Depression is a serious public health problem and an important factor leading to disease-related disability. Influenced by many factors, such as psychological, hormonal, and genetic factors, the incidence rate of depression in females is approximately two times that in males. However, in preclinical neuroscience research, the selection of the animals’ sex for use in depression models has been controversial. At present, in most preclinical studies, the animals generally chosen in depression models have been male rodents rather than female rodents. It remains doubtful whether the data obtained from male animals can be generalized to female animals. The performance of female animals in preclinical studies of depression has been inconclusive. Based on a review of a large number of original studies in the PubMed database, it was found that although male rodents are more commonly used in the study of depression, the use of female animals also shows good modeling of depression and has its advantages. The influence of the animals’ sex in the chronic unpredictable mild stress (CUMS) model needs further research.
Background: Converging evidence indicates that glutamatergic system and glia are directly implicated in the pathophysiology of depression. Clinical studies indicate that electroacupuncture (EA) has antidepressant-like effect with low side effects for depression. However, the underlying antidepressant mechanism of acupuncture remains obscure. Methods: Chronic unpredictable mild stress (CUMS)-induced depressive rats were used to induce depressive-like behavior, and evaluated by the weight change, open field test, sucrose preference test, and novelty suppressed feeding test. EA, NMDA receptor subunit 2A antagonist (NR2A RA) or NMDA receptor subunit 2B antagonist (NR2B RA) was used for comparison. High performance liquid chromatography (HPLC) was performed to detect the content of hippocampal glutamate, while western blot for the hippocampal protein expression levels of calcium/calmodulin-dependent protein kinase II (CaMKII), Bax, caspase 3 and B-cell lymphoma-2 (Bcl-2). The distribution of glutamate ionotropic receptor NMDA type subunit 2A (NR2A), neuronal nuclear protein (NeuN), glutamate ionotropic receptor NMDA type subunit 2B (NR2B) and glial fibrillary acidic protein (GFAP) were detected by immunofluorescence. Results: Significant depression behavior (reduced body weight and sucrose preference, increased feeding and immobility time) was produced in CUMS-induced depressive rats, which was reversed significantly by EA. EA decreased hippocampal glutamate level. EA led to a significant decrease in expression levels of Bax, caspase 3 and CaMKⅡ accompanied by increased Bcl-2 expression level. Furthermore, EA significantly increased NR2A expression level as well as decreased NR2B expression level in hippocampus. Conclusion: EA ameliorated depression-like behavior in CUMS rats, which might be mediated, at least in part, by regulating the glutamate, NMDA receptors and apoptosis in the hippocampus.
Correlations amongst the rat glutamatergic system, glia, and depression, as well as the underlying mechanism of astrocyte impairment, as a trigger of depression, were investigated. Rats were submitted to different durations of chronic unpredictable mild stress to induce depressive-like behavior and evaluated by weight change, sucrose preference test, open field test, and novelty suppressed feeding test. High-performance liquid chromatography was employed to detect glutamate content of hippocampal protein expression during Western blot and immunofluorescence. Results showed that 21-day chronic unpredictable mild stress was sufficient for inducing significant depressive-like behavior (reduced body weight and sucrose preference, increased feeding, and immobility time) in a model of depression. Chronic unpredictable mild stress increased the level of hippocampal glutamate, while intervention caused a considerable rise in the expression levels of Bax, caspase 3, and calcium/calmodulin-dependent protein kinase II, accompanied by a down-regulated level of Bcell lymphoma-2. Exposure to this stress model reduced hippocampal glutamate ionotropic receptor N-methyl-Daspartic acid type subunit 2A, neuronal nuclear protein, and glial fibrillary acidic protein expression levels while it raised the level of ionotropic glutamate receptor N-methyl-D-aspartic acid type subunit 2B level. It is concluded that chronic stress induces excessive glutamate release and overstimulation of N-methyl-D-aspartic acid receptors, followed by astrocytic apoptosis. Also, in depression, calcium overload in astrocytes is attributed to an underlying mechanism of astrocyte impairment.
Inflammation and glutamate (GLU) are widely thought to participate in the pathogenesis of depression, and current evidence suggests that the development of depression is associated with the activation of the kynurenine pathway (KP). However, the exact mechanism of KP among the inflammation, GLU and depression remain poorly understood. In this study, we examined the involvement of KP, inflammation and GLU in depressive phenotype induced by chronic unpredictable mild stress (CUMS) in C57B/6 J mice. Our results showed that CUMS caused depressive like-behavior in the sucrose preference test, tail suspension test and forced swimming test. From a molecular perspective, CUMS upregulated the peripheral and central inflammatory response and activated indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of KP, which converts tryptophan (TRP) into kynurenine (KYN). KYN is a precursor for QA in microglia, which could activate the N-methyl-D-aspartate receptor (NMDAR), increasing the GLU release, mirrored by increased IDO activity, quinolinic acid and GLU levels in the hippocampus, prefrontal cortex and serum. However, intervention with IDO inhibitor 1-methyl-DL-tryptophan (50 mg/kg/s.c.) and 1-methyl-L-tryptophan (15 mg/kg/i.p.) reversed the depressive-like behaviors and adjusted central and peripheral KP’s metabolisms levels as well as GLU content, but the inflammation levels were not completely affected. These results provide certain evidence that KP may be a vital pathway mediated by IDO linking inflammation and glutamate, contributing to depression.
Objective. Depression is a global mental health problem with high disability rate, which brings a huge disease burden to the world. Electroacupuncture (EA) has been shown to be an effective method for the treatment of depression. However, the mechanism underling the antidepressant effect of EA has not been clearly clarified. The change of synaptic plasticity is the focus in the study of antidepressant mechanism. This study will observe the effect of EA on LTP of hippocampal synaptic plasticity and explore its possible mechanism. Methods. The depression-like behavior rat model was established by chronic unpredictable mild stress (CUMS). EA stimulation (Hegu and Taichong) was used to treat the depressed rats. The depression-like behavior of rats was tested by weight measurement, open field test, depression preference test, and novelty suppressed feeding test. Long-term potentiation (LTP) was recorded at CA1 synapses in hippocampal slices by electrophysiological method. N-methyl-D-aspartate receptor subunit 2B (NR2B) and calmodulin-dependent protein kinase II (CaMK II) protein levels were examined by using western blot. Results. After the establishment of CUMS-induced depression model, the weight gain rate, sucrose preference rate, line crossing number, and rearing times of rats decreased, and feeding time increased. At the same time, the LTP in hippocampus was impaired, and the expressions of NR2B and CaMK II were upregulated. After EA treatment, the depression-like behavior of rats was improved, the impairment of LTP was reversed, and the expression levels of NR2B and CaMK II protein were downregulated. Conclusion. EA can ameliorate depression-like behaviors by restoring LTP induction, downregulating NR2B and CaMK II expression in CUMS model rats, which might be part of the mechanism of EA antidepressant.
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