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Chronic Stress in a Rat Model of Depression Disturbs the Glutamine-Glutamate-GABA Cycle in the Striatum, Hippocampus, and Cerebellum.

ABSTRACT: Background:Major depressive disorder (MDD) is a complex psychiatric illness involving multiple brain regions. Increasing evidence indicates that the striatum is involved in depression, but the molecular mechanisms remain unclear. Methods:In this study, we performed a gas chromatography-mass spectrometer (GC/MS)-based metabolomic analysis in the striatum of depressed rats induced by chronic unpredictable mild stress (CUMS). We then compared striatal data with our previous data from the hippocampus and cerebellum to systematically investigate the potential pathogenesis of depression. Results:We identified 22 differential metabolites in the striatum between the CUMS and control groups; these altered metabolites were mainly involved in amino acid, carbohydrate, and nucleotide metabolism. Pathway analysis revealed that the shared metabolic pathways of the striatum, hippocampus, and cerebellum were mainly involved in the glutamine-glutamate metabolic system. Four genes in the striatum (GS, GLS2, GLT1, and SSADH), six genes in the hippocampus (GS, SNAT1, GAD1, SSADH, VGAT, and ABAT), and five genes in the cerebellum (GS, ABAT, SNAT1, VGAT, and GDH) were found to be significantly altered using RT-qPCR. Correlation analysis indicated that these differential genes were strongly correlated. Conclusion:These results suggest that chronic stress might induce depressive behaviors by disturbing the glutamine-glutamate-GABA cycle in the striatum, hippocampus, and cerebellum, and that the glutamine-glutamate-GABA cycle among these three brain regions might generate cooperative action in response to chronic stress.

SUBMITTER: Xu S

PROVIDER: S-EPMC7047974 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Chronic Stress in a Rat Model of Depression Disturbs the Glutamine-Glutamate-GABA Cycle in the Striatum, Hippocampus, and Cerebellum.

Xu Shaohua S Liu Yiyun Y Pu Juncai J Gui Siwen S Zhong Xiaogang X Tian Lu L Song Xuemian X Qi Xunzhong X Wang Haiyang H Xie Peng P

Neuropsychiatric disease and treatment 20200224

<h4>Background</h4>Major depressive disorder (MDD) is a complex psychiatric illness involving multiple brain regions. Increasing evidence indicates that the striatum is involved in depression, but the molecular mechanisms remain unclear.<h4>Methods</h4>In this study, we performed a gas chromatography-mass spectrometer (GC/MS)-based metabolomic analysis in the striatum of depressed rats induced by chronic unpredictable mild stress (CUMS). We then compared striatal data with our previous data from ...[more]

PMID: 32158215

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Project description:Background: Women are twice as likely as men to develop major depression. The brain mechanisms underlying this sex disparity are not clear. Disruption of the glutamate-glutamine cycle has been implicated in psychiatric disturbances. This study identifies sex-based impairments in the glutamate-glutamine cycle involving astrocytes using an animal model of depression. Methods: Male and female adult Long-Evans rats were exposed to chronic social defeat stress (CSDS) for 21 days, using a modified resident-intruder paradigm. Territorial aggression was used for males and maternal aggression was used for females to induce depressive-like deficits for intruders. The depressive-like phenotype was assessed with intake for saccharin solution, weight gain, estrous cycle, and corticosterone (CORT). Behaviors displayed by the intruders during daily encounters with residents were characterized. Rats with daily handling were used as controls for each sex. Ten days after the last encounter, both the intruders and controls were subjected to a no-net-flux in vivo microdialysis to assess glutamate accumulation and extracellular glutamine in the nucleus accumbens (NAc). The contralateral hemispheres were used for determining changes in astrocytic markers, including glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1). Results: Both male and female intruders reduced saccharin intake over the course of CSDS, compared to their pre-stress period and to their respective controls. Male intruders exhibited submissive/defensive behaviors to territorial aggression by receiving sideways threats and bites. These males showed reductions in striatal GLT-1 and spontaneous glutamine in the NAc, compared to controls. Female intruders exhibited isolated behaviors to maternal aggression, including immobility, rearing, and selfgrooming. Their non-reproductive days were extended. Also, they showed reductions in prefrontal and accumbal GFAP+ cells and prefrontal GLT-1, compared to controls. When 10 ?M of glutamate was infused, these females showed a significant accumulation of glutamate compared to controls. Infusions of glutamate reduced extracellular glutamine for both male and female intruders compared to their respective controls. Conclusion: Twenty-one days of territorial or maternal aggression produced a depressive-like phenotype and impaired astrocytes in both male and female intruders. Disruption of the glutamate-glutamine cycle in the PFC-striatal network may be linked to depressive-like deficits more in females than in males.

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Dataset Information

Chronic Stress in a Rat Model of Depression Disturbs the Glutamine-Glutamate-GABA Cycle in the Striatum, Hippocampus, and Cerebellum.

Publications

Chronic Stress in a Rat Model of Depression Disturbs the Glutamine-Glutamate-GABA Cycle in the Striatum, Hippocampus, and Cerebellum.

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