocampi of a control and a stressed rat was run with decreasing volume of cDNA to show linear range of product accumulation. B, Intensity of BDNF bands as a percentage of GFP. After stress, mRNA levels in ER/GR tissues (n = 5) were higher than in GFP tissues (n = 5). One sample analysis with 95% confidence interval; *p < 0.05.

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