A method for modeling a neuron-astrocyte tripartite synapse

Abstract

The application is a modeling method of neuron-astrocyte three-way synapse, which divides astrocyte into cytoplasm compartment, mitochondrion compartment and endoplasmic reticulum compartment by compartment, and respectively calculates flux; the calculation formula of glucose glycolysis flux J pyr in the mitochondrion compartment is GLC, wherein the glucose concentration GLC is obtained by obtaining k C The cone cell, the intermediate neuron and the astrocyte are coupled by the following formula, the feedback function of the astrocyte to the neuron is used to quantify the feedback effect, the astrocyte feedback current is obtained; the astrocyte feedback current is combined into the neuron model, and the neuron-astrocyte three-way synapse model is obtained. The feedback mechanism of glycolysis reaction rate and calcium ion is introduced, which makes up for the limitation that the previous model cannot simulate the degree of sugar metabolism.

Description

Technical Field

[0001] This invention relates to the field of neural computing, specifically to a method for modeling neuron-astrocytic trigonometric synapses. Background Technology

[0002] In addition to neurons, the nervous system contains a large number of astrocytes, which play a crucial role in dynamically regulating synaptic plasticity and influencing neuronal firing characteristics. Research is increasingly focusing on the intrinsic mechanisms of neuron-astrocytocyte interaction. The feedback effect of astrocytes on neurons depends on cytoplasmic calcium ions, and current research models primarily consider calcium ion exchange between the endoplasmic reticulum and the cytoplasm. Most existing neuron-astrocytocyte trigonometric synapse models have not yet adequately considered the impact of mitochondrial presence on astrocyte regulation mechanisms, or they only consider the protective mechanisms of protein-coupled receptors without addressing the regulatory mechanisms of glycolysis and calcium ion levels on blood glucose. Further refinement is needed. Summary of the Invention

[0003] The purpose of this invention is to provide a method for modeling neuronal-astrocytic trigonal synapses. This method introduces a feedback mechanism of glycolysis rate and calcium ions into the glucose metabolism equation, which overcomes the limitation of previous models that could not simulate the degree of glucose metabolism. Furthermore, by changing this parameter, different physical states (such as hypoglycemia and diabetes) can be simulated, achieving the effect of simulating neuronal electrical activity under various physical states. This method can obtain a neuronal-astrocytic trigonal synapse model that takes into account the influence of mitochondrial metabolism.

[0004] To achieve the above objectives, the technical solution of the present invention is as follows:

[0005] A method for modeling neuron-astrocytic trigonal synapses, the specific steps of which are as follows:

[0006] Step 1: Divide astrocytes into cytoplasmic compartments, mitochondrial compartments, and endoplasmic reticulum compartments using compartments;

[0007] Step 2: Calculate various fluxes during the reaction process for the compartment containing the mitochondria: the flux J generated after glucose glycolysis participating in the citric acid cycle. pdh And glucose glycolysis flux J pyr Oxidation consumption flux J O And the flux consumed to drive protons out of the mitochondria J hres The flux generated by the exchange of mitochondrial ATP and cytoplasmic ADP J ant The flux J produced by phosphorylation of ATPase in mitochondria pf1 ATPase proton flux J hf1 and proton leakage flux J hl, the unidirectional transporter flux J uni , Ca 2+ and Na + exchange flux J nc ;

[0008] The calculation formula of the glucose glycolysis flux J pyr is wherein the glucose concentration GLC is obtained by The k C is obtained by the following formula

[0009]

[0010] wherein k GLC describes the chemical reaction constant of glucose; k Set is the glycolysis reaction rate, is a variable parameter, k C is the change rate of glucose, [Ca 2+ ] c is the calcium ion concentration in the cell cytoplasm, k N is a constant, and Θ is the Heaviside step function, [NADH] m is the concentration of NADH in the mitochondria, [NADH] th is the concentration threshold of NADH in the mitochondria;

[0011] Step 3: Calculate the fluxes of the endoplasmic reticulum compartment and the cell cytoplasm compartment;

[0012] Step 4: Coupling the pyramidal cells, the interneurons and the astrocytes, using the astrocyte feedback function on the neurons to quantify the feedback effect, and obtaining the astrocyte feedback current;

[0013] Step 5: Using the Hodgkin-Huxley neuron model for the neuron part, combining the astrocyte feedback current of Step 4 into the neuron model in addition to the external stimulation current and the synaptic current, and obtaining the neuron-astrocyte tripartite synapse model.

[0014] The expression of the flux J pdh generated by the citric acid cycle after the glucose glycolysis is:

[0015]

[0016] [NAD] m = N tot -[NADH] m ,

[0017] wherein p a , p bis a dimensionless constant, [Ca 2+ ] m is the mitochondrial calcium concentration, [NADH] m is the concentration of NADH in the mitochondria, [NADH] th is the concentration threshold of NADH in the mitochondria; N tot is a dimensionless constant; [NAD] m is the concentration of NAD in the mitochondria;

[0018] Setting the oxygen level as a dynamic variable, the oxidative consumption flux J O and the consumption flux J hres driving the protons out of the mitochondria are expressed as:

[0019]

[0020] where O is the oxygen concentration, O out is the extracellular oxygen concentration, a is a rate constant; k0, k3, k4, k9, k 10 , k 11 , k 13 , k 0x are dimensionless constants; Ψ2, Ψ3 are the mitochondrial membrane potential values and are constants; ΔΨ is the membrane potential of the mitochondria relative to the cytosol;

[0021] The expression of the flux J ant generated by the exchange of ATP and cytosolic ADP in the mitochondria is:

[0022]

[0023] where A mtot is the total conservation between ATP and ADP, k5, k6 are dimensionless constants; [ADP] m is the concentration of ADP in the mitochondria;

[0024] The expression of the flux J pf1 generated by the phosphorylation of ATPase in the mitochondria is:

[0025]

[0026] where k7, k8, Ψ1, A tot are dimensionless constants;

[0027] The expressions of the proton flux J hf1 and the proton leak flux J hl of the ATPase are:

[0028] J hf1 = k 12 J ant ,

[0029] J hl = 0.2 (ΔΨ + 24.6),

[0030] where k 12 is a dimensionless constant whose value indicates the degree of ATPase oxidation and the relationship between ATP and ADP exchange;

[0031] The mitochondrial unidirectional transporter flux J uni is:

[0032]

[0033]

[0034] where p uni is a dimensionless constant, [Ca 2+ ] c is the cytosolic calcium concentration, VD uni is the driving force of the mitochondrial membrane potential; Ca 2+ and Na + exchange flux J nc is expressed as:

[0035]

[0036] where dmito is a dimensionless constant, VD nc is the driving force of the mitochondrial membrane potential on this process.

[0037] The fluxes of the endoplasmic reticulum compartment and the cytosolic compartment include the endoplasmic reticulum release Ca 2+ flux J erout and the Ca 2+ pumping back to the endoplasmic reticulum flux J serca , expressed as follows:

[0038]

[0039] where h ip3 is a variable for the slow inactivation of the IP3 channel, v leak is the calcium leakage rate, d act and d inh are dimensionless constants, τ h is the time delay constant, v ip3 is the inositol triphosphate release constant, [Ca 2+ ] er is the calcium concentration of the endoplasmic reticulum, [Ca 2+ ] c is the calcium concentration in the cytosol, f e , e and vol er are the endoplasmic reticulum Ca2+ Buffer, endoplasmic reticulum protein amount, and endoplasmic reticulum volume, f c For the cell cytoplasm Ca 2+ Buffer, vol er For the cell cytoplasm volume, v serca For the calcium ion pump-out rate, k serca For the system constant.

[0040] The expression of the astrocytic feedback current is as follows:

[0041]

[0042] Where F is the neuron feedback function, t is time, τ Ca 2+ And k are the relaxation time constant and the proportional coefficient, respectively, Θ is the Heaviside step function, [Ca 2+ ] th Is the calcium ion concentration threshold, And Are the feedback currents of the astrocyte to the pyramidal cell and the interneuron, respectively, ε1 and ε2 are the proportional coefficients of the feedback current.

[0043] The process of combining the astrocytic feedback current into the neuron model is as follows:

[0044] The model of the pyramidal cell is as follows:

[0045]

[0046] The model of the interneuron is as follows:

[0047]

[0048] Where

[0049] I Na = g Na m 3 h(V x -E Na ),

[0050] I K = g K n 4 (V x -E K ),

[0051] I L = g L (V x -E L ), x = PY, IN.

[0052] In the formula, V PN And VIN Transmembrane membrane potential of pyramidal cell and interneuron, respectively, m Capacitance of neuron lipid bilayer; External current received by pyramidal cell, Synaptic current of interneuron, Negative feedback current of astrocyte to pyramidal cell;I Na , I K and I L Current of sodium channel, potassium channel and leak channel, respectively, g Na , g K Maximum conductance of sodium channel and potassium channel, respectively, g L Leak conductance; E Na , E K and E L Inversion potential of neuron sodium channel, potassium channel and leak, respectively; m, n and h are the opening probability of ion channel.

[0053] Compared with the prior art, the beneficial effects of the present application are:

[0054] (1) The present application considers the glycolysis degree as an index in mitochondrial glucose metabolism. Therefore, abnormal states of low blood sugar and high blood sugar can be simulated according to the set parameters, and kinetic analysis and regulation under abnormal blood sugar can be completed.

[0055] (2) The feedback regulation mechanism of calcium ions on blood glucose (Kc parameter expression) is used in the physiological process, which is more consistent with the influence of calcium ions on the glucose metabolism process of mitochondria in astrocytes in the real nervous system. At the same time, the coupling of mitochondrial astrocyte and neuron model is considered, so as to explore the influence of mitochondrial metabolism on neuron firing activity, and to broaden the research direction of kinetics.

[0056] (3) The present application considers the glycolysis degree and calcium ion feedback in the mitochondrial glucose metabolism model (formula (2)) and combines multiple models. The present application can simulate other cells by changing the parameters of the compartment, thereby expanding the experiment, and can change the volume and protein mass of the compartment to simulate abnormal cell conditions and complete model exploration under disease state.

[0057] The modeling method of the neuron-astrocyte three-way synapse system model of the application effectively combines astrocytes, neurons and coupling mechanisms together, introduces mitochondria in the model of astrocytes, provides calcium ion exchange mechanisms of mitochondria, endoplasmic reticulum and cell cytoplasm, introduces glucose concentration to simulate a more real mitochondrial metabolism process by constructing a glycolysis process and a feedback mechanism of calcium ion-regulated blood glucose, and changes the glucose metabolism by changing the glycolysis rate to construct a model under different blood glucose levels. In addition, the change of the size of glucose and the numerical size of the glycolysis rate can affect the regulation mechanism of astrocytes to neurons. The model obtained by the method of the application is helpful for studying the synchronous dynamic characteristics and exploring the influence of mitochondrial metabolism on the neuron firing characteristics according to the data analysis results, and is conducive to helping people further understand the internal mechanism and principle of neurodegenerative diseases caused by abnormal mitochondrial metabolism.

[0058] In the application, the mitochondria act as a Ca 2+ storage, have the functions of isolating Ca 2+ and releasing free Ca 2+ , and can affect the shape, frequency and amplitude of the Ca 2+ signal. The size of the glucose concentration plays an important role in the steady state of astrocytes and Ca 2+ signal transmission, and the glycogen content of astrocytes has a stabilizing effect on hippocampal memory regulation. The application fully considers the glycolysis degree and the calcium regulation mechanism of blood glucose, which is helpful for further effectively describing the internal mechanism of the nervous system.

[0059] The method of the application can change the glucose concentration to simulate the mitochondrial metabolism, and the numerical simulation results can be compared, summarized and summarized with physiological experiments, which has a theoretical guiding effect on some neurogenic diseases caused by abnormal mitochondrial metabolism. BRIEF DESCRIPTION OF DRAWINGS

[0060] Figure 1 It is a schematic diagram of the neuron-astrocyte three-way synapse model. DETAILED DESCRIPTION

[0061] In order to more clearly illustrate the technical solutions of the application, the following further introduces the drawings and examples of the application, but does not take this as a limitation on the protection scope of the present application.

[0062] The application is a modeling method of neuron-astrocyte three-way synapse, which considers the influence of mitochondrial metabolism on neuron-astrocyte information transmission, uses glucose concentration to represent the cell metabolism state, exchanges the calcium ion concentration in the cell cytoplasm through the flux of the compartment, and combines with the model of neurons to form a neuron-astrocyte three-way synapse model, which specifically includes the following steps:

[0063] Step 1: divide the astrocyte into three compartments, cytosol compartment, mitochondria compartment and endoplasmic reticulum compartment;

[0064] The astrocyte is divided into three compartments, cytosol, mitochondria and endoplasmic reticulum. The concentration calculation method in different compartments is as follows: the total flux of each compartment is obtained by multiplying the volume of the corresponding compartment by its protein density; the concentration is obtained by dividing the total flux of the compartment by the volume of the compartment.

[0065] Step 2: calculate the various fluxes in the compartment where the mitochondria are located during the reaction process: the flux J pdh of glucose glycolysis participating in the citric acid cycle to produce; pyr The flux J O of oxidative consumption driving protons out of the mitochondria; hres The flux J ant of ATP and cytosolic ADP exchange generated by mitochondria; pf1 The flux J hf1 of ATPase phosphorylation in mitochondria; hl The flux J uni of one-way transporter; 2+ The exchange flux J + of Ca nc and Na 2+ ;

[0066] The differential equation describing the change of the parameter concentration in the physiological process in the mitochondria is described by the following formula in the mitochondria compartment, in which pyruvate is produced by glucose glycolysis in the mitochondria, pyruvate participates in the citric acid cycle to produce reduced coenzyme I (NADH), NADH is oxidized and phosphorylated to produce protons and electrons, and protons are combined with ADP to generate ATP. Its expression is as follows.

[0067]

[0068] In the formula, subscript m represents the mitochondria, ΔΨ is the membrane potential of the mitochondria relative to the cytosol, [Ca 2+ ] m is the calcium ion concentration in the mitochondria, [H] m is the proton concentration in the mitochondria. The constant m m is the amount of mitochondrial protein, f m , C n , vol m and vol c correspond to the calcium ion buffer in the mitochondria, the mitochondrial membrane capacitance, the volume of the mitochondria and the volume of the cytosol, respectively. τ min is a constant, and the time scale is changed from minutes to seconds, γ mAs a constant, the concentration is changed from μM to mM. J pdh The flux generated by glucose glycolysis participating in the citric acid cycle, J pyr The flux of glucose glycolysis is expressed as follows:

[0069]

[0070] In the formula p a p b and p c [Ca] is a dimensionless constant. 2+ ] m This refers to the mitochondrial calcium ion concentration, k. GLC The chemical reaction constant describing glucose; NADH is the reduction product of NAD; the concentrations of NADH and NAD follow a conservation equation; k N and N tot k is a dimensionless constant. C For the rate of change of glucose, k in equation 2 C The feedback of cytoplasmic calcium ion concentration on glucose glycolysis in the parameters; k Set The glycolysis rate is a variable parameter; its magnitude can be changed to describe the degree of glycolysis and thus simulate different bodily states. [Ca] 2+ ] c Θ represents the calcium ion concentration in the cytoplasm, and [NADH] is the Heaviside step function. m The concentration of NADH in mitochondria, [NADH] th This represents the concentration threshold of NADH in mitochondria. Mitochondrial oxygen consumption is divided into oxidative consumption flux (J). O And the flux consumed to drive protons out of the mitochondria J hres Meanwhile, oxygen level is set as a dynamic variable, and the equation is:

[0071]

[0072] In the formula, O represents the oxygen concentration. out Let be the extracellular oxygen concentration, and α be the rate constant. k0, k3, k4, k9, k 10 k 11 k 13 k 0x Ψ2 and Ψ3 are dimensionless constants. Ψ2 and Ψ3 are numerical values ​​of mitochondrial membrane potentials and are constants.

[0073] J ant The flux generated by the exchange of mitochondrial ATP and cytoplasmic ADP is expressed as:

[0074]

[0075] In the formula Amtot is the total conservation between ATP and ADP, and k5, k6 are dimensionless constants. The flux of ATPase phosphorylation in mitochondria is J pf1 The expression is:

[0076]

[0077] where k7, k8, Ψ1, A tot are dimensionless constants. There is ATPase phosphorylation and proton transport in mitochondria, so the proton flux of ATPase J hf1 and the proton leakage flux J hl The expression is:

[0078]

[0079] where k 12 is a dimensionless constant, and its value indicates the degree of ATPase oxidation and the exchange relationship between ATP and ADP. Mitochondria contain a unidirectional transporter responsible for transporting calcium ions from the cell cytoplasm to mitochondria against the gradient, so it is related to the size of the mitochondrial membrane potential, and the unidirectional transporter flux J uni The equation is as follows:

[0080]

[0081] where J uni1 is the transport capacity measured by the concentration of calcium ions in the cell cytoplasm, and ρ uni is a dimensionless constant, [Ca 2+ ] c is the concentration of calcium ions in the cell cytoplasm, and VD uni is the driving force of the mitochondrial membrane potential. The mitochondria and the cell cytoplasm will produce the exchange of Ca 2+ and Na + , and the exchange ratio is 3 Na + and 1 Ca 2+ , and the exchange flux J 2+ of Ca + and Na nc is expressed as:

[0082]

[0083] where dmito is a dimensionless constant, VD nc is the driving force of the mitochondrial membrane potential on this process; and ρ nc is a dimensionless constant.

[0084] The physiological activities in mitochondria include glycolysis, citric acid cycle, oxidative consumption, exchange between mitochondrial ATP and cytosolic ADP, ADP phosphorylation, glycolysis phosphorylation, unidirectional transporter driven calcium ion, calcium ion and sodium ion exchange, and proton transfer. The glucose concentration is introduced in the glycolysis to represent the glycolysis process.

[0085] The above equations (1)-(8) constitute a model of mitochondria in astrocytes.

[0086] Step 3: Calculate the fluxes of endoplasmic reticulum compartment and cytosol compartment;

[0087] The calcium ion conduction part on the endoplasmic reticulum model and cytosol is based on the Li-Rinzel model and combined with the expression of the compartment and refers to the expression of the compartment in equation (1) for the endoplasmic reticulum and cytosol. It mainly includes the release of Ca 2+ The flux J erout and Ca 2+ pumped back from the cytosol to the endoplasmic reticulum flux J serca , the expression is as follows:

[0088]

[0089] In the formula, h ip3 is a variable for slow inactivation of IP3 channel, v leak is the calcium ion leakage rate, d act and d inh are dimensionless constants, τ h is the time delay constant, v ip3 is the inositol triphosphate release constant, [Ca 2+ ] er is the calcium ion concentration of the endoplasmic reticulum, [Ca 2+ ] c is the calcium ion concentration in the cytosol, f e , e and vol er are the endoplasmic reticulum Ca 2+ buffer, the amount of endoplasmic reticulum protein and the volume of endoplasmic reticulum, f c is the cytosolic Ca 2+ buffer, vol er is the cytosolic volume, v serca is the calcium ion pumping rate, k serca is a system constant. The expression of cytosolic calcium ion concentration combines the unidirectional transporter flux J uni , the exchange flux J 2+ of Ca + and Na nc .

[0090] Equation (9) is the endoplasmic reticulum model of the astrocyte and the cytoplasm model of the cell: wherein the value of [IP3] is obtained by equation (19).

[0091] Step 4: coupling the pyramidal cell, the interneuron and the astrocyte, when the cytoplasm calcium ion concentration of the astrocyte exceeds the threshold value, the astrocyte adjusts and feeds back to the neuron, the feedback function F of the astrocyte to the neuron is used to quantify the feedback effect, and the astrocyte feedback current is obtained, and the specific expression is as follows:

[0092]

[0093] wherein and k are the relaxation time constant and the proportional coefficient respectively, Θ is the Heaviside step function, [Ca 2+ ] th is the calcium ion concentration threshold value, when the threshold value is exceeded, the astrocyte has a feedback effect on the neuron. and are the feedback currents of the astrocyte to the pyramidal cell and the interneuron respectively, ε1 and ε2 are the proportional coefficients of the feedback current, and the size thereof affects the regulation strength of the astrocyte to the neuron.

[0094] Step 5: the neuron part uses the Hodgkin-Huxley neuron model (H-H model), in addition to the external stimulation current and the synaptic current, the feedback currents of the astrocyte to the pyramidal cell and the interneuron in step 4 are combined into the neuron model, and a neuron-astrocyte three-party synapse model is obtained, and the specific expression is as follows: and

[0095] The model of the pyramidal cell is as follows:

[0096]

[0097] The model of the interneuron is as follows:

[0098]

[0099] wherein

[0100] I Na =g Na m 3 h(V x -E Na ),

[0101] I K =g K n 4 (V x -E K ),​

[0102] I L = g L (V x - E L ), x = PY, IN. (13)

[0103] where V PN and V IN are the transmembrane membrane potentials of the pyramidal cell and the interneuron, respectively, C m is the capacitance of the neuron lipid bilayer. The pyramidal cell is subject to an external current stimulus, as well as a synaptic current from the interneuron and a negative feedback current from the astrocyte. Similarly, the interneuron has an external current stimulus, a synaptic current from the pyramidal cell, and a positive feedback current from the astrocyte. In the Hodgkin-Huxley model, I Na , I K , and I L are the currents of the sodium, potassium, and leak channels, respectively, g Na , g K are the maximum conductances of the sodium and potassium channels, respectively, and g L is the leak conductance. E Na , E K , and E L are the reversal potentials of the neuron sodium, potassium, and leak channels, respectively. m, n, and h are the opening probabilities of the ion channels, and the differential equations are:

[0104]

[0105] α u and β u represent the on and off constants of the ion channel gates, and the sodium ion channel has three activation gate variables m and one inactivation gate variable h, while the potassium ion channel has four activation gate variables n. The sizes of these activation and inactivation variables are affected by the membrane potentials of the pyramidal cell and the interneuron, and are given by:

[0106]

[0107] The sizes of the synaptic currents and are related to the neurotransmitter concentrations that affect the synaptic variables s PY and s IN , and the concentration of neurotransmitter released into the synaptic cleft [T] x depends on the driving of the membrane potential size, and the differential equations for the neurotransmitter concentrations are:

[0108]

[0109] The synaptic variable differential equation is:

[0110]

[0111] The synaptic current equation is:

[0112]

[0113] where [T] PY and [T] IN are the concentrations of neurotransmitters released by the pyramidal cells and interneurons into the synaptic cleft. Since the synaptic channels are analogous to ion channels, the synaptic variable s PY and s IN also have coefficients a s , b s that describe the increase and decay of the channels. g se and g si are the excitatory and inhibitory coupling strengths, respectively, and V si and V se are the inhibitory and excitatory synaptic reversal potentials.

[0114] After the neuron generates an action potential, it releases neurotransmitters into the synaptic cleft. Astrocytes are sensitive to the neurotransmitters and bind to some of them, causing the release of IP3. The IP3 mechanism in the astrocyte is expressed as:

[0115]

[0116] where a is the IP3 decay coefficient, [IP3] * is the equilibrium concentration of IP3, and a is the rate of IP3 production after the neuron fires. The release of IP3 promotes the release of Ca 2+ from the endoplasmic reticulum (ER) into the cytoplasm of the astrocyte. Due to the increase in cytoplasmic Ca 2+ , the astrocyte releases calcium-dependent glial transmitters (e.g., glutamate and ATP) into the synaptic cleft, which act on the neurons to modulate the electrical activity of the neurons.

[0117] Equations (10)-(18) constitute the neuron model.

[0118] Figure 1The schematic diagram of the neuron-astrocyte three-way synaptic model is composed of a pyramidal cell (PY), an intermediate neuron (IN) and an astrocyte. The astrocyte contains endoplasmic reticulum, mitochondria and cytoplasm. The endoplasmic reticulum, mitochondria and cytoplasm in the astrocyte are divided according to the compartments, and the schematic diagram mainly reflects the calcium ion conduction related process in the astrocyte. The unidirectional transporter of the mitochondria drives the cytoplasm calcium ion into the mitochondria through the mitochondrial membrane potential, which is related to formula 7 in step 2, and the mitochondria and cytoplasm exchange calcium ion and sodium ion, which is related to formula 8 in step 2. Formula 7 and formula 8 are related to the mitochondrial membrane potential, and the size of the mitochondrial membrane potential is also closely related to the size of each flux in step 2. The calcium ion conduction between the endoplasmic reticulum and the cytoplasm is related to formula 9 in step 3, in which the cytoplasm calcium ion is pumped into the endoplasmic reticulum through the pump on the endoplasmic reticulum, and the endoplasmic reticulum also flows into the cytoplasm through the IP3R receptor and calcium ion leakage. When the calcium ion concentration in the cytoplasm exceeds the threshold value, it will feedback to the neuron, and the feedback effect formula is shown in formula 10. The astrocyte is a negative feedback to the pyramidal cell and a positive feedback to the intermediate neuron, and the specific formula is shown in formula 10. The pyramidal cell and the intermediate neuron also interact with each other, and the pyramidal cell is a positive feedback to the intermediate neuron, and the intermediate neuron is a negative feedback to the pyramidal cell, and the formula is shown in formula 18. The above process constitutes the neuron-astrocyte three-way synaptic model.

[0119] Table 1 is the numerical value and unit of the parameters in the neuron-astrocyte three-way synaptic model

[0120]

[0121]

[0122] The unmentioned part of the present application is applicable to the prior art.

Claims

1. A method of modeling a neuronal-astrocytic tripartite synapse, characterized by, The specific steps are as follows: Step 1: divide the astrocyte into a cell cytoplasm compartment, a mitochondrion compartment and an endoplasmic reticulum compartment by using the compartments; Step 2: Calculate various fluxes during the reaction process for the compartment containing the mitochondria: the flux J generated after glucose glycolysis participating in the citric acid cycle. pdh And glucose glycolysis flux J pyr Oxidation consumption flux J O And the flux consumed to drive protons out of the mitochondria J hres The flux generated by the exchange of mitochondrial ATP and cytoplasmic ADP J ant The flux J produced by phosphorylation of ATPase in mitochondria pf1 ATPase proton flux J hf1 and proton leakage flux J hl 1. Unidirectional transporter flux J uni Ca 2+ and Na + Exchange flux J nc ; The glucose glycolysis flux J pyr The calculation formula is where the glucose concentration GLC is obtained by k C is obtained from the following formula where k GLC describes the chemical reaction constant for glucose; k Set is the rate of glycolysis, is a variable parameter, k C is the rate of change of glucose, [Ca 2+ ] c is the concentration of calcium ions in the cytoplasm of the cell, k N is a constant, Θ is the Heaviside step function, [NADH] m is the concentration of NADH in the mitochondria, [NADH] th is the threshold concentration of NADH in the mitochondria; Step 3: calculate the fluxes of the endoplasmic reticulum compartment and the cell cytoplasm compartment; Step 4: couple the pyramidal cell, the interneuron and the astrocyte, use the astrocyte feedback function on the neuron to quantify the feedback effect, and obtain an astrocyte feedback current; The expression of the astrocyte feedback current is: where F is a neuron feedback function, t is time, and k are the relaxation time constant and the proportional coefficient, respectively, Θ is the Heaviside step function, [Ca 2+ ] th is the calcium ion concentration threshold, and are the feedback currents of astrocytes to pyramidal cells and interneurons, respectively, and ε1 and ε2 are the proportional coefficients of the feedback currents. Step 5: use the Hodgkin-Huxley neuron model for the neuron part, in addition to the external stimulus current and the synaptic current, combine the astrocyte feedback current of step 4 into the neuron model, and obtain a neuron-astrocyte three-party synapse model.

2. The method of modeling a neuron-astrocyte tripartite synapse according to claim 1, wherein glucose flux J produced by the citric acid cycle after glycolysis pdh The expression thereof is: [NAD] m = N tot -[NADH] m , where p a , p b is a dimensionless constant, [Ca 2+ ] m is the mitochondrial calcium ion concentration, [NADH] m is the concentration of NADH in the mitochondria, [NADH] th is the threshold concentration of NADH in the mitochondria; N tot is a dimensionless constant; [NAD] m is the concentration of NAD in the mitochondria The concentration of NAD in the astrocyte; Setting the oxygen level as a dynamic variable, the oxidative consumption flux J O and the consumption flux J driving the proton out of the mitochondria hres is given by the expression: where O is the oxygen concentration, O out is the extracellular oxygen concentration, and a is a rate constant; k0, k3, k4, k9, k 10 , k 11 , k 13 , k 0x are dimensionless constants; Ψ2, Ψ3 are the mitochondrial membrane potential values and are constants; ΔΨ is the membrane potential of the mitochondria relative to the cytosol; The flux J resulting from the exchange of mitochondrial ATP and cellular cytosolic ADP ant The expression is: where A mtot is the total conserved quantity between ATP and ADP, k5, k6 are dimensionless constants; [ADP] m is the concentration of ADP in the mitochondria; The flux J produced by the phosphorylation of ATPase in mitochondria pf1 The expression is: wherein k7, k8, ψ1, A tot is a dimensionless constant; The proton flux J of the ATPase hf1 and the proton leak flux J hl is given by the expression: J hf1 = k 12 J ant , J hl = 0.2(ΔΨ + 24.6), (6) where k 12 is a dimensionless constant whose value indicates the degree of ATPase acidification and the relationship between ATP and ADP exchange; The mitochondrial unidirectional transporter flux J uni Is: where p uni is a dimensionless constant, [Ca 2+ ] c is the cytosolic calcium ion concentration, VD uni is the driving force for the mitochondrial membrane potential; Ca 2+ and Na + exchange flux J nc is represented as: where dmito is a dimensionless constant, VD nc is driven by the mitochondrial membrane potential.

3. The method of modeling a neuron-astrocyte tripartite synapse according to claim 1, wherein, The fluxes of the endoplasmic reticulum compartment and the cytosolic compartment include the release of Ca 2+ The flux J erout and Ca 2+ The flux J serca from the cytosol back to the endoplasmic reticulum, expressed as follows: where h ip3 is a variable for IP3 channel slow inactivation, v leak is the calcium ion leak rate, d act and d inh is a dimensionless constant, τ h is a time delay constant, v ip3 is a constant for inositol triphosphate release, [Ca 2+ ] er is the calcium ion concentration in the endoplasmic reticulum, [Ca 2+ ] c is the calcium ion concentration in the cell cytoplasm, f e , e, and vol er are the endoplasmic reticulum Ca 2+ buffer, the amount of endoplasmic reticulum protein, and the endoplasmic reticulum volume, f c is the cell cytoplasm Ca 2+ buffer, vol er is the cell cytoplasm volume, v serca is the calcium ion pump out rate, k serca is a system constant.

4. The method of modeling a neuron-astrocyte tripartite synapse according to claim 1, wherein, The process of combining the astrocyte feedback current into the neuron model is: The model of the pyramidal cell is as follows: The model of the interneuron is as follows: wherein I Na = g Na m 3 h(V x - E Na ), I K = g K n 4 (V x -E K ), I L = g L (V x - E L ), x = PY, IN. where V PN and V IN are the transmembrane membrane potentials of the pyramidal cell and the interneuron, respectively, C m is the capacitance of the neuron lipid bilayer; is the external current received by the pyramidal cell, is the synaptic current of the interneuron, is the negative feedback current of the astrocyte to the pyramidal cell; I Na , I K , and I L are the currents of the sodium channel, the potassium channel, and the leak channel, respectively, g Na , g K are the maximum conductances of the sodium channel and the potassium channel, respectively, g L is the leak conductance; E Na , E K , and E L are the reversal potentials of the neuron sodium channel, the potassium channel, and the leak, respectively; m, n, and h are the opening probabilities of the ion channels.

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