Prefrontal Metabonomic A Rat Model Of Depression

BACKGROUND:Major depressive disorder (MDD) is a debilitating mood disorder with a lifetime prevalence of 16% that produces several detrimental socioeconomic effects including increased healthcare expenditures and suicide rates. However, the molecular mechanism underlying depression remain largely unknown.The prefrontal cortex (PFC) is associated with regulating emotion, cognition, and learned response, and a large number of functional imaging, lesion, and brain stimulation studies have implicated the PFC in depression. For example, depressed patients show significantly decreased cerebral blood flow and glucose metabolism in the PFC accompanied by a corresponding reduction in PFC grey matter volume. In particular, dysfunction in the PFC’s glutamanergic neurotransmission has been implicated in the pathophysiology of depression. Resting state dorsolateral PFC(DLPFC) hypoactivation has been well-established in depression through fMRI neuroimaging, and this hypoactivation has been observed to increase toward normal levels with antidepressant treatment. Moreover, high-frequency repetitive transcranial magnetic stimulation (rTMS) of the left DLPFC has been shown to be effective in treating treatment-resistant depression.Objective:This study was designed to reveal the possible molecular mechanisms in PFC of a rat model of depression by metabolomic technology.Methods:16 healthy male SD rats were divided into the two groups randomly(CMS group and Healthy Control group), all rats were given suffered to a four-week CMS, while control rats were normal feeding. At the end of CMS, the sucrose preference test, the open field test and forced swimming test were conducted. Employing a gas chromotography/mass spectrometry(GC/MS) metabolomic method, the PFC of depression model metabolomics profiling analysis, multivariate statistical analysis were used to obtaining the different metabolites between CMS and control, analyzing the potential effect of these small molecular metabolites in the pathogenesis of depression.Results:After 28 days of chronic stress, compared with control groups, sucrose preference was significantly decreased in CMS group. Meanwhile, CMS rats presented some differences in body weight, open field test. Thus, we conclude that CMS rat model of depression was successfully built.Employing GC/MS metabolomic method, we get the PFC of CMS rat model whole spectroscopy, the data were significantly separated by multivariate statistical analysis. Finally,4 differential metabolites were discovered.2 among them were down-regulated, they are L-isoleucine and glycerol; and 2 among them were up-regulated, they are N-acetylaspartate andβ-alanine.Conclusion:Employing a GC/MS-based metabolomic approach, this study revealed significantly perturbed levels of N-acetylaspartate, L-isoleucine,β-alanine, and glycerol in the PFC of CMS rats relative to CON rats. These findings should provide insight into the pathophysiological mechanism underlying MDD and preliminary leads relevant to diagnostic biomarker discovery for depression.