Research reportThe identification of metabolic disturbances in the prefrontal cortex of the chronic restraint stress rat model of depression
Introduction
Major depressive disorder, with a lifetime prevalence of up to 16% [1], is a complex psychiatric disorder characterized by pervasive and persistent low mood that is accompanied by a loss of interest or pleasure, feelings of guilt or low self-worth, and disturbed sleep and/or appetite [2]. According to the World Health Organization, depression is predicted to be the leading cause of disease burden by 2030 [3]. Persistent symptoms of depression are associated with impairments in cognitive and social functioning, which has considerable impact on individuals, their partners and families, and wider society. Depression often co-occurs with other psychiatric disorders, such as anxiety [4], attention-deficit hyperactivity disorder [5], substance abuse disorders [6], and other physical and mental health problems. Despite the abundance of published research into this disease, the underlying molecular mechanisms of depression remain largely unknown.
Chronic stress plays an important role in the development of depression. Pre-clinical and clinical studies suggest that repeated stress (e.g. 21 days of chronic restraint stress; CRS) causes functional and structural changes in certain brain regions such as the prefrontal cortex (PFC) [7]. The PFC is associated with emotion regulation, cognition, and learning [8]. There is an abundance of neuroscientific evidence from functional imaging, lesioning, and brain stimulation studies that has implicated the PFC in depression [9]. For example, data from neuroimaging indicated that decreased activity and gray matter volume in the subgenual region of the PFC is an important change in the pathology of depression [10], [11]. In particular, dysfunction in the PFC’s glutamatergic neurotransmission has been implicated in the pathophysiology of depression [12], [13].
Chronic stress, including chronic mild stress (CMS) and CRS, is the most important and widely used animal model of depression [14]. However, the CMS model has been criticized for being difficult to replicate across laboratories [15], and for the high operating costs associated with the long period required for modeling. In contrast, CRS – in which rats are usually placed in a small body-sized device for several hours a day during a long period – has been widely used in stress-induced depressive-like behavior studies, primarily because this stress treatment procedure is readily accessible [16]. Only those animals that are particularly vulnerable – that is, show high sensitivity to chronic stress – develop pathologies [17]. As a result, the subgroup of rats with depressive-like behaviors after CRS can be used for investigating the pathophysiology of depression.
The recently developed “Omics” have been used in the discovery of biomarkers in severe diseases. Following on from genomics [18], transcriptomics [19], and proteomics [20], metabolomics, which can profile the small molecules within biological systems in given biosamples without bias, has become a powerful tool in elucidating the biomarkers and key pathways involved in many diseases [21], [22], [23]. Metabolic profiling techniques, such as nuclear magnetic resonance (NMR) [24], liquid chromatography–mass spectrometry (LC–MS) [25], and gas chromatography–mass spectrometry (GC–MS) coupled with multivariate statistical modeling [26] have been used to investigate metabolic changes in depressive disorders. In our laboratory, rat CMS models of depression [27], [28], [29] and naturally occurring depression in macaques [30] have been well established for uncovering the molecular mechanisms of depression. We have also utilized biological fluids from depression patients for metabolic analysis [24], [25], [26].
In this study, a non-targeted metabolomics approach based on GC–MS technology, with high-throughput, −sensitivity, and −resolution [31], was applied to investigate significant metabolic changes in the PFC of CRS rats. Our primary aim was to identify the CRS-induced metabolic disturbances in information transmission in the PFC, an important brain region in the pathology of depression, in order to better understand the underlying molecular mechanisms of depression.
Section snippets
Ethics statement
All procedures in this study were performed in accordance with the guidelines established by the National Institutes of Health for Animal Research [32], and were approved by the Ethics Committee of Chongqing Medical University, Chongqing, China.
CRS rat model
Thirty-five male Sprague-Dawley rats weighing 200–250 g were purchased from the animal facility at Chongqing Medical University. The rats were single-housed under a reversed 12-h light/12-h dark cycle (lights on at 19:00 h; lights off at 07:00 h) at
Assessment of CRS model quality
We used both the LAT and SPT data to determine outliers [44]. Values beyond the 95% reference interval in the LAT or the 95% percentile interval in the SPT were regarded as spurious values and eliminated from the data. As a result, five outliers were excluded following the LAT and SPT (Fig. S1A and B), leaving 20CRS and 10CON rats. No significant statistical differences in locomotor activity or sucrose preference were found between the two groups (Fig. S1C and D). After CRS exposure, eight rats
Discussion
As a non-invasive protocol, repeated CRS is similar to human psychological stress [47], making it a reliable animal model of depression with good replicability. In the present study, we divided animals in the CRS group into susceptible and resilient subgroups based on sucrose preference. In the susceptible subgroup, we observed decreased sucrose preference and increased immobility in the FST after the CRS protocol, indicating aggravated depression-related anhedonia- and despair-like behaviors,
Acknowledgments
This work was financially supported by the Natural Science Foundation of China (Grant no. 31271189) and the National Basic Research Program of China (973 Program, Grant no. 2009CB918300).
References (71)
- et al.
Major depressive disorder: new clinical, neurobiological, and treatment perspectives
Lancet
(2012) - et al.
Depressive syndrome in major psychoses: a study on 1351 subjects
Psychiatry Res.
(2004) - et al.
Interactions between orbital prefrontal cortex and amygdala: advanced cognition learned responses andinstinctive behaviors
Curr. Opin. Neurobiol.
(2010) - et al.
The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex
Behav. Brain Res.
(2009) - et al.
Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in majordepression
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2009) - et al.
Insulin-like growth factor 2 mitigates depressive behavior in a rat model of chronic stress
Neuropharmacology
(2015) - et al.
Epigenetic programming of the stress response in male and female rats by prenatal restraint stress
Brain Res. Rev.
(2008) - et al.
Proteomics reveals energy and glutathione metabolic dysregulation in the prefrontal cortex of a rat model of depression
Neuroscience
(2013) - et al.
Identification and validation of urinary metabolite biomarkers for major depressive disorder
Mol. Cell. Proteomics
(2013) - et al.
Amino acid metabolic dysfunction revealed in the prefrontal cortex of a rat model of depression
Behav. Brain Res.
(2015)
Behavioural and neurochemical effects induced by chronic mild stress applied to two different rat strains
Behav. Brain Res.
Sex differences and phase of light cycle modify chronic stress effects on anxiety and depressive-like behavior
Behav. Brain Res.
Electroconvulsive stimulations normalizes stress-induced changes in the glucocorticoid receptor and behavior
Behav. Brain Res.
Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats
Behav. Brain Res.
Restraint stress in biobehavioral research: recent developments
Neurosci. Biobehav. Rev.
Dysfunctional glutamatergic and γ-aminobutyric acidergic activities in prefrontal cortex of mice in social defeatmodel of depression
Biol. Psychiatry
Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders
Neuropharmacology
Targeting glial physiology and glutamate cycling in the treatment of depression
Biochem. Pharmacol.
Glial and glutamatergic markers in depression alcoholism, and their comorbidity
J. Affect. Disord.
Glutamate-based depression GBD
Med. Hypotheses
Metabolic profiling reveals disorder of amino acid metabolism in four brain regions from a rat model of chronic unpredictable mild stress
FEBS Lett.
Methamphetamine-induced neuronal protein NAT8L is the NAA biosynthetic enzyme: implications for specializedacetyl coenzyme A metabolism in the CNS
Brain Res.
In vivo (1)H MRS study of potential associations between glutathione, oxidative stress and anhedonia in major depressive disorder
Neurosci. Lett.
Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy indings
Prog. Neuropsychopharmacol. Biol. Psychiatry
The increasing burden of depression
Neuropsychiatr. Dis. Treat.
Comorbidity of anxiety and depression in children and adolescents: 20 years after
Psychol. Bull.
Comorbidity of ADHD and subsequent bipolar disorder among adolescents and young adults with major depression: a nationwide longitudinal study
Bipolar Disord.
Assessment and treatment of mood disorders in the context of substance abuse
Dialogues Clin. Neurosci.
Mechanisms of stress in the brain
Nat. Neurosci.
Subgenual prefrontal cortex abnormalities in mood disorders
Nature
Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders
Mol. Psychiatry
Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression
Int. J. Neuropsychopharmacol.
Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS
Neuropsychobiology
Optimization of chronic stress paradigms using anxiety- and depression-Like behavioral parameters
J. Neurosci. Res.
Identifying blood biomarkers for mood disorders using convergent functional genomics
Mol. Psychiatry
Cited by (75)
Progress of depression mechanism based on Omics method
2024, Journal of Pharmaceutical and Biomedical AnalysisRestorative effect of NitroSynapsin on synaptic plasticity in an animal model of depression
2023, NeuropharmacologyThe effect of prenatal stress on offspring depression susceptibility in relation to the gut microbiome and metabolome
2023, Journal of Affective DisordersAlteration of sweet taste receptor expression in circumvallate papillae of mice with decreased sweet taste preference induced by social defeat stress
2022, Journal of Nutritional BiochemistryEnergy metabolism in major depressive disorder: Recent advances from omics technologies and imaging
2021, Biomedicine and Pharmacotherapy
- 1
These authors contributed equally to this work.