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

Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10187-E10196. doi: 10.1073/pnas.1804412115. Epub 2018 Oct 9.


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.

Keywords: brain; chronic social stress; glucose; metabolism; resilience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Benzhydryl Compounds / pharmacology
  • Brain / metabolism
  • Brain / physiopathology
  • Chronic Disease / drug therapy
  • Chronic Disease / psychology*
  • Glucose / metabolism
  • Glucosides / pharmacology
  • Hyperglycemia / drug therapy
  • Hyperglycemia / metabolism
  • Hyperglycemia / physiopathology*
  • Hyperglycemia / psychology
  • Male
  • Memory Disorders / drug therapy
  • Memory Disorders / metabolism
  • Memory Disorders / physiopathology*
  • Memory Disorders / psychology
  • Mice
  • Mice, Inbred C57BL
  • Social Desirability
  • Spatial Memory / drug effects
  • Spatial Memory / physiology*
  • Stress, Psychological / drug therapy
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology*
  • Stress, Psychological / psychology


  • Benzhydryl Compounds
  • Glucosides
  • empagliflozin
  • Glucose