A Modeling Study Of NMAD Modulation Of Serotonergic Neurons In Mesencephalic Locomotor Region In Mice

Locomotion is the most fundamental behavior of movement in vertabrates,such as human's walking,bird's flying,and horse's running.The study of locomotion is not only important to reveal the biological mechanism underlying movement,but also plays a critical role in the research of motion control in modern artificial intelligence.Studies have shown that the locomotion is initiated and controlled in mesencephalic locomotor region(MLR)of the midbrain and that serotonin(5-HT)neurons in this region play an important role in initiating locomotion.Due to technical difficulty,little study is fucosed on 5-HT neurons in this area.Especially,it remains unclear about the moduation of excitability of the 5-HT neurons by neurotransmitters.In the recent research carried out in our laboratory,we have discovered some unique membrane properties of 5-HT neurons and their modulatory properties by neurotransmittes.However,due to the complexity of the nervous system,the mechanisms responsible for these phenomena have not been investigated in detail through physiological experiments,yet.Therefore,in this study we used NEURON software to build a 5-HT neuron model with five compatments,based on the experimental data collected from the 5-HT neurons in the MLR of the mouse midbrain.We used this model to investigate the excitability of 5-HT neurons modulated by neurotransmitter NMDA.The model contains six ionic channels including transient sodium channel(NaT),delayed-rectifier potassium channels(K(DR)),persistent sodium channels(NaP),calcium-dependent SK-type potassium channels,calciumdependent BK-type potassium channels and L-type calcium channels(CaL).In addition,a ligand-gated NMDA channel is included in dendrite compartment.This model could well duplicate the membrane properties of 5-HT neurons.Experiment data showed that NMDA(10 ?M)enhanced the excitability of 5-HT neurons mainly shown as two points:(1)NMDA decreased(hyperpolarized)the voltage threshold of 5-HT neurons for generation of action potentials by 2.3±0.8 mV(n = 20);(2)NMDA shifted the frequency-current relationship to the left(?I =-2.0±0.9 pA)with reduction of the F-I line slope(?K =-0.1±0.1 Hz / pA).The simulation results showed that NMDA could not cause significant hyperpolarization of the voltage threshold.Therefore,we proposed that the NMDA channel may couple with other ionic channels to produce combined effects on the voltage threshold for action potential generation.It was shown in previous studies that the transient sodium channel(NaT)and delayed rectifyer potassium channel(K(DR))modulate the neuronal excitability.The simulation results in this study demonstated that NMDA could modulate these two ionic channels to hyperpolarize the voltage threshold by the amount comparable to the experimental observations.However,the slope of F-I relationship of the model was increased by NMDA,contrary to the experiment results.Therefore,we further proposed that the L-type calcium ion channels(CaL)might be involved in regulating the F-I relationship.The simulation results confirmed this prediction.In summary,the simulation results from the 5-HT neuron model demonstrated that:(1)NMDA could reduce the voltage threshold of 5-HT neurons by 2.6 mV,comparable to the experimental amount,through hyperpolarizing both the activation curve of K(DR)channels by 4.5 mV and the activation curve of NaT channels by 3 mV.(2)NMDA could alter the F-I relationship of the 5-HT neurons consistently with experimental observations through coupled-increasing the conductance of CaL channels by 33%.The conclusions of this study are:(1)The NMDA increased excitability of 5-HT neurons.Modulatoion of voltage threshold of the 5-HT neurons could be coupled with transient sodium channels and delayed rectifier potassium channels to hyperpolarize the voltage threshold for action potential generation.(2)The NMDA modulatoion of the F-I relationship of the 5-HT neurons could be coupled mainly with L-type calcium channels to shift the F-I relationship to the left with a reduction of the slope.The simulation results from the present study could provide predictions for subsequent physiological research and guidelines for development of motion control in artificial intelligence.The present study could also promote the neurophysiological research and artificial intelligence in spinal cord motor control.