Chronic restraint stress induces hippocampal memory deficits by impairing insulin signaling

Hanwoong Woo,Seongwon Choe,Caroline Jeeyeon Hong,Seong-Woon Yu,Seonghee Jung

doi:10.1186/s13041-018-0381-8

Hanwoong Woo, Seongwon Choe + Show 3 more

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https://doi.org/10.1186/s13041-018-0381-8

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Abstract

Chronic stress is a psychologically significant factor that impairs learning and memory in the hippocampus. Insulin signaling is important for the development and cognitive function of the hippocampus. However, the relation between chronic stress and insulin signaling at the molecular level is poorly understood. Here, we show that chronic stress impairs insulin signaling in vitro and in vivo, and thereby induces deficits in hippocampal spatial working memory and neurobehavior. Corticosterone treatment of mouse hippocampal neurons in vitro caused neurotoxicity with an increase in the markers of autophagy but not apoptosis. Corticosterone treatment impaired insulin signaling from early time points. As an in vivo model of stress, mice were subjected to chronic restraint stress. The chronic restraint stress group showed downregulated insulin signaling and suffered deficits in spatial working memory and nesting behavior. Intranasal insulin delivery restored insulin signaling and rescued hippocampal deficits. Our data suggest that psychological stress impairs insulin signaling and results in hippocampal deficits, and these effects can be prevented by intranasal insulin delivery.

Highlights

Stress affects various parts of our body and causes diverse physiological changes, which are manifested in symptoms such as headache, stomachache, heartburn, fatigue, overeating, or undereating
An increase in Microtubule-associated protein light chain 3 (LC3)-II level is typically regarded as an indicator of increased autophagy flux, impaired autophagy flux and blockage of autophagic degradation can result in LC3-II accumulation level, because LC3-II itself is degraded by autophagy
CORT impairs insulin signaling in mouse hippocampal neurons in vitro we examined whether CORT affects insulin signaling, since insulin signaling is closely related to autophagy and is important for hippocampal development and function, and for survival of hippocampal neural stem cells and neurons [47, 48, 60]

Summary

Introduction

Stress affects various parts of our body and causes diverse physiological changes, which are manifested in symptoms such as headache, stomachache, heartburn, fatigue, overeating, or undereating. Severe and long-lasting adverse effects induced by stress include insomnia, anxiety, depression, or post-traumatic stress disorder [1, 2]. These physiological outcomes of psychological stress are mainly caused by stress hormones [2]. CRH induces anterior pituitary to release adrenocorticotrophic hormone (ACTH). ACTH affects the adrenal cortex and increases synthesis and release of corticosteroids. Corticosteroids include glucocorticoids, which regulate glucose metabolism, and mineralocorticoids, which regulate water balance and blood pressure.

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