sst2-receptor gene deletion exacerbates chronic stress-induced deficits: Consequences for emotional and cognitive ageing

https://doi.org/10.1016/j.pnpbp.2018.01.022Get rights and content

Highlights

  • UCMS in middle-aged WT and sst2KO mice has short- and long-term effects.

  • sst2 gene deletion produces hypercorticosteronemia and increased stress sensitivity.

  • Emotional deficits in old sst2KO mice are exacerbated by previous exposure to UCMS.

  • Combination of sst2 gene deletion with UCMS induces cognitive deficits in old mice.

  • UCMS-induced hypercorticosteronemia predicts ageing brain functions.

Abstract

This study investigated whether sst2 gene deletion interacts with age and chronic stress exposure to produce exacerbated emotional and cognitive ageing. Middle-aged (10–12 month) sst2 knockout (sst2KO) and wild-type (WT) mice underwent an unpredictable chronic mild stress (UCMS) procedure for 6 weeks or no stress for control groups. This was followed by a battery of tests to assess emotional and cognitive functions and neuroendocrine status (CORT level). A re-evaluation was performed 6 months later (i.e. with 18-month-old mice). UCMS reproduced neuroendocrine and behavioral features of stress-related disorders such as elevated circulating CORT levels, physical deteriorations, increased anxiety- and depressive-like behaviors and working memory impairments. sst2KO mice displayed behavioral alterations which were similar to stressed WT and exhibited exacerbated changes following UCMS exposure. The evaluations performed in the older mice showed significant long-term effects of UCMS exposure. Old sst2KO mice previously exposed to UCMS exhibited spatial learning and memory accuracy impairments and high levels of anxiety-like behaviors which drastically added to the effects of normal ageing. Spatial abilities and emotionality scores (mean z-scores) measured both at the UCMS outcome and 6 months later were correlated with the initially measured CORT levels in middle-age. The present findings indicate that the deletion of the sst2 receptor gene produces chronic hypercorticosteronemia and exacerbates sensitivity to stressors which over time, have consequences on ageing brain function processes.

Introduction

Stress and ageing are among the most widespread challenges facing modern society today. It is now acknowledged that stress exerts serious adverse effects on health which parallel those observed in the elderly, suggesting that the underlying pathophysiology of ageing and stress share common mechanisms (Ding et al., 2015; Prenderville et al., 2015). Studies have linked detrimental effects of both stress and ageing to an increase in the excitatory/inhibitory ratio, which may be attributed to a loss of GABAergic neurons (Fee et al., 2017; Levinson et al., 2010; Rozycka and Liguz-Lecznar, 2017). Unpredictable chronic mild stress (UCMS) is a well-documented animal model that produces depressive-like behaviors that are clinically relevant for studying human depressive symptoms and neurobiological changes in animal models (Willner, 2017). In rodents, UCMS impairs GABAergic functions by affecting the integrity of parvalbumin-expressing neurons and somatostatin (SOM)-expressing cells in critical brain structures including the hippocampus and the frontal cortex (Czeh et al., 2015; Hu et al., 2010). The SOM systems of the hippocampus and cortical areas also appear to be especially more sensitive to ageing than other interneuron subtypes (French et al., 2017; Martel et al., 2012; Rozycka and Liguz-Lecznar, 2017; Stanley et al., 2012).

SOM biosynthesis involves a large precursor molecule that subsequently yields two bioactive peptides, the originally discovered 14 amino acid peptide and the C-terminally extended form with 28 amino acids. SOM systems are widely expressed in the different brain regions and are involved in numerous processes from sensory to cognitive and emotional functions as illustrated by the decrease of SOM concentrations observed in various neurodegenerative diseases (i.e. Alzheimer's disease and Parkinson's disease) as well as neuropsychiatric diseases (i.e. schizophrenia and major depressive disorders), (Epelbaum et al., 2009; Martel et al., 2012). More specifically, SOM contents decrease in the cerebrospinal fluid and down-regulation of SOM expression occurs in the dorsolateral prefrontal cortex (Sibille et al., 2011), the subgenual cingulate cortices (Tripp et al., 2011), and the amygdala (Guilloux et al., 2012) of patients with major depressive disorders. Accordingly, mice lacking SOM exhibit elevated behavioral emotionality, high basal plasma CORT levels and reduced expression of select genes such as BDNF and GAD67, together recapitulating behavioral, neuroendocrine and molecular features of human depression and stress related disorders (Lin and Sibille, 2015).

Five somatostatin receptor subtypes have been identified, known as sst1 to sst5 receptor subtypes. All belong to the G-protein-coupled receptor family and also bind cortistatin, another brain peptide mainly expressed in the hippocampus and cortical areas, with high affinity (Martel et al., 2012; Viollet et al., 2008). All receptor subtypes are present in the brain (Hannon et al., 2002; Martel et al., 2012). The availability of genetically modified animal models (Zeyda and Hochgeschwender, 2008) contributed to a better understanding of individual sst receptor characteristics and their roles in brain functions and disorders including learning and memory deficits, anxiety, depression and stress (Gastambide et al., 2010; Gastambide et al., 2009; Stengel and Tache, 2017; Viollet et al., 2000). Recent data demonstrated that sst4 gene-deleted mice display higher vulnerability to chronic stress-induced behavioral and neuroendocrine alterations (Scheich et al., 2017). Pharmacological evidence confirmed that sst4 activation reduces anxiety- and depression-like behaviors in mouse models, indicating a role for sst4 in emotional reactivity (Scheich et al., 2016). In addition, the sstr4 rs2567608 TT genotype, a functional polymorphism of the gene for the sst4 receptor subtype in humans is associated with alcohol dependency and higher risk of suicide in patients with adverse childhood experiences (Berent et al., 2017). However, sst2 receptor subtype activation also has strong anxiolytic-like effects in both rats and mice (Engin and Treit, 2009; Prevot et al., 2017) whereas sst2 knockout mice display high basal CORT levels, increased release of ACTH and increased emotionality (Prevot et al., 2017; Viollet et al., 2000), suggesting that sst2 receptor subtype dysfunctions can also generate stress-related disorders.

Long lasting effects of chronic stress from early life or adolescence to adulthood is now acknowledged (Danese and McEwen, 2012; Scharf et al., 2013; Sterlemann et al., 2008; Sterlemann et al., 2010), but sufficient attempts to understand the impact of stress on ageing and age-related decline in brain functions have not been made despite a tremendous number of publications using chronic stress models (Prenderville et al., 2015; Willner, 2017). The aim of the present study was to investigate how sst2 gene deletion and UCMS exposure interplay to produce exacerbated emotional and cognitive ageing. Exposure to UCMS was performed in middle-aged sst2 knockout (sst2KO) and wild-type (WT) mice, followed by a battery of tests to assess emotional and cognitive outcomes and neuroendocrine status immediately after UCMS and 6 months later as the mice began to age.

Section snippets

Animals

Sst2 knockout (sst2KO; N = 22) mice, originally generated by (Zheng et al., 1997) and their littermates (WT; N = 23) were obtained by intercrossing heterozygous (±) sst2 mice previously backcrossed to C57Bl/6 background for at least 14 generations. Mice were bred under standard conditions in an animal room (artificial 12 h light/dark cycle from 7:00 AM on, room temperature 22 ± 1 °C) with water and food ad libitum. For the unpredictable chronic mild stress (UCMS) protocol, animals from the same

Immunohistochemistry

First, as illustrated in Fig. 1, sst2 receptors were highly detectable in all deep cortical layers, in the dendritic fields of the dentate gyrus and in the medial habenula (A1), within the amygdalian and hypothalamic networks (A3) as well as in the claustrum, the endopiriform nucleus, the septal areas and the diagonal band nucleus (A5) and labeling vanished in sst2KO mouse brains (A2,4,6) consistent with previous reports (Allen et al., 2003; Gastambide et al., 2010; Videau et al., 2003; Viollet

Discussion

Glucocorticoids are involved in the emergence of cognitive deficits (Dorey et al., 2012; Lupien et al., 1994; Stranahan et al., 2008), decreased neurogenesis (Montaron et al., 2006) and mood disorders (Berardelli et al., 2013; Young, 2004). UCMS in mice is becoming a well-validated paradigm to induce a depression-like syndrome with high face validity for human depression (Mineur et al., 2006). The UCMS protocol used here reproduces neuroendocrine and behavioral features of depression such as

Conclusion

The present findings expand our understanding of somatostatin dysregulations in ageing. Given that sst2 gene deletion leads to an increased emotionality and cognitive deficits exacerbated by chronic stress exposure at short and long time, these results support the notion that acceleration in ageing processes occurs when brain somatostatinergic neurotransmission decreases (Ding et al., 2015). The deletion of the sst2 receptors might thus mimic an extreme chronic stress model (i.e. chronic

Financial disclosures

This work was supported by the Centre National de la Recherche Scientifique (CNRS) and by The University of Bordeaux. TDP was awarded with a PhD fellowship from the Council of the Aquitaine Region. All authors report no financial interests or potential conflicts of interest.

Ethical statement

All experiments were conducted in compliance with EU Directive 2010/63/EU and was approved by the Animal Care and Use Committee of Bordeaux under the number 5012098-A.

Acknowledgements

The authors thank all the personnel of the Animal Facility of the Institute de Neuroscience Cognitive et Integrative d'Aquitaine (INCIA) for their help throughout the study, Nadia Henkous and Axelle Simon for their technical assistance regarding these experiments. We also thank Dr. Corey Fee from the University of Toronto for his helpful corrections and comments on the manuscript.

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