Mechanism of Chaijin Jieyu Anshen Tablets in regulating abnormal ACC-vHPC glutaminergic neural circuit to alleviate synaptic remodeling of ventral hippocampal neurons in depressed rats
This study aims to reveal the molecular mechanism of Chaijin Jieyu Anshen Tablets(CJJYAS)in regulating the abnor-mal anterior cingulate cortex(ACC)-ventral hippocampus(vHPC)glutaminergic neural circuit to alleviate synaptic remodeling of ven-tral hippocampal neurons in depressed rats.Firstly,the study used chemogenetics to localize glutaminergic adeno-associated virus(AAV)into the ACC brain region of rats.The model of depressed rats was established by chronic unpredictable mild stress(CUMS)combined with independent feeding.The rats were randomly divided into control group,model group,AAV empty group,AAV group,AAV+glucocorticoid receptors(GR)blocker group,AAV+chemokine receptor 1(CX3CR1)blocker group,and AAV+CJJYAS group.Depressive-like behaviors of rats were evaluated by open-field,forced-swimming,and Morris water maze tests,combined with an animal behavior analysis system.The morphological and structural changes of ACC and vHPC neurons in rats were observed by he-matoxylin-eosin(HE)staining.Immunofluorescence and nuclear phosphoprotein(c-Fos)were used to detect glutaminergic neural cir-cuit activation of ACC-vHPC in rats.The changes in dendrites,synaptic spines,and synaptic submicrostructure of vHPC neurons were observed by Golgi staining and transmission electron microscopy,respectively.The expressions of synaptic remodeling-related proteins N-methyl-D-asprtate receptor 2A(GRIN2A),N-methyl-D-asprtate receptor 2B(GRIN2B),Ca2+/calmodulin-dependent protein ki-nase Ⅱ(CaMKⅡ),mitogen-activated protein kinase-activated protein kinase 2(MK2),and a ubiquitous actin-binding protein(cofi-lin)in vHPC glutaminergic neurons of rats were detected by immunofluorescence and Western blot,respectively.The results indicated that the activated glutaminergic AAV aggravated the depressive-like behaviors phenotype of rats in the model group and deteriorated the damage of morphology and structure of ACC and vHPC neurons and synaptic ultrastructure.However,both GR and CX3CR1 bloc-kers could reverse the abnormal changes to varying degrees,suggesting that the abnormal activation of ACC-vHPC glutaminergic neural cir-cuit mediated by GR/CX3CR1 signals in gliocytes in the ACC brain region may be closely related to the occurrence and development of depression.Interestingly,CJJYAS significantly inhibited the activation of the ACC-vHPC glutaminergic neural circuit induced by AAV and the elevated Glu level.Furthermore,CJJYAS could also effectively reverse the aggravation of depressive-like behaviors and synap-tic remodeling of vHPC neurons of rats in the model group induced by the activated AAV.Additionally,the findings suggested that the molecular mechanism of CJJYAS in improving synaptic damage of vHPC neurons might be related to the regulation of synaptic remode-ling-related signals such as NR/CaMKⅡ and MK2/cofilin.In conclusion,this research confirms that CJJYAS effectively regulates the abnormal ACC-vHPC glutaminergic neural circuit and alleviates the synaptic remodeling of vHPC glutaminergic neurons in depressed rats,and the molecular mechanism might be associated with the regulation of synapse-related NR/CaMKⅡ and MK2/cofilin signaling pathways,which may be the crucial mechanism of its antidepressant effect.
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