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Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory.

ABSTRACT: Stringent glucose demands render the brain susceptible to disturbances in the supply of this main source of energy, and chronic stress may constitute such a disruption. However, whether stress-associated cognitive impairments may arise from disturbed glucose regulation remains unclear. Here we show that chronic social defeat (CSD) stress in adult male mice induces hyperglycemia and directly affects spatial memory performance. Stressed mice developed hyperglycemia and impaired glucose metabolism peripherally as well as in the brain (demonstrated by PET and induced metabolic bioluminescence imaging), which was accompanied by hippocampus-related spatial memory impairments. Importantly, the cognitive and metabolic phenotype pertained to a subset of stressed mice and could be linked to early hyperglycemia 2 days post-CSD. Based on this criterion, ?40% of the stressed mice had a high-glucose (glucose >150 mg/dL), stress-susceptible phenotype. The relevance of this biomarker emerges from the effects of the glucose-lowering sodium glucose cotransporter 2 inhibitor empagliflozin, because upon dietary treatment, mice identified as having high glucose demonstrated restored spatial memory and normalized glucose metabolism. Conversely, reducing glucose levels by empagliflozin in mice that did not display stress-induced hyperglycemia (resilient mice) impaired their default-intact spatial memory performance. We conclude that hyperglycemia developing early after chronic stress threatens long-term glucose homeostasis and causes spatial memory dysfunction. Our findings may explain the comorbidity between stress-related and metabolic disorders, such as depression and diabetes, and suggest that cognitive impairments in both types of disorders could originate from excessive cerebral glucose accumulation.

SUBMITTER: van der Kooij MA

PROVIDER: S-EPMC6205456 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory.

van der Kooij Michael A MA Jene Tanja T Treccani Giulia G Miederer Isabelle I Hasch Annika A Voelxen Nadine N Walenta Stefan S Müller Marianne B MB

Proceedings of the National Academy of Sciences of the United States of America 20181009 43

Stringent glucose demands render the brain susceptible to disturbances in the supply of this main source of energy, and chronic stress may constitute such a disruption. However, whether stress-associated cognitive impairments may arise from disturbed glucose regulation remains unclear. Here we show that chronic social defeat (CSD) stress in adult male mice induces hyperglycemia and directly affects spatial memory performance. Stressed mice developed hyperglycemia and impaired glucose metabolism ...[more]

PMID: 30301805

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Project description:Chronic stress is a key risk factor for a variety of diseases, but the determinants of individual stress susceptibility are still unclear. Using a recently developed paradigm for chronic social stress in mice we identified animals that were resistant or susceptible to the persistent effects of chronic stress exposure. Gene expression analysis in laser-microdissected hippocampal subfields of both groups revealed differentially regulated AMPA receptor subunits, which might affect the susceptibility of an individual to chronic social stress. To test this hypothesis, animals were treated with the AMPA receptor potentiator LY451646 or vehicle during the last 4 weeks of chronic stress exposure. Enhanced AMPA receptor function in chronically stressed animals ameliorated the lasting effects of the chronic stress exposure on physiological, neuroendocrine and behavioural parameters. Our data suggest that differences in AMPA receptor function may underlie individual stress susceptibility and support AMPA receptor potentiators as potential medication in stress-related diseases. Keywords: phenotype, chronic stress, AMPA We have subjected 120 individuals to the chronic social stress procedure, which was recently shown to result in robust effects on neuroendocrine and behavioural parameters (Sterlemann V, 2008). Following the stress procedure all animals were single housed for 7 days. Corticosterone secretion was significantly increased in the chronic stress group compared to controls after one week of single housing. Within the chronic stress group we observed a large variation, where some individuals had recovered from the stress procedure, while others still showed a largely increased corticosterone secretion. After 4 more weeks of single housing, the difference in basal corticosterone secretion between the animals susceptible to chronic stress and unsusceptible or control subjects was still evident. From the group extremes in the chronically stressed animals we selected the 6 most-affected and the 6 most resistant individuals. To investigate the mechanisms underlying the observed differences in individual stress susceptibility between these mice we laser dissected the CA1 and the dentate gyrus region of the hippocampus in the selected mice and performed a gene expression profiling analysis. Pooled amplified RNA samples were then hybridised on Illumina mouse BeadChips (N=4 per group) and detected in the Illumina BeadArray Reader (Illumina, Inc., San Diego, CA).

Dataset Information

Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory.

Publications

Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory.

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