Study On The Therapeutic Effects And Mechanisms Of Repetitive Transcranial Magnetic Stimulation In Mice Models Of Depression And Alzheimer’s Disease With Comorbid Depression

Objective: Based on the treatment of repetitive transcranial magnetic stimulation for depression as the main target,we first discussed therapeutic effects of different levels of high-frequency r TMS in mice with chronic stress-induced depression,and compared effects of two frequencies r TMS on neuronal survival,neurogenesis,synaptic plasticity and investigated the possible mechanism.Then we discussed the effects of r TMS on neuroinflammation in depressed mice.Furthermore,we explored the therapeutic effects and the possible mechanism of r TMS in AD mice with comorbidity depression.Methods: 1.Chronic unpredictable mild stress was used to establish a mouse model of depression.Mice were given high-frequency r TMS at 15 Hz and 25 Hz for 4 weeks.The depression-like and anxiety-like behaviors of mice were observed by sucrose preference test,open field test,forced swimming test and tail suspension test.Immunofluorescence staining was used to detect neuronal survival and neurogenesis.The apoptosis level was detected by TUNEL staining.Western blot was used to detect the expression of apoptosis-related proteins,synapse-related proteins and proteins of possible signaling pathway.2.The CUMS method was used to establish a depressed mouse model.Mice were given 15 Hz r TMS for 4 weeks and the depression-like behaviors were detected.The activation of microglia and astrocytes in the hippocampus were detected by immunofluorescence staining.The levels of hippocampal pro-inflammatory cytokines IL-6,IL-1βand TNF-α were determined by quantitative real-time polymerase chain reaction(q RT-PCR)and enzyme-linked immunosorbent assay(ELISA).Western blot was used to detect levels of proteins involved in the TLR4 / NFκB/NLRP3 signaling pathway.3.3x Tg AD transgenic mice were used to establish a comorbidity model of AD and depression,and were treated with 15 Hz r TMS and sertraline for 4 weeks.SPT,FST and OFT were used to observe depression-like and anxiety-like behaviors.Morris water maze detected the cognitive function of mice.Immunofluorescence staining was used to detect the levels of hippocampal microglia,astrocytes,neurons,apoptosis and Aβdeposition.The levels of hippocampal pro-inflammatory cytokines IL-6,IL-1β,TNF-α and soluble Aβ42 were determined by ELISA.Western blot analyzed protein levels of the TLR4/NF B/NLRP3 inflammatory pathway in the hippocampus.Results: 1,Both 15 Hz and 25 Hz high-frequency rTMS improved the depression-like and anxiety-like behaviors of mice.High-frequency r TMS at 15 Hz and 25 Hz exerted protective roles by inhibiting neuronal loss and apoptosis and promoting neurogenesis and synaptic plasticity.15-Hz and 25-Hz r TMS may lay particular emphasis respectively on certain aspects of the above-mentioned effects.The neuroprotective effects of high-frequency r TMS may be related to the p11/BDNF/Homer1 a signaling pathway.2.15 Hz r TMS could reduce the level and activation of hippocampal microglia in depressed mice,and reverse the down-regulation of astrocytes.In addition,r TMS inhibited the production of hippocampal pro-inflammatory cytokines,including IL-6,IL-1βand TNF-α.r TMS inhibited the overexpression of proteins associated with the TLR4 / NFκB /NLRP3 inflammatory signaling pathway.3.The mice model of depression with AD background was established successfully.15 Hz r TMS could ameliorate depression-like behaviors and cognitive impairment in 3x Tg AD mice with comorbid depression.The therapeutic role might associated with effects of r TMS on a variety of neuroinflammation process,including inhibiting of activation of microglia,reducing the levels of pro-inflammatory cytokines and inhibiting overexpression of TLR4 / NFκB/NLRP3 inflammation pathways,thereby reducing Aβ deposition and alleviate neuronal loss and apoptosis.Conclusion: High-frequency r TMS could exert neuroprotective effects via multiple targets on depression caused by chronic stress and depression associated with AD in mice,promote the recovery of depression-like behaviors and cognitive function,which provided a new theoretical basis for clinical application of r TMS on depression and depression associated with AD.