Post-stress expression of genes involved in neuroplasticity in the hippocampus and blood of rats with different level of nervous system excitability

Abstract

The causes and mechanisms of most mental disorders remain unclear. While stress is known to trigger depressive and anxiety disorders, the role of genetically determined individual differences in forming vulnerability to post-stress neurochemical disorders, including those that affect neuroplasticity, remains unresolved.

Early studies suggest that acute and chronic stress lead to elevated glucocorticoid levels in the bloodstream and alter the expression of glucocorticoid and mineralocorticoid receptors. Additionally, both forms of stress can decrease the levels of brain-derived neurotrophic factor (BDNF), which plays a role in neuronal growth, development, and synapse building [1]. However, current studies insufficiently explain the complete mechanism of the stress response as they only explore variations in post-stress alteration of gene expression for proteins related to differing nervous system functional characteristics.

The strains of rats from the Biocollection of the Pavlov Institute of Physiology, RAS, are a convenient model for studying the impact of genetically determined nervous system features on stress reactivity. The strains, selected based on the threshold of nervous system excitability [2], include HT (high threshold of excitability, low excitability) and LT (low threshold of excitability, high excitability) strains. These strains display contrasting responses to extended emotional and painful stress and exhibit unique changes in brain structures implicated in emotional regulation and stress reactivity at the molecular, cellular, and epigenetic levels [2].

The aim of this study is to examine the mRNA levels of genes encoding glucocorticoid and mineralocorticoid receptors (NR3C1, NR3C2) and brain-derived neurotrophic factor (BDNF) in the hippocampus and blood of rat strains that exhibit contrasting nervous system excitability. The study investigates interstrain variations in animals under non-stressful conditions and changes in response to prolonged exposure to emotional and painful stimuli.

The experiment utilized 96 animals, with 6 animals in both the control and experimental groups at each time point. The stress model utilized was long-term emotional and painful stress as per K. Gecht [2]. The study assessed the expression of genes for glucocorticoid receptors and neurotrophic factor by isolating RNA from the hippocampus and blood of rats of two strains decapitated at 1, 7, 24, and 60 days post-stress. Gene expression analysis was conducted through real-time PCR and underwent further data processing using the ΔΔCt method. The statistical tests employed included the Kruskal–Wallis and Mann–Whitney tests.

The analysis of the expression of the observed genes in intact animals demonstrates that highly excitable LT rats have a significantly lower level of expression of the nr3c2 gene, which encodes the mineralocorticoid receptor in the hippocampus, when compared to the low excitable HT strain. When studying the short-term and long-term effects of stress on the expression of the observed genes (nr3c1, nr3c2, bdnf), a decline was observed in the level of bdnf mRNA in the hippocampus of the LT strain 60 days after stress.

The study suggests that the genetically determined characteristics of highly excitable animals affect the weakened adaptive abilities of their nervous system. One of the markers of this weakening is the reduced level of mRNA for the nr3c2 gene in the hippocampus under normal conditions, as well as a decrease in the expression of the bdnf gene in response to stress.

Keywords

neuroplasticity / stress / nervous system excitability / NR3C1 / NR3C2 / BDNF / rats

References

[1] Murakami S, Imbe H, Morikawa Y, et al. Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neuroscience Research. 2005;53(2):129–139. doi: 10.1016/j.neures.2005.06.008

[2] Murakami S., Imbe H., Morikawa Y., et al. Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly // Neuroscience Research. 2005. Vol. 53, N 2. P. 129–139. doi: 10.1016/j.neures.2005.06.008

[3] Vaido A, Shiryaeva N, Pavlova M, et al. Selected rat strains HT, LT as a model for the study of dysadaptation states dependent on the level of excitability of the nervous system. Laboratory Animals for Science. 2018;(3). doi: 10/29926/2618723X-2018-03-02

[4] Вайдо А.И., Ширяева Н.В., Павлова М.Б. Селектированные линии крыс с высоким и низким порогом возбудимости: модель для изучения дезадаптивных состояний, зависимых от уровня возбудимости нервной системы // Лабораторные животные для научных исследований. 2018. № 3. doi: 10/29926/2618723X-2018-03-02

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