The identification of metabolic disturbances in the prefrontal cortex of the chronic restraint stress rat model of depression

Behav Brain Res. 2016 May 15;305:148-56. doi: 10.1016/j.bbr.2016.03.005. Epub 2016 Mar 3.


Major depressive disorder, with serious impairment in cognitive and social functioning, is a complex psychiatric disorder characterized by pervasive and persistent low mood and a loss of interest or pleasure. However, the underlying molecular mechanisms of depression remain largely unknown. In this study, we used a non-targeted metabolomics approach based on gas chromatography-mass spectrometry of the prefrontal cortex in chronic restraint stress (CRS)-treated rats. CRS was induced in the stress group by restraining rats in a plastic restrainer for 6h every day. This stress paradigm continued for 21 days. Body weight measurement and behavior tests were applied, including the sucrose preference test for anhedonia, the forced swimming test for despair-like behavior, and open field test and the elevated plus-maze to test for anxiety-like behaviors in rats after CRS. Differentially expressed metabolites associated with CRS-treated rats were identified by combining multivariate and univariate statistical analysis and corrected for multiple testing using the Benjamini-Hochberg procedure. A heat map of differential metabolites was constructed using Matlab. Ingenuity Pathways Analysis was applied to identify the predicted pathways and biological functions relevant to the bio-molecules of interest. Our findings showed that CRS induces depression-like behaviors and not anxiety-like behaviors. Thirty-six metabolites were identified as potential depression biomarkers involved in amino acid metabolism, energy metabolism and lipid metabolism, as well as a disturbance in neurotransmitters. Consequently, this study provides useful insights into the molecular mechanisms of depression.

Keywords: Chronic restraint stress; Depression; Gas chromatography–mass spectrometry; Metabolomics; Rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / physiology
  • Brain Diseases, Metabolic* / diagnosis
  • Brain Diseases, Metabolic* / etiology
  • Brain Diseases, Metabolic* / pathology
  • Depression / complications*
  • Depression / etiology
  • Disease Models, Animal
  • Exploratory Behavior / physiology
  • Food Preferences
  • Gas Chromatography-Mass Spectrometry
  • Locomotion / physiology
  • Male
  • Metabolic Networks and Pathways / physiology
  • Prefrontal Cortex / metabolism*
  • Principal Component Analysis
  • Rats
  • Rats, Sprague-Dawley
  • Restraint, Physical / adverse effects*
  • Sucrose / administration & dosage
  • Swimming / psychology
  • Time Factors


  • Sucrose