Study On The Effect And Mechanism Of Deep Brain Stimulation On Cognitive Impairment After Traumatic Brain Injury

Objective:Traumatic brain injury（TBI）is of great importance as a disease that seriously threatens human health.Cognitive impairment after traumatic brain injury is a common functional disorder affecting people’s work efficiency and life quality.As a neuromodulation technique,deep brain stimulation（DBS）has been widely used in treating Parkinson’s disease,essential tremor,epilepsy and other diseases,but its effect on cognitive impairment after traumatic brain injury remains to be explored.In this experiment,based on the traumatic brain injury model,we establish a mouse deep brain stimulation model to observe the effect of DBS on the cognitive function of the TBI model mice as well as to explore whether its mechanism is related to the neurogenesis of the hippocampal dentate gyrus.Methods:1.We establish a traumatic brain injury model using the controlled cortical injury（CCI）method and use the revised neurobehavioral severity scale（NSS-R）to evaluate the severity of craniocerebral trauma.The open field test and water maze test are used to study the autonomous exploration behavior,anxiety state and cognitive function performance after traumatic brain injury.2.We establish the deep brain stimulation model and use immunofluorescence to detect the cfos expression half an hour after deep brain stimulation.3.Using Nestin-GFP^Tg/+transgenic mice,high-frequency electrical stimulation is applied to the anterior nucleus of the thalamus（ATN）for 2 hours after recovering for 7 days in CCI model.The immunofluorescence technique is used to study the expression of nestin and DCX on 2 days,7 days and 14 days after stimulation.4.The NSS-R is used to evaluate the influence of added electrode implantation to CCI model.The effect of deep brain stimulation on autonomous exploration behavior,anxiety state and cognitive function performance after traumatic brain injury is studied by open field test and water maze test.Results:1.After traumatic brain injury,the NSS-R scores of the CCI groups are significantly higher than that in the Na?ve group.The scores in each group gradually decrease and stabilize at a certain level over time.CCI model with a striking depth of 1 mm,3 mm and 5 mm can mimic mild,mild/moderate and moderate traumatic brain injury.The results of the open field test show that one week after the traumatic brain injury,the autonomous exploration behavior and anxiety state of the mice in the CCI 1mm group do not change significantly.Compared with the Na?ve group,time spent in the central area and vertical activity in the CCI 3mm group decrease.Independent exploration activities of the CCI 5mm group change greatly.The results of the water maze test show that the spatial memory of all CCI groups is impaired 7 days after traumatic brain injury.2.After deep brain stimulation of the anterior nucleus of the thalamus,cfos expression is enhanced bilaterally in the dentate gyrus（DG）of the hippocampus.3.Deep brain stimulation can improve the cognitive function of mice with mild traumatic brain injury but has no obvious effect on autonomous exploration behavior and anxious state.4.Deep brain stimulation affects neurogenesis in the DG region of the hippocampus in our traumatic brain injury model.After TBI,the number of neural stem cells on the ipsilateral side of the trauma is higher than that on the contralateral side.Compared with the DBS-off group,2 days after stimulation,the neurogenesis of the DBS-on group is enhanced in DG bilaterally;7 days after stimulation,neurogenesis of the contralateral DG in the DBS-on group is enhanced;14 days after stimulation,the DG neurogenesis in the DBS-on group is increased bilaterally.5.Deep brain stimulation affects the differentiation and migration of neonatal cells in our traumatic brain injury model.After TBI,the number of migratory cells on the ipsilateral side of the injury is higher than that on the contralateral side.Compared with the DBS-off group,2 days after stimulation,the number of migratory cells in the ipsilateral DG area in the DBS-on group increases;7 days after stimulation,the number of migratory cells in the DG increases bilaterally in the DBS-on group;14 days after stimulation,the number of migratory cells in the ipsilateral hippocampal DG region in the DBS-on group increases.Conclusions:Deep brain stimulation has a potential therapeutic effect on post-traumatic cognitive impairment.The underlying mechanism is related to neurogenesis of the hippocampal dentate gyrus,which is reflected by the increased number and enhanced migration of newly born neural stem cells.