Axonal High-Frequency Stimulations In Hippocampus Alter Neuronal Firing Patterns In The Projection Area

Deep brain stimulation(DBS)has been widely investigated for treating varieties of neurological disorders in clinic.However,mechanisms of high-frequency stimulation(HFS)utilized in DBS have not yet been elucidated,limiting the promotion and application of this promising therapy.Previous studies focused on HFS-induced changes in neuronal firing rate;whereas,recent studies suggest that HFS could change the firing pattern of neuronal activity,which may correlate with symptom alleviation.In order to explore the role of HFS in changing the firing rate and pattern of downstream neuronal activity,HFS was applied on the Schaffer collaterals,which are the afferent fibers of hippocampal CA1 region in rats.Thus,spikes recorded in the downstream region were analyzed by multiple parameters such as firing rate,entropy,latency and phase-locking value(PLV).The main results are summarized as follows:(1)Axonal HFS excited downstream neurons and regularized a new firing patternDuring axonal HFS,neuronal firing rates of multiple unit activity(MUA)and single unit activity(SUA)in CA1 region were significantly higher than baseline;thus,there were silent periods without spikes immediately following the end of HFS,These phenomena indicate that axonal HFS could excite neurons in the downstream region while inhibiting upstream spontaneous neural signals.Probability distribution of inter-spike interval(ISI)shows that during HFS,downstream neurons generated a new regular firing pattern,which made the ISI concentratedly distributed near the times that are integer multiples of the inter-pulse interval(IPI);indicates axonal HFS could modulate neuronal activity in the downstream region,replacing the disordered intrinsic firing pattern.(2)Axonal HFS reduced information transmission ability of neurons in the downstream regionAxonal HFS could reduce the entropy of neuronal ISI sequence in the downstream region by entrain neuronal firing into modulated pattern,indicates the reduction of information transmission ability of downstream neurons,thus HFS could increase firing rate while achieving the same effect as lesion.In addition,Axonal HFS has higher excitability,phase-locking,and entropy-reducing effects on mono-synaptic modulated interneurons,indicating that after multi-level synaptic conduction,the firing pattern of neuronal action potentials in the wider brain region is gradually approaching baseline state without stimulus.(3)Continuous HFS reduced axons and their terminals’ ability to conduct action potentialsDuring the initial 10-s of HFS,the firing rate of neuronal SUA decreased and the latency prolonged significantly;while the firing rate of neurons(pyramidal neurons and internurons)stabilized during the initial 1-min of HFS,the latency of spikes was still prolonged,and the phase-locked relationship between spikes and stimulation pulses was gradually weaken.These phenomena may reveal the rapid functional changes of axons and their terminals(axonal block,neurotransmitter depletion,changes in synaptic plasticity,etc.)in the early stage of HFS,indicating that local axonal conduction block was gradually deepen as HFS persisted.HFS may enhance the desynchronization of stimulation by reducing the phase-locked relationship between spikes and stimulation pulses.In summary,this paper studies the modulation effect of axonal HFS in rat hippocampal on the firing rate and firing pattern of downstream neurons.The results of studies on axonal HFS excited and modulated downstream neurons,weaken neuronal information transmission ability,and reduced axons and their terminals’ ability to conduct action potentials can be used to explain the reason why DBS could achieve the similar effect as lesion.These results provide new ideas for revealing the mechanism of DBS and is of great significance for developing new technologies for treating brain diseases.