Simulations of modulation of HCN channels in L5PCs (Mäki-Marttunen and Mäki-Marttunen, 2022)

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"... In this work, we build upon existing biophysically detailed models of thick-tufted layer V pyramidal cells and model the effects of over- and under-expression of Ih channels as well as their neuromodulation by dopamine (gain of Ih function) and acetylcholine (loss of Ih function). We show that Ih channels facilitate the action potentials of layer V pyramidal cells in response to proximal dendritic stimulus while they hinder the action potentials in response to distal dendritic stimulus at the apical dendrite. We also show that the inhibitory action of the Ih channels in layer V pyramidal cells is due to the interactions between Ih channels and a hot zone of low voltage-activated Ca2+ channels at the apical dendrite. Our simulations suggest that a combination of Ih-enhancing neuromodulation at the proximal apical dendrite and Ih-inhibiting modulation at the distal apical dendrite can increase the layer V pyramidal excitability more than any of the two neuromodulators alone..."
1 . Mäki-Marttunen T, Mäki-Marttunen V (2022) Excitatory and inhibitory effects of HCN channel modulation on excitability of layer V pyramidal cells Plos Comp Biol [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Neuron or other electrically excitable cell;
Brain Region(s)/Organism:
Cell Type(s): Neocortex layer 5 pyramidal cell;
Gap Junctions:
Receptor(s): AMPA; NMDA; Gaba;
Transmitter(s): Acetylcholine; Dopamine; Glutamate; Gaba;
Simulation Environment: NEURON;
Model Concept(s): Neuromodulation;
Implementer(s): Maki-Marttunen, Tuomo [tuomomm at];
Search NeuronDB for information about:  AMPA; NMDA; Gaba; Acetylcholine; Dopamine; Gaba; Glutamate;
TITLE AMPA and NMDA receptor with presynaptic short-term plasticity 

AMPA and NMDA receptor conductance using a dual-exponential profile
presynaptic short-term plasticity based on Fuhrmann et al. 2002
Implemented by Srikanth Ramaswamy, Blue Brain Project, July 2009
Etay: changed weight to be equal for NMDA and AMPA, gmax accessible in Neuron



        POINT_PROCESS ProbUDFsyn2group  
        RANGE tau_r, tau_d, Nsyns
        RANGE Use, u, Dep, Fac, u0
        RANGE i, g, e, gmax


        tau_r = 0.2   (ms)  : dual-exponential conductance profile
        tau_d = 1.7    (ms)  : IMPORTANT: tau_r < tau_d
        Use = 1.0   (1)   : Utilization of synaptic efficacy (just initial values! Use, Dep and Fac are overwritten by BlueBuilder assigned values) 
        Dep = 100   (ms)  : relaxation time constant from depression
        Fac = 10   (ms)  :  relaxation time constant from facilitation
        e = 0     (mV)  : AMPA and NMDA reversal potential
    	gmax = .001 (uS) : weight conversion factor (from nS to uS)
    	u0 = 0 :initial value of u, which is the running value of Use
        Nsyns = 10 : How many synapses are there actually

The Verbatim block is needed to generate random nos. from a uniform distribution between 0 and 1 
for comparison with Pr to decide whether to activate the synapse or not


#ifndef NRN_VERSION_GTEQ_8_2_0
double nrn_random_pick(void* r);
void* nrn_random_arg(int argpos);
extern int ifarg(int iarg);
extern int vector_capacity(void* vv);
extern void* vector_arg(int iarg);
#define RANDCAST
#define RANDCAST (Rand*)



        v (mV)
        i (nA)
	g (uS)
        space       : A pointer to the vector containing the synapse times. Note that the underlying vector should not be touched after initialization by setVec().

        A       : state variable to construct the dual-exponential profile - decays with conductance tau_r_AMPA
        B       : state variable to construct the dual-exponential profile - decays with conductance tau_d_AMPA


  LOCAL tp
	A = 0
  B = 0
	tp = (tau_r*tau_d)/(tau_d-tau_r)*log(tau_d/tau_r) :time to peak of the conductance
	factor = -exp(-tp/tau_r)+exp(-tp/tau_d) : Normalization factor - so that when t = tp, gsyn = gpeak
        factor = 1/factor


        SOLVE state METHOD cnexp
        g = gmax*(B-A) :compute time varying conductance as the difference of state variables B and A
        i = g*(v-e) :compute the driving force based on the time varying conductance, membrane potential, and reversal


        A' = -A/tau_r
        B' = -B/tau_d

NET_RECEIVE (weight, Pv, Pr, u, myInd, tsyn (ms), Pv_tmp){

        :Randomize which of the synapses is activated. Note that an additional random number is generated by rand() - this may interfere with the random number order in parallel simulations.
          void** vv = (void**)(&space);
          double *x;
          int nx = vector_instance_px(*vv, &x);
          int myInd = rand()%((int)Nsyns);
          _args[4] = myInd;
          _args[5] = x[myInd];                //tsyn
          _args[1] = x[myInd+(int)Nsyns];     //Pv
          _args[3] = x[myInd+2*((int)Nsyns)]; //u
        ::printf("NET_RECEIVE_beg: Pv = %g, Pr = %g, u = %g, myInd = %g, tsyn = %g, t = %g\n", Pv, Pr, u, myInd, tsyn, t)
        :printf("NET_RECEIVE_beg:  myInd = %g/%g, Pv = %g, u = %g, tsyn = %g, t = %g. ", myInd, Nsyns, Pv, u, tsyn, t)

        : calc u at event-
        if (Fac > 0) {
          u = u*exp(-(t - tsyn)/Fac) :update facilitation variable if Fac>0 Eq. 2 in Fuhrmann et al.
        } else {
          u = Use  
        if(Fac > 0){
          u = u + Use*(1-u) :update facilitation variable if Fac>0 Eq. 2 in Fuhrmann et al.

        Pv_tmp  = 1 - (1-Pv) * exp(-(t-tsyn)/Dep) :Probability Pv for a vesicle to be available for release, analogous to the pool of synaptic
                                                  :resources available for release in the deterministic model. Eq. 3 in Fuhrmann et al.
        Pr  = u * Pv_tmp                          :Pr is calculated as Pv * u (running value of Use)
        Pv_tmp  = Pv_tmp - u * Pv_tmp             :update Pv as per Eq. 3 in Fuhrmann et al.
        :printf("Pv = %g\n", Pv)
        :printf("Pr = %g\n", Pr)
	if (erand() < Pr){
          tsyn = t
          Pv = Pv_tmp
          A = A + weight*factor
          B = B + weight*factor
          ::printf ( "Released! value = %g, Pr = %g\n" , erand(), Pr )
          :printf ( "R! Pr = %g\n" , Pr )
        } else {
          ::printf("Not released! value = %g, Pr = %g\n", erand(), Pr )
          :printf ( "NR! Pr = %g\n" , Pr )
          x[myInd] = _args[5];
          x[myInd+(int)Nsyns] = _args[1];
          x[myInd+2*((int)Nsyns)] = _args[3];

         * This function takes a NEURON Random object declared in hoc and makes it usable by this mod file.
         * Note that this method is taken from Brett paper as used by netstim.hoc and netstim.mod
         * which points out that the Random must be in negexp(1) mode
        void** pv = (void**)(&_p_rng);
        if( ifarg(1)) {
            *pv = nrn_random_arg(1);
        } else {
            *pv = (void*)0;

FUNCTION erand() {
	    //FILE *fi;
        double value;
        if (_p_rng) {
                :Supports separate independent but reproducible streams for
                : each instance. However, the corresponding hoc Random
                : distribution MUST be set to Random.negexp(1)
                value = nrn_random_pick(RANDCAST _p_rng);
		        //fi = fopen("RandomStreamMCellRan4.txt", "w");
                //fprintf(fi,"random stream for this simulation = %lf\n",value);
                //printf("random stream for this simulation = %lf\n",value);
                return value;
                : the old standby. Cannot use if reproducible parallel sim
                : independent of nhost or which host this instance is on
                : is desired, since each instance on this cpu draws from
                : the same stream
                erand = exprand(1)
        :erand = value :This line must have been a mistake in Hay et al.'s code, it would basically set the return value to a non-initialized double value.
                       :The reason it sometimes works could be that the memory allocated for the non-initialized happened to contain the random value
                       :previously generated. However, here we commented this line out.

PROCEDURE setVec() {    : Sets the times of firing of each synapse. This should be done only once for each ProbAMPANMDA2group,
                        : before the running of the simulation, and the underlying vector should be untouched after that.
  void** vv;
  vv = (void**)(&space);
  *vv = (void*)0;
  if (ifarg(1)) {
    *vv = vector_arg(1);
    Nsyns = vector_capacity(*vv)/3;

PROCEDURE printVec() { : Prints the previous times of firing of each synapse.
    void** vv = (void**)(&space);
    double *x;
    int nx = vector_instance_px(*vv, &x);
    int i1;
    for (i1=0; i1<Nsyns;i1++) {
      printf("tsyns[%i] = %g, Pv[%i] = %g, u[%i] = %g\n", i1, x[i1], i1, x[i1+(nx/3)], i1, x[i1+2*(nx/3)]);

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