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

TY - JOUR

T1 - Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory

AU - van der Kooij, Michael A

AU - Jene, Tanja

AU - Treccani, Giulia

AU - Miederer, Isabelle

AU - Hasch, Annika

AU - Voelxen, Nadine

AU - Walenta, Stefan

AU - Müller, Marianne B

N1 - Copyright © 2018 the Author(s). Published by PNAS.

PY - 2018/10/23

Y1 - 2018/10/23

N2 - 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 stressassociated 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.

AB - 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 stressassociated 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.

KW - Brain

KW - Chronic social stress

KW - Glucose

KW - Metabolism

KW - Resilience

UR - http://www.scopus.com/inward/record.url?scp=85055596992&partnerID=8YFLogxK

U2 - 10.1073/pnas.1804412115

DO - 10.1073/pnas.1804412115

M3 - Journal article

C2 - 30301805

SN - 0027-8424

VL - 115

SP - E10187-E10196

JO - Proceedings of the National Academy of Sciences (PNAS)

JF - Proceedings of the National Academy of Sciences (PNAS)

IS - 43

ER -