Investigation Of The Post-stimulation Effects Of High-frequency Electrical Stimulation In Hippocampus And Possible Mechanisms

Deep brain stimulation has been applied in clinical movement disorders such as Parkinson's disease,dystonia,and other psychotic disorders such as epilepsy and depression.In contrast to traditional drug therapy or surgical therapy of resecting related focus,DBS has the advantages of being minimally invasive,reversible and minor side effects.However,the mechanisms of DBS have been poorly understood.DBS with different stimulus parameters may produce different stimulation effects on the neural network.In the application of DBS,high frequency stimulation is widely employed,and the duration of stimulation is an important adjustable parameter.HFS with varying durations may elicit distinct stimulation effects,and short term HFS may induce evoked epileptogenic activity,while prolonged stimulation can be safely applied to treat clinical diseases.Therefore,it is important for us to study the effects of HFS with different time patterns on the neural network during and after stimulation,which is important for revealing the mechanisms of DBS,evaluating the safety of stimulation and promoting the application of DBS.The hippocampus is closely related to learning and memory and emotional regulation,and it is the DBS target of epilepsy and Alzheimer's disease as well.Therefore,in this dissertation,the rat hippocampal CA1 was selected as the target region,in which 100 Hz high frequency electrical stimulations with distinct time patterns were administered on the Schaffer collateral of CA1 afferent axonal tracts.Using microelectrode array in-vivo recording technology,the rat hippocampus neural electrophysiological signals were recorded.Combining the baseline results before stimulation,we analyzed the responses during HFS and population spike amplitude and latency as well as the excitatory postsynaptic potential induced by test pulses after HFS to investigate the subsequential effects after HFS,and then we discussed the potential mechanisms.The main results of this dissertation were summarized as follows:(1)Short term axonal HFS could increase the excitability of downstream neuronsThe results showed that short term stimulation can evoke epileptiform activity after HFS,and especially the afterdischarge(AD)following 5 s HFS could persist more than 5 s.After the end of AD following 5 s HFS,PSs evoked by test pulses were more prone to be double wave,and the amplitude of PS and the slope of field excitatory postsynaptic potential were larger than baseline values before HFS,while the latencys were shorter than baseline values.And these excitability increases like above could last over 20 min,which might be the results of synaptic plasticity potentiation induced by short term HFS.In addition,this plasticity potentiation could last more than 1 hour after the termination of 3 series of 1 s HFS.(2)5 s short term HFS could induce spreading depressionThe results showed that 5 s short term HFS will significantly increase the excitability of the downstream neuronal population,and even it will induce spreading depression(SD).The experimental results indicated that SD slow wave may firstly appear in the apical dendrites of pyramidal neurons,and then spread to the cell body layer.The multiple unit activity vanished at once after the appearance of SD.Only about 3?5 min after SD,the spike then reappeared gradually.Moreover,about 10 min after SD,the PS responses induced by test pulse were basically returned to baseline level.(3)Sustained long term stimulation could weaken the excessive excitability elicited by early short stimulation,and change the neural network induced by previous stimulationThe results indicated that there was no subsequent AD following the termination of 2 min long HFS,while tens of seconds resting period with no spike activities emerged.At the early period after the end of HFS(about 5?6 min),the amplitude of PS induced by test pulses decreased,while the latency of PS increased;then the amplitude and latency of PS could recover to the baseline level gradually,and there were no significant differences between them.In addition,after 30 min of the end of HFS,the input-output(I/O)test results manifested that there were no significant differences of the amplitude and latency of PS evoked by I/O compared with the baseline values after 2 min long HFS.Nevertheless,the amplitude values of PS of I/O response following 5 s short term HFS were significantly larger than that following 2 min long term HFS,and the latency values of PS of I/O response were smaller than that following 2 min long term HFS.These results above demonstrated that short term HFS would produce long lasting excitatory effects on downstream neurons,and even spreading depression,while long HFS could weaken the excitatory effects elicited by the early short stimulus,and change neural network effects on downstream neuronal population induced by the initial stimulation.Due to the short term stimulus is in the early stage of long stimulation,the mechanism may be that sustained long time HFS produced axonal block,reduced the excitatory effect of stimulation on axonal terminals,synaptic connections and postsynaptic neurons,and thus changed the effects of HFS in the early stage.In conclusion,this dissertation investigated the post-stimulation effects induced by HFS with distinct temporal patterns on downstream neuronal population through in-vivo study.The results showed that the prolonged HFS could reverse the long lasting stimulation effects elicited by the initial period of long HFS,which made the activities of downstream neurons rapidly recover to their states before stimulation.It can be seen that long enough HFS may be a prerequisite for the good reversibility of DBS.This study is of great significance for revealing the new mechanisms of DBS and promoting the clinical application safely of DBS.