Behavioral deficits, abnormal corticosterone, and reduced prefrontal metabolites of adolescent rats subject to early life stress
Introduction
Major depressive disorder is a debilitating mental illness and worldwide leading cause of disability [31]. Environmental risk factors, especially early life stress, appear to play a pivotal role in the pathophysiology of major depression [12]. Therefore, investigating the neurobiological mechanisms of early life stress is essential for a better understanding of major depression, and perhaps other stress-related psychiatric disorders [12]. Clinical studies have associated history of child abuse with abnormal neuroendocrine responses and increased risk of major depression [11]. Moreover, the prefrontal cortex and the hippocampus, two brain regions implicated in stress response, were found to have reduced volume in adults exposed to early life stress [3], [35]. Consistent with these human findings, preclinical evidence from both rodents and nonhuman primates showed behavioral deficits with long-term neurobiological alterations induced by early life stress [7], [22]. Thus, early life stress in animals provides a unique model for investigating the neurodevelopmental mechanisms of major depression.
Adolescence is a vital phase of development demonstrating high neuroplasticity and sensitivity to early adverse events [21]. Several neuropsychiatric disorders, including major depression, may first present during adolescence [1], [25]. Yet, the effects of early adversities have not been extensively studied in adolescent animals. A study by Ichise et al. reported abnormalities in the serotoninergic system of peer-reared non-human primates adolescents [15]. However, the developmental effects of early stress on the glutamatergic system are not well understood.
The aim of the current study was to examine whether early life stress will induce depressive-like behavior and alter the glutamatergic system in adolescent rats. For this purpose, we used proton magnetic resonance spectroscopy (1H MRS) to quantify the level of glutamate and other brain metabolites in the prefrontal cortex. The prefrontal cortex was selected as the brain region of interest given its crucial role in emotional regulation and stress response [17]. Metabolites measured by 1H MRS included: glutamate, glutamine, N-acetylaspartate (NAA), choline compounds (Cho), myo-inositol, and creatine (Cr). For detailed description of the physiologic function of these metabolites please see the recent review by Maddock and Buonocore [20]. Briefly, glutamate and glutamine are an amino acid neurotransmitter and its derivative, respectively. Their levels may reflect local neuronal activity. NAA, the most abundant neuronal amino acid, is commonly used as a marker of neuronal integrity. Cho increases have been interpreted to reflect increased cell membrane turnover, and myo-inositol was associated with astroglial metabolism. Cr increases have been associated with increased myelination, however, Cr tends to be stable in the absence of major pathology [20]. Prior 1H MRS studies in neonatal [19] and adult [13], [14] animals exposed to early life stress have reported altered levels of glutamate, NAA, Cho, and myo-inositol. The current study extends prior evidence to investigate the developmental effect of early life stress on prefrontal metabolites in adolescent rats.
Section snippets
Animals
Parental Sprague-Dawley rats were purchased from Animal Center of Shantou University Medical College and mated (one male with two females) in Shantou University Mental Health Center animal facility two weeks after their arrival. A total of 32 rats were studied. The early life stress group had 8 males and 8 females. Similarly, the control group had 8 males and 8 females. All animals were housed in a temperature (22 ± 1 °C) and humidity (55 ± 4%) controlled room on a 12-h light/dark cycle (lights on
Sucrose preference test
Two-way ANOVA revealed a significant group effect [F(1,28) = 36.2, p < 0.001] and sex effect [F(1,28) = 4.9, p = 0.04], but no group-by-sex interaction (p = 0.30). Post hoc comparisons indicated that early life stress reduced sucrose preference in females [control mean ± S.E. = 90 ± 3 to stress mean ± S.E. = 64 ± 4, F(1,28) = 12.3, p = 0.002] and males [control mean ± S.E. = 83 ± 6 to stress mean ± S.E. = 46 ± 8, F(1,28) = 25.0, p < 0.00] (Fig. S2-A).
Forced swimming test
Two-way ANOVA revealed a significant group effect [F(1,28) = 40.1, p < 0.001], but no sex
Discussion
In this study, adolescent rats exposed to early life stress showed reduced glutamate, glutamine, and NAA levels in the prefrontal cortex. Myo-inositol, a putative marker of astroglial function [2], was numerically reduced yet not statistically significant (p = 0.09). The effect of early stress on glutamate was limited to females. Early life stress animals showed depressive-like behavior and increased serum corticosterone during adolescence. Of interest, in the stress group we found a negative
Conflicts of interest
The authors report no biomedical financial interests or potential conflicts of interest.
Contributors
Renhua Wu, Yaowen Chen and Jie Zhang designed the study and wrote the first draft of the paper. Yaowen Chen, Tianhua Huang, Jie Zhang, and Chadi G. Abdallah conceptualized the MRS study and contributed to the interpretation of the data. Qingjun Huang, Chongtao Xu, Jie Zhang, Yeyu Xiao, Yan Ding, and Yuzhen Liu, performed animal behavior test and serum corticosterone determination. All authors contributed to and have approved the final manuscript.
Acknowledgements
The works were supported by grant 20930027 from the Major Program of National Natural Science Foundation of China, and grant 60971075 from National Natural Science Foundation of China. NIDA T32-DA022975 and the Clinical Neurosciences Division of the National Center for Posttraumatic Stress Disorder provided salary support to Chadi G. Abdallah. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to
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