load_file("nrngui.hoc")
//The user can stimulate the terminals with capsaicin by adjusting Capsaicin_stimulation.hoc and uncommenting the last line of this file.
celsius = 25
//
// Nociceptive terminal model
//
// Barkai et al. 2020
//
//////////////////// VARIABLES /////////////////////
tstop = 3000
CENTRAL_DIAM = 0.4
///////////////// MORPHOLOGY ///////////////////////
Term_Branch = 27//Number of Terminal Branches
Peri_Seg = 6// Number peripheral axon regions
Term_Length = 1000 //Terminal Branches length
NavLessNum=14
NavLessLength=25 // was 35 // original 25
SF=1 //Scaling factor for terminal
print NavLessLength
CENTRAL_DIAM = 0.4
//create soma, central,terminal[Term_Branch], peri, tjcentral, tjperi, stem, cone, NavLess[NavLessNum]
create soma, central,terminal[Term_Branch], peri[Peri_Seg], tjcentral, tjperi, stem, cone, NavLess[NavLessNum]
l_seg = 10 //segment size
l_seg_skinterminal = 5 //segment size for terminals (for more accuracy)
peri[0] {nseg=25 L=1000 diam = .8} // peripherial axon
peri[1] {nseg=25 L=1000 diam = .7}
peri[2] {nseg=25 L=1000 diam = .6}
peri[3] {nseg=25 L=1000 diam = .5}
peri[4] {nseg=25 L=1000 diam = .4}
peri[5] {nseg=25 L=1000 diam = .3}
tjperi {nseg=100 L=100 diam = .8} // tjunction axon
tjcentral {nseg=100 L=100 diam = CENTRAL_DIAM} // tjunction axon
central {nseg=100 L=5000 diam = CENTRAL_DIAM} // central axon
stem {nseg=100 L=75 diam = 0.8} // stem axon
soma {nseg=1 L=25 diam =25} // soma
Rorg=1 //Mitochondira etc. resistance at terminals
//////// Connectivity //////////
//terminal connect peri(0),1
peri[0] connect tjperi(0),1
tjperi connect stem(0),1
stem connect soma(0),1
tjperi connect tjcentral(0),1
tjcentral connect central(0),1
//Terminal branch morphology and connectivity
term_L=100
term_nseg=term_L/l_seg //Dividing the compartment to l size segment
term_diam=0.25
connect peri[0](0), peri[1](1)
connect peri[1](0), peri[2](1)
connect peri[2](0), peri[3](1)
connect peri[3](0), peri[4](1)
connect peri[4](0), peri[5](1)
connect peri[5](0), terminal[0](1)
// connect terminal[0](1), cone(0)
// connect peri(0), cone(1)
terminal[0]{nseg=term_nseg L=term_L diam=term_diam}
// Terminal Morphology
terminal[0] {nseg=term_nseg L=300*SF diam=term_diam}
terminal[1] {nseg=term_nseg L=120*SF diam=term_diam}
terminal[2] {nseg=term_nseg L=120*SF diam=term_diam}
terminal[3] {nseg=term_nseg L=400*SF diam=term_diam}
terminal[4] {nseg=term_nseg L=250*SF diam=term_diam}
terminal[5] {nseg=term_nseg L=95*SF-NavLessLength diam=term_diam}
terminal[6] {nseg=term_nseg L=175*SF-NavLessLength diam=term_diam}
terminal[7] {nseg=term_nseg L=40*SF diam=term_diam}
terminal[8] {nseg=term_nseg L=40*SF diam=term_diam}
terminal[9] {nseg=term_nseg L=40*SF diam=term_diam}
terminal[10] {nseg=term_nseg L=160*SF diam=term_diam}
terminal[11] {nseg=term_nseg L=100*SF-NavLessLength diam=term_diam}
terminal[12] {nseg=term_nseg L=100*SF-NavLessLength diam=term_diam}
terminal[13] {nseg=term_nseg L=100*SF-NavLessLength diam=term_diam}
terminal[14] {nseg=term_nseg L=100*SF-NavLessLength diam=term_diam}
terminal[15] {nseg=term_nseg L=350*SF diam=term_diam}
terminal[16] {nseg=term_nseg L=175*SF-NavLessLength diam=term_diam}
terminal[17] {nseg=term_nseg L=185*SF-NavLessLength diam=term_diam}
terminal[18] {nseg=term_nseg L=85*SF diam=term_diam}
terminal[19] {nseg=term_nseg L=200*SF-NavLessLength diam=term_diam}
terminal[20] {nseg=term_nseg L=200*SF-NavLessLength diam=term_diam}
terminal[21] {nseg=term_nseg L=155*SF-NavLessLength diam=term_diam}
terminal[22] {nseg=term_nseg L=200*SF diam=term_diam}
terminal[23] {nseg=term_nseg L=150*SF-NavLessLength diam=term_diam}
terminal[24] {nseg=term_nseg L=80*SF diam=term_diam}
terminal[25] {nseg=term_nseg L=75*SF-NavLessLength diam=term_diam}
terminal[26] {nseg=term_nseg L=180*SF-NavLessLength diam=term_diam}
connect terminal[1](1),terminal[0](0)
connect terminal[2](1),terminal[0](0)
connect terminal[3](1),terminal[1](0)
connect terminal[4](1),terminal[1](0)
connect terminal[5](1),terminal[2](0)
connect NavLess[13](1), terminal[5](0)
connect terminal[6](1),terminal[2](0)
connect NavLess[12](1), terminal[6](0)
connect terminal[7](1),terminal[3](0)
connect terminal[8](1),terminal[3](0)
connect terminal[9](1),terminal[4](0)
connect terminal[10](1),terminal[4](0)
connect terminal[11](1),terminal[7](0)//skin
connect NavLess[11](1), terminal[11](0)
connect terminal[12](1),terminal[7](0)//skin
connect NavLess[10](1), terminal[12](0)
connect terminal[13](1),terminal[8](0)//skin
connect NavLess[9](1), terminal[13](0)
connect terminal[14](1),terminal[8](0)//skin
connect NavLess[8](1), terminal[14](0)
connect terminal[15](1),terminal[9](0)
connect terminal[16](1),terminal[9](0)
connect NavLess[7](1), terminal[16](0)
connect terminal[17](1),terminal[10](0)
connect NavLess[6](1), terminal[17](0)
connect terminal[18](1),terminal[10](0)
connect terminal[19](1),terminal[15](0)//skin
connect NavLess[5](1), terminal[19](0)
connect terminal[20](1),terminal[15](0)//skin
connect NavLess[4](1), terminal[20](0)
connect terminal[21](1),terminal[18](0)
connect NavLess[3](1), terminal[21](0)
connect terminal[22](1),terminal[18](0)
connect terminal[23](1),terminal[22](0)//skin
connect NavLess[2](1), terminal[23](0)
connect terminal[24](1),terminal[22](0)
connect terminal[25](1),terminal[24](0)//skin
connect NavLess[1](1), terminal[25](0)
connect terminal[26](1),terminal[24](0)//skin
connect NavLess[0](1), terminal[26](0)
objref DRG // create new object called DRG
DRG = new SectionList() // Define DRG as a list of sections
tjperi DRG.append() // DRG sections: tjunction, stem, and soma
tjcentral DRG.append()
stem DRG.append()
soma DRG.append()
objref TermSec // create new object called TermSec for terminals
TermSec = new SectionList()
cone TermSec.append()
for i=0, Term_Branch-1 {
terminal[i] TermSec.append()
}
objref NavLessSec
NavLessSec = new SectionList()
for i=0, NavLessNum-1 {
NavLess[i] NavLessSec.append()
}
objref TermSkin // Skin inervating Terinals (for Goldstein et al.)
TermSkin = new SectionList()
terminal[26] TermSkin.append()
terminal[25] TermSkin.append()
terminal[23] TermSkin.append()
terminal[21] TermSkin.append()
terminal[20] TermSkin.append()
terminal[19] TermSkin.append()
terminal[17] TermSkin.append()
terminal[16] TermSkin.append()
terminal[14] TermSkin.append()
terminal[13] TermSkin.append()
terminal[12] TermSkin.append()
terminal[11] TermSkin.append()
terminal[5] TermSkin.append()
terminal[6] TermSkin.append()
/////////////////// INITIALIZATION /////////////////
///// GENERAL INITIALIZATION /////////
forall{ // for all compartments
insert na_ion //A bug fix for point_process
insert k_ion //A bug fix for point_process
//Na Channels
insert nattxs_withF
gnabar_nattxs_withF = 0
insert nattxs_noF
gnabar_nattxs_noF = 0.07
insert nav1p9
gbar_nav1p9=0.0003
insert nav1p8
gbar_nav1p8=0.065 // was 0.01 // on 10/22 adjusted to 0.003
insert nap
gbar_nap=5e-5
//K Channels
insert kdr
gbar_kdr=0.0007
insert ka
gkbar_ka=0.004 // was gkbar_ka=0.018 // original 0.0015 On 10/22 adjusted to 0.035
insert km
gbar_km=0.0004 // original 0.00034
//insert kf
//Ca channels
insert calL_Shah
gcalbar_calL_Shah=0.0015 // was 0.003
insert calT_Shah
gcatbar_calT_Shah=0.0005 // was 0.001
//H channels
insert hd
ghdbar_hd=0.00015 // was 0.00075 // was 0.00033
insert pas // insert leak channels
g_pas = 1/2500 // was g_pas =1/10000 //set Rm = 10000 ohms-cm2
v = -60 // set Vrest
e_pas = -60
Ra = 100 // intracellular resistance
}
// Lower Nav1p8 density away from periphery
soma.gbar_nav1p8=0.003 // 0.00328
stem.gbar_nav1p8=0.003 // 0.00328
central.gbar_nav1p8=0.003 // 0.00328
tjcentral.gbar_nav1p8=0.003 // 0.00328
tjperi.gbar_nav1p8=0.003 // 0.00328
for i=0,5 {peri[i].gbar_nav1p8=0.003} // 0.00328
for i=0,2 {terminal[i].gbar_nav1p8=0.003} // 0.00328
// Heating in all compartments
for i=0,26 {terminal[i].localtemp_nattxs_withF = 44}
for i=0,26 {terminal[i].localtemp_nattxs_noF = 44}
for i=0,26 {terminal[i].localtemp_nav1p8 = 44}
for i=0,26 {terminal[i].localtemp_nav1p9 = 44}
for i=0,26 {terminal[i].localtemp_ka = 44}
for i=0,26 {terminal[i].localtemp_kdr = 44}
for i=0,26 {terminal[i].localtemp_km = 44}
for i=0,26 {terminal[i].localtemp_hd = 44}
for i=0,5 {peri[i].localtemp_nattxs_withF = 44}
for i=0,5 {peri[i].localtemp_nattxs_noF = 44}
for i=0,5 {peri[i].localtemp_nav1p8 = 44}
for i=0,5 {peri[i].localtemp_nav1p9 = 44}
for i=0,5 {peri[i].localtemp_ka = 44}
for i=0,5 {peri[i].localtemp_kdr = 44}
for i=0,5 {peri[i].localtemp_km = 44}
for i=0,5 {peri[i].localtemp_hd = 44}
tjperi.localtemp_nattxs_withF = 44
tjcentral.localtemp_nattxs_withF = 44
central.localtemp_nattxs_withF = 44
stem.localtemp_nattxs_withF = 44
soma.localtemp_nattxs_withF = 44
tjperi.localtemp_nattxs_noF = 44
tjcentral.localtemp_nattxs_noF = 44
central.localtemp_nattxs_noF = 44
stem.localtemp_nattxs_noF = 44
soma.localtemp_nattxs_noF = 44
tjperi.localtemp_nav1p8 = 44
tjcentral.localtemp_nav1p8 = 44
central.localtemp_nav1p8 = 44
stem.localtemp_nav1p8 = 44
soma.localtemp_nav1p8 = 44
tjperi.localtemp_nav1p9 = 44
tjcentral.localtemp_nav1p9 = 44
central.localtemp_nav1p9 = 44
stem.localtemp_nav1p9 = 44
soma.localtemp_nav1p9 = 44
tjperi.localtemp_ka = 44
tjcentral.localtemp_ka = 44
central.localtemp_ka = 44
stem.localtemp_ka = 44
soma.localtemp_ka = 44
tjperi.localtemp_kdr = 44
tjcentral.localtemp_kdr = 44
central.localtemp_kdr = 44
stem.localtemp_kdr = 44
soma.localtemp_kdr = 44
tjperi.localtemp_km = 44
tjcentral.localtemp_km = 44
central.localtemp_km = 44
stem.localtemp_km = 44
soma.localtemp_km = 44
tjperi.localtemp_hd = 44
tjcentral.localtemp_hd = 44
central.localtemp_hd = 44
stem.localtemp_hd = 44
soma.localtemp_hd = 44
forsec NavLessSec{
Ra=15*peri.Ra
g_pas=g_pas/4 //Accoring to Dmytro V. Vasylyev and Stephen G. Waxman, Journal of Neurophysiology 2012
nseg=L/l_seg
L=NavLessLength //-ShortenBy
diam=term_diam
distance()
insert transducer_pas
//Distrubuting No NaV channels in the distal end of the terminal
gnabar_nattxs_withF=0
gnabar_nattxs_noF=0
gbar_nav1p9=0
gbar_nav1p8=0
gbar_nap=0
g_transMAX=0.0025
Tau_Puff=7.04 //(from Golstein et al. 2017)
for (x){
xdist = distance(x)
g_transducer_pas(x)=g_transMAX*exp(-(x*L)/Tau_Puff) //look at Capsaicin_Puff_Exponent_Check.m if you want to verify this
}
}
forsec TermSec{
g_pas=g_pas/4 //Accoring to Dmytro V. Vasylyev and Stephen G. Waxman, Journal of Neurophysiology 2012
}
forsec TermSkin{
//L=L+ShortenBy
//nseg=L/l_seg
insert transducer_pas
Ra=15*peri.Ra
g_transMAX=0.0025
Tau_Puff=7.04
g_MIN=g_transMAX*exp(-(NavLessLength)/Tau_Puff)
//(from Golstein et al. 2017)
distance()
nseg=L/l_seg_skinterminal //make the terminal of stimulation with a higher (nseg) resolution
for (x){
xdist = distance(x)
g_transducer_pas(x)=g_MIN*exp(-(x*L)/Tau_Puff) //look at Capsaicin_Puff_Exponent_Check.m if you want to verify this
}
}
proc init(){ // INITIALIZATION FUNCTION
dt=0.05 //0.1
forall {
v=-60 // VREST FOR ALL COMPARTMENTS (Change to -54mV to get rid of the spontaneous first spike)
ena=60
ek=-85
ehd_hd=-20
finitialize(v) // reset all state variables
fcurrent() // calculate all currents
}
} /// end of initialization
//The user can also choose which terminals to stimulate by changing Capsaicin_stimulation.hoc file and uncommenting the next line
//load_file("Capsaicin_stimulation.hoc") // puts the electrodes in specific or all terminals