Early Life Stress Increases Brain Glutamate and Induces Neurobehavioral Manifestations in Rats

Abstract

Background: Early life stress (ELS) is associated with an increased risk of developing depression and anxiety disorders. Disturbances of the neurobiological glutamatergic system are implicated in depression; however, the long-term effects of early life stress on glutamate (Glu) metabolites remain unclear. Our study used 7T proton magnetic resonance spectroscopy (7T 1 HMRS) to detect metabolic Glu in a rat model to investigate maternal deprivation (MD)-induced ELS. Methods: MD was established in Sprague-Dawley rats by periodic separation from mothers and peers. Changes in the hippocampal volume and Glu metabolism were detected by 7T 1 HMRS after testing for depression-like behavior via open field, sucrose preference, and Morris water maze tests. Findings: Adult MD offspring exhibited depression-like behavior. Compared to control, the MD group exhibited reduced ratio of central activity time to total time and decreased sucrose consumption (18 ± 6 g vs. 31 ± 12 g, p = 0·02). MD rats spent less time in the fourth quadrant, where the platform was originally placed, in the Morris water maze test. According to 7T 1 HMRS, MD rats had elevated Glu and glutamate+glutamine (Glu+Gln) levels compared with the control group hippocampi, but Gln and gamma-aminobutyric acid (GABA), glutamate+glutamine (Glu+Gln) in the prefrontal cortex of MD rats showed a downward trend. Interpretation: Depression-like behavior and cognition deficits related to ELS may induce region-specific changes in Glu metabolism in the prefrontal cortex and hippocampus. The novel, noninvasive 7T 1 HMRS-identified associations between Glu levels and ELS may guide future clinical studies. Funding Statement: The Key Program of the National Natural Science Foundation of China, No. 30930027; Program of the National Natural Science Foundation of China, No. 60971075; Natural Science Foundation of Guangdong Province of China, Nos.S2011010005194 and 2015A030313444; Shantou University Scientific Research Foundation for the Doctoral Scholar of China, No.NTF10010; The Department of Education, Guangdong Government under the Top-tier University Development Scheme for Research and Control of Infectious Diseases of China, No. 2015034. Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics Approval Statement: All procedures used in the study were reviewed and approved by the Ethics Committee of School of Medicine, Shantou University Medical College, and comply with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals (NIH publication no. 85-23, revised 1985). In the handling and care of all animals, we followed the international guiding principles for animal research, as stipulated by the World Health Organization (WHO) Chronicle (World Health Organization, 1985), as adopted by the Laboratory Animal Center, Shantou University Medical College.