Neurodegenerative evidences during early onset of depression in CMS rats as detected by proton magnetic resonance spectroscopy at 7 T

Abstract

Depression is a complex psychiatric disorder characterized by anhedonia and feeling of sadness and chronic mild stress (CMS) seems to be a valuable animal model of depression. CMS animal model was induced and validated using behavioral studies. In the present study we investigated the neuro-metabolite changes occurring in prefrontal cortex and hippocampus during the onset of depression, in CMS rat model using in vivo proton magnetic resonance spectroscopy (¹H MRS) at field strength of 7 T. Results showed that CMS caused depression-like behavior in rats, as indicated by the decrease in sucrose consumption and locomotor activity. ¹H MRS was performed in both control and CMS rats (n = 10, in each group) and the quantitative assessment of the neurometabolites was done using LC model. Relative concentrations of all the metabolites along with the macromolecules were calculated for analysis. The results revealed a significant decrease of glutamate (Glu), glutamine (Gln), NAA + NAAG, Glx and GABA levels in both hippocampus and prefrontal cortex of CMS animals and an elevated level of myo-ionisitol (mI) and taurine (Tau) was observed only in hippocampus. These metabolite fluctuations revealed by proton MRS indicate that there might be change in the neuronal integrity of the glial cells and neurons within prefrontal cortex and hippocampus in CMS model of depression. The present study also suggests that there may be a degenerative process concerning the brain morphology in the CMS rats. The overall finding using ¹H MRS suggests that, there might be a major role of the glia and neuron in the onset of depression.

Introduction

Depression is a complex psychiatric disorder characterized by anhedonia and feelings of sadness [1]. The etiology of depression is not fully understood but may involve changes in the nervous, immunological and endocrine systems [2], [3], [4]. Long-term exposure to multiple stressors has been suggested to play a role in the development of human depression [5], [6]. To obtain a better understanding of the phenomena existing in depression, different animal models have been developed to mimic these conditions. Out of many animal models available for depression, the chronic mild stress (CMS) procedure is a valid animal model of depression, based on its resemblance with several human depressive symptoms [7]. This model attempts to analyze putative stressors that contribute to the onset of depression and produce depressive symptoms [8]. Furthermore, many studies have employed CMS as a model for studying the relationship between depression and immunologic [9], neuroendocrine [10], neurobiological [11], cardiovascular [12] and physiological [13] alterations. All of these findings have contributed to a better understanding of depression. The CMS animal model of depression has good face validity, construct validity and predictive validities, which makes it suitable for investigating the metabolic alterations of depression [7]. It is well known that hippocampus and prefrontal cortex (PFC) are affected in depression. Hippocampus is a part of the limbic stress pathway that is substantially sensitive to the neurotoxic effects of elevated levels of glucocorticoids, as observed following recurrent stress episodes and PFC has been implicated in planning complex cognitive behaviors, personality expression, decision making, execution and moderating correct social behavior. Many studies have been carried out on brain regions associated with depression and have documented the involvement of the limbic system [14]. Pause et al. [15] reported that there are abnormalities in cerebral cortex, in particular the dorsolateral prefrontal cortex (DLPFC), along with hypometabolism in the anterior cingulate cortex (ACC) [16], [17] in depressed patients. Although numerous studies have evaluated the relationship between brain activity and depression, few studies have empirically analyzed the mechanisms of depression induced by CMS. Since, depression and other psychotic conditions are not associated with gross brain pathology, the availability of tools allowing non-invasive assessment of the brain regions prove critical to elucidate their neurobiology. The development of neuroimaging technologies that permit in vivo characterization of the anatomical, physiological and neurochemical correlates of depression has enabled significant advances toward illuminating the pathophysiology of these conditions. Notably, the results of neuroimaging studies and the post mortem studies that have been guided by neuroimaging have given rise to neurocircuitry-based models in which both functional and structural brain pathology play roles in the development of depression. Proton magnetic resonance spectroscopy (¹H MRS) is a non-invasive neuroimaging technique that allows the quantification of various neurochemicals/metabolites which can be used clinically as well as in animal models to assess the integrity of neural tissue following any exposure or changes.

In the present study, we examined the neurometabolite alterations occurring in brain during the onset of depression. These neurometabolite alterations can explain about the brain tissue integrity during the onset of depression. In order to investigate these metabolic perturbation an in vivo ¹H MRS spectra was acquired on PFC and hippocampus. To best of our knowledge this is the first MRS study performed at 7 T on CMS rats in both these areas simultaneously.