:Pyramidal Cells to Pyramidal Cells AMPA+NMDA with local Ca2+ pool

NEURON {
	POINT_PROCESS pyrD2pyrVDA_STFD
	USEION ca READ eca	
	NONSPECIFIC_CURRENT inmda, iampa
	RANGE initW
	RANGE Cdur_nmda, AlphaTmax_nmda, Beta_nmda, Erev_nmda, gbar_nmda, W_nmda, on_nmda, g_nmda
	RANGE Cdur_ampa, AlphaTmax_ampa, Beta_ampa, Erev_ampa, gbar_ampa, W, on_ampa, g_ampa
	RANGE eca, ICa, P0, fCa, tauCa, iCatotal
	RANGE Cainf, pooldiam, z
	RANGE lambda1, lambda2, threshold1, threshold2
	RANGE fmax, fmin, Wmax, Wmin, maxChange, normW, scaleW, srcid, destid
	RANGE pregid,postgid, thr_rp
	RANGE F, f, tauF, D1, d1, tauD1, D2, d2, tauD2
	RANGE facfactor
}

UNITS { 
	(mV) = (millivolt)
        (nA) = (nanoamp)
	(uS) = (microsiemens)
	FARADAY = 96485 (coul)
	pi = 3.141592 (1)
}

PARAMETER {

	srcid = -1 (1)
	destid = -1 (1)
	
	Cdur_nmda = 16.7650 (ms)
	AlphaTmax_nmda = .2659 (/ms)
	Beta_nmda = 0.008 (/ms)
	Erev_nmda = 0 (mV)
	gbar_nmda = .5e-3 (uS)

	Cdur_ampa = 1.4210 (ms)
	AlphaTmax_ampa = 3.8142 (/ms)
	Beta_ampa = 0.1429 (/ms)
	Erev_ampa = 0 (mV)
	gbar_ampa = 1e-3 (uS)

	eca = 120

	Cainf = 50e-6 (mM)
	pooldiam =  1.8172 (micrometer)
	z = 2

	tauCa = 50 (ms)
	P0 = .015
	fCa = .024
	
	lambda1 = 5 : 10 : 5 : 5 : 2.5
	lambda2 = .03
	threshold1 = 0.3 :  0.45 : 0.35 :0.35:0.2 :0.50 (uM)
	threshold2 = 0.55 : 0.50 : 0.40 :0.4 :0.3 :0.60 (uM)

	:AMPA Weight
	initW = 1 :  0.9 : 2 : 0.7 : 2 : 3 : 4 : 2: 4 : 1 : 0.3: 2 :1.5
	fmax = 4
	fmin = .8
	
	DAstart1 = 39500
	DAstop1 = 40000	
	DAstart2 = 35900
	DAstop2 = 36000	

	DA_t1 = 1 : 1
	DA_t2 = 1
	DA_S = 1.3 : 0.85 : 0.6	
	Beta1 = 0.001  (/ms) : 1/decay time for neuromodulators
	Beta2 = 0.0001  (/ms)
	
	GAPstart1 = 96000
	GAPstop1 = 196000	

	thr_rp = 1 : .7
	
	facfactor = 1
	: the (1) is needed for the range limits to be effective
        f = 0 (1) < 0, 1e9 >    : facilitation
        tauF = 20 (ms) < 1e-9, 1e9 >
        d1 = 0.95 (1) < 0, 1 >     : fast depression
        tauD1 = 40 (ms) < 1e-9, 1e9 >
        d2 = 0.9 (1) < 0, 1 >     : slow depression
        tauD2 = 70 (ms) < 1e-9, 1e9 >		
}

ASSIGNED {
	v (mV)

	inmda (nA)
	g_nmda (uS)
	on_nmda
	W_nmda

	iampa (nA)
	g_ampa (uS)
	on_ampa
	W

	t0 (ms)

	ICa (mA)
	Afactor	(mM/ms/nA)
	iCatotal (mA)

	dW_ampa
	Wmax
	Wmin
	maxChange
	normW
	scaleW
	
	pregid
	postgid

	rp
	tsyn
	
	fa
	F
	D1
	D2
}

STATE { r_nmda r_ampa capoolcon }

INITIAL {
	on_nmda = 0
	r_nmda = 0
	W_nmda = initW

	on_ampa = 0
	r_ampa = 0
	W = initW

	t0 = -1

	Wmax = fmax*initW
	Wmin = fmin*initW
	maxChange = (Wmax-Wmin)/10
	dW_ampa = 0

	capoolcon = Cainf
	Afactor	= 1/(z*FARADAY*4/3*pi*(pooldiam/2)^3)*(1e6)

	fa =0
	F = 1
	D1 = 1
	D2 = 1
}

BREAKPOINT {
	SOLVE release METHOD cnexp
}

DERIVATIVE release {
	if (t0>0) {
		if (rp < thr_rp) {
			if (t-t0 < Cdur_nmda) {
				on_nmda = 1
			} else {
				on_nmda = 0
			}
			if (t-t0 < Cdur_ampa) {
				on_ampa = 1
			} else {
				on_ampa = 0
			}
		} else {
			on_nmda = 0
			on_ampa = 0
		}
	}
	r_nmda' = AlphaTmax_nmda*on_nmda*(1-r_nmda)-Beta_nmda*r_nmda
	r_ampa' = AlphaTmax_ampa*on_ampa*(1-r_ampa)-Beta_ampa*r_ampa

	dW_ampa = eta(capoolcon)*(lambda1*omega(capoolcon, threshold1, threshold2)-lambda2*GAP1(GAPstart1, GAPstop1)*W)*dt

	: Limit for extreme large weight changes
	if (fabs(dW_ampa) > maxChange) {
		if (dW_ampa < 0) {
			dW_ampa = -1*maxChange
		} else {
			dW_ampa = maxChange
		}
	}

	:Normalize the weight change
	normW = (W-Wmin)/(Wmax-Wmin)
	if (dW_ampa < 0) {
		scaleW = sqrt(fabs(normW))
	} else {
		scaleW = sqrt(fabs(1.0-normW))
	}

	W = W+ dW_ampa*scaleW
	
	:Weight value limits
	if (W > Wmax) { 
		W = Wmax
	} else if (W < Wmin) {
 		W = Wmin
	}

	g_nmda = gbar_nmda*r_nmda*facfactor*DA1(DAstart1,DAstop1)*DA2(DAstart2,DAstop2)        : Dopamine effect on NMDA to reduce NMDA current amplitude
	inmda = W_nmda*g_nmda*(v - Erev_nmda)*sfunc(v)

	g_ampa = gbar_ampa*r_ampa*facfactor
	iampa = W*g_ampa*(v - Erev_ampa)

	ICa = P0*g_nmda*(v - eca)*sfunc(v)
	capoolcon'= -fCa*Afactor*ICa + (Cainf-capoolcon)/tauCa
}

NET_RECEIVE(dummy_weight) {
	t0 = t
	rp = unirand()	
	
	:F  = 1 + (F-1)* exp(-(t - tsyn)/tauF)
	D1 = 1 - (1-D1)*exp(-(t - tsyn)/tauD1)
	D2 = 1 - (1-D2)*exp(-(t - tsyn)/tauD2)
 :printf("%g\t%g\t%g\t%g\t%g\t%g\n", t, t-tsyn, F, D1, D2, facfactor)
	::printf("%g\t%g\t%g\t%g\n", F, D1, D2, facfactor)
	tsyn = t
	
	facfactor = F * D1 * D2

	:F = F+f  :F * f
	
	if (F > 3) { 
	F=3	}
	if (facfactor < 0.5) { 
	facfactor=0.5
	}	
	D1 = D1 * d1
	D2 = D2 * d2
:printf("\t%g\t%g\t%g\n", F, D1, D2)
}

:::::::::::: FUNCTIONs and PROCEDUREs ::::::::::::

FUNCTION sfunc (v (mV)) {
	UNITSOFF
	sfunc = 1/(1+0.33*exp(-0.06*v))
	UNITSON
}

FUNCTION eta(Cani (mM)) {
	LOCAL taulearn, P1, P2, P4, Cacon
	P1 = 0.1
	P2 = P1*1e-4
	P4 = 1
	Cacon = Cani*1e3
	taulearn = P1/(P2+Cacon*Cacon*Cacon)+P4
	eta = 1/taulearn*0.001
}

FUNCTION omega(Cani (mM), threshold1 (uM), threshold2 (uM)) {
	LOCAL r, mid, Cacon
	Cacon = Cani*1e3
	r = (threshold2-threshold1)/2
	mid = (threshold1+threshold2)/2
	if (Cacon <= threshold1) { omega = 0}
	else if (Cacon >= threshold2) {	omega = 1/(1+50*exp(-50*(Cacon-threshold2)))}
	else {omega = -sqrt(r*r-(Cacon-mid)*(Cacon-mid))}
}
FUNCTION DA1(DAstart1 (ms), DAstop1 (ms)) {
	LOCAL DAtemp1, DAtemp2, DAtemp3, DAtemp4, DAtemp5, DAtemp6, DAtemp7, DAtemp8, DAtemp9, DAtemp10, DAtemp11, DAtemp12, DAtemp13, DAtemp14, DAtemp15, DAtemp16, DAtemp17, DAtemp18,s
	DAtemp1 = DAstart1+4000
	DAtemp2 = DAtemp1+4000
	DAtemp3 = DAtemp2+4000
	DAtemp4 = DAtemp3+4000
	DAtemp5 = DAtemp4+4000
	DAtemp6 = DAtemp5+4000
	DAtemp7 = DAtemp6+4000
	DAtemp8 = DAtemp7+4000
	DAtemp9 = DAtemp8+4000
	DAtemp10 = DAtemp9+4000
	DAtemp11 = DAtemp10+4000
	DAtemp12 = DAtemp11+4000
	DAtemp13 = DAtemp12+4000
	DAtemp14 = DAtemp13+4000
	DAtemp15 = DAtemp14 + 4000 + 100000     : 100sec Gap
	DAtemp16 = DAtemp15 + 4000 
	DAtemp17 = DAtemp16 + 4000
	DAtemp18 = DAtemp17 + 4000

	if (t <= DAstart1) { DA1 = 1.0}
	else if (t >= DAstart1 && t <= DAstop1) {DA1 = DA_t1}					: 2nd tone in conditioning
		else if (t > DAstop1 && t < DAtemp1) {DA1 = 1.0 + (DA_t1-1)*exp(-Beta1*(t-DAstop1))}  			: Basal level
	else if (t >= DAtemp1 && t <= DAtemp1+500) {DA1=DA_t1}					: 3rd tone
		else if (t > DAtemp1+500 && t < DAtemp2) {DA1 = 1.0 + (DA_t1-1)*exp(-Beta1*(t-(DAtemp1+500)))} 		: Basal level
	else if (t >= DAtemp2 && t <= DAtemp2+500) {DA1=DA_t1}					: 4th tone
		else if (t > DAtemp2+500 && t < DAtemp3) {DA1 = 1.0 + (DA_t1-1)*exp(-Beta1*(t-(DAtemp2+500)))} 		: Basal level	
	else if (t >= DAtemp3 && t <= DAtemp3+500) {DA1=DA_t1}					: 5th tone
		else if (t > DAtemp3+500 && t < DAtemp4) {DA1 = 1.0 + (DA_t1-1)*exp(-Beta1*(t-(DAtemp3+500)))} 		: Basal level
	else if (t >= DAtemp4 && t <= DAtemp4+500) {DA1=DA_t1}					: 6th tone
		else if (t > DAtemp4+500 && t < DAtemp5) {DA1 = 1.0 + (DA_t1-1)*exp(-Beta1*(t-(DAtemp4+500)))} 		: Basal level
	else if (t >= DAtemp5 && t <= DAtemp5+500) {DA1=DA_t1}					: 7th tone
		else if (t > DAtemp5+500 && t < DAtemp6) {DA1 = 1.0 + (DA_t1-1)*exp(-Beta1*(t-(DAtemp5+500)))} 		: Basal level
	else if (t >= DAtemp6 && t <= DAtemp6+500) {DA1=DA_t1}					: 8th tone
		else if (t > DAtemp6+500 && t < DAtemp7) {DA1 = 1.0 + (DA_t1-1)*exp(-Beta1*(t-(DAtemp6+500)))} 		: Basal level
	else if (t >= DAtemp7 && t <= DAtemp7+500) {DA1=DA_t1}					: 9th tone
		else if (t > DAtemp7+500 && t < DAtemp8) {DA1 = 1.0 + (DA_t1-1)*exp(-Beta1*(t-(DAtemp7+500)))} 		: Basal level
	else if (t >= DAtemp8 && t <= DAtemp8+500) {DA1=DA_t1}					: 10th tone  
		else if (t > DAtemp8+500 && t < DAtemp9) {DA1 = 1.0 + (DA_t1-1)*exp(-Beta1*(t-(DAtemp8+500)))} 		: Basal level
	
	else if (t >= DAtemp9 && t <= DAtemp9+500) {DA1=DA_t2}					: 11th tone   - Second Step
		else if (t > DAtemp9+500 && t < DAtemp10) {DA1 = 1.0 + (DA_t2-1)*exp(-Beta2*(t-(DAtemp9+500)))}		: Basal level	
	else if (t >= DAtemp10 && t <= DAtemp10+500) {DA1=DA_t2}					: 12th tone
		else if (t > DAtemp10+500 && t < DAtemp11) {DA1 = 1.0 + (DA_t2-1)*exp(-Beta2*(t-(DAtemp10+500)))}	: Basal level
	else if (t >= DAtemp11 && t <= DAtemp11+500) {DA1=DA_t2}					: 13th tone
		else if (t > DAtemp11+500 && t < DAtemp12) {DA1 = 1.0 + (DA_t2-1)*exp(-Beta2*(t-(DAtemp11+500)))}	: Basal level
	else if (t >= DAtemp12 && t <= DAtemp12+500) {DA1=DA_t2}					: 14th tone 
		else if (t > DAtemp12+500 && t < DAtemp13) {DA1 = 1.0 + (DA_t2-1)*exp(-Beta2*(t-(DAtemp12+500)))}	: Basal level
	else if (t >= DAtemp13 && t <= DAtemp13+500) {DA1=DA_t2}					: 15th tone
		else if (t > DAtemp13+500 && t < DAtemp14) {DA1 = 1.0 + (DA_t2-1)*exp(-Beta2*(t-(DAtemp13+500)))}	: Basal level
	else if (t >= DAtemp14 && t <= DAtemp14+500) {DA1=DA_t2}					: 16th tone
		else if (t > DAtemp14+500 && t < DAtemp15) {DA1 = 1.0 + (DA_t2-1)*exp(-Beta2*(t-(DAtemp14+500)))} 	: Basal level
	
	else if (t >= DAtemp15 && t <= DAtemp15+500) {DA1=DA_t2/2}					: 1st tone in Extinction
		else if (t > DAtemp15+500 && t < DAtemp16) {DA1 = 1.0 + (DA_t2-1)*exp(-Beta2*(t-(DAtemp15+500)))}	: Basal level
	else if (t >= DAtemp16 && t <= DAtemp16+500) {DA1=DA_t2/2}					: 2nd tone
		else if (t > DAtemp16+500 && t < DAtemp17) {DA1 = 1.0 + (DA_t2-1)*exp(-Beta2*(t-(DAtemp16+500)))}	: Basal level
	else if (t >= DAtemp17 && t <= DAtemp17+500) {DA1=DA_t2/2}					: 3rd tone
		else if (t > DAtemp17+500 && t < DAtemp18) {DA1 = 1.0 + (DA_t2-1)*exp(-Beta2*(t-(DAtemp17+500)))}	: Basal level	
	else if (t >= DAtemp18 && t <= DAtemp18+500) {DA1=DA_t2/2}					: 4th tone	
		else  {	DA1 = 1.0}
}
FUNCTION DA2(DAstart2 (ms), DAstop2 (ms)) {
	LOCAL DA2temp1, DA2temp2, DA2temp3, DA2temp4, DA2temp5, DA2temp6, DA2temp7, DA2temp8, DA2temp9, DA2temp10, DA2temp11, DA2temp12, DA2temp13, DA2temp14, DA2temp15, DA2temp16,s
	DA2temp1 = DAstart2 + 4000
	DA2temp2 = DA2temp1 + 4000
	DA2temp3 = DA2temp2 + 4000
	DA2temp4 = DA2temp3 + 4000
	DA2temp5 = DA2temp4 + 4000
	DA2temp6 = DA2temp5 + 4000
	DA2temp7 = DA2temp6 + 4000
	DA2temp8 = DA2temp7 + 4000
	DA2temp9 = DA2temp8 + 4000
	DA2temp10 = DA2temp9 + 4000
	DA2temp11 = DA2temp10 + 4000
	DA2temp12 = DA2temp11 + 4000 
	DA2temp13 = DA2temp12 + 4000
	DA2temp14 = DA2temp13 + 4000
	DA2temp15 = DA2temp14 + 4000
	
	if (t <= DAstart2) { DA2 = 1.0}
	else if (t >= DAstart2 && t <= DAstop2) {DA2 = DA_S }					: 1st shock
		else if (t > DAstop2 && t < DA2temp1) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DAstop2+500)))}  					 
	else if (t >= DA2temp1 && t <= DA2temp1+100) {DA2=DA_S}					: 2nd shock
		else if (t > DA2temp1+100 && t < DA2temp2) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp1+100)))}    				 
	else if (t >= DA2temp2 && t <= DA2temp2+100) {DA2=DA_S}					: 3rd shock
		else if (t > DA2temp2+100 && t < DA2temp3) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp2+100)))}   				 
	else if (t >= DA2temp3 && t <= DA2temp3+100) {DA2=DA_S}					: 4th shock
		else if (t > DA2temp3+100 && t < DA2temp4) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp3+100)))}   				 
	else if (t >= DA2temp4 && t <= DA2temp4+100) {DA2=DA_S}					: 5th shock
		else if (t > DA2temp4+100 && t < DA2temp5) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp4+100)))}   				 
	else if (t >= DA2temp5 && t <= DA2temp5+100) {DA2=DA_S}					: 6th shock
		else if (t > DA2temp5+100 && t < DA2temp6) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp5+100)))}    				 
	else if (t >= DA2temp6 && t <= DA2temp6+100) {DA2=DA_S}					: 7th shock
		else if (t > DA2temp6+100 && t < DA2temp7) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp6+100)))}   				 
	else if (t >= DA2temp7 && t <= DA2temp7+100) {DA2=DA_S}					: 8th shock
		else if (t > DA2temp7+100 && t < DA2temp8) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp7+100)))}   				    
	else if (t >= DA2temp8 && t <= DA2temp8+100) {DA2=DA_S }					: 9th shock
		else if (t > DA2temp8+100 && t < DA2temp9) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp8+100)))}   				    
	else if (t >= DA2temp9 && t <= DA2temp9+100) {DA2=DA_S }					: 10th shock
		else if (t > DA2temp9+100 && t < DA2temp10) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp9+100)))}   				    
	else if (t >= DA2temp10 && t <= DA2temp10+100) {DA2=DA_S}					: 11th shock
		else if (t > DA2temp10+100 && t < DA2temp11) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp10+100)))}   				 
	else if (t >= DA2temp11 && t <= DA2temp11+100) {DA2=DA_S }					: 12th shock
		else if (t > DA2temp11+100 && t < DA2temp12) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp11+100)))}   				 
	else if (t >= DA2temp12 && t <= DA2temp12+100) {DA2=DA_S}					: 13th shock
		else if (t > DA2temp12+100 && t < DA2temp13) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp12+100)))}   				 
	else if (t >= DA2temp13 && t <= DA2temp13+100) {DA2=DA_S }					: 14th shock
		else if (t > DA2temp13+100 && t < DA2temp14) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp13+100)))}   				 
	else if (t >= DA2temp14 && t <= DA2temp14+100) {DA2=DA_S}					: 15th shock
		else if (t > DA2temp14+100 && t < DA2temp15) {DA2 = 1.0 + (DA_S-1)*exp(-Beta2*(t-(DA2temp14+100)))}   				 
	else if (t >= DA2temp15 && t <= DA2temp15+100) {DA2=DA_S}					: 16th shock
		else  {	DA2 = 1.0}
}
FUNCTION GAP1(GAPstart1 (ms), GAPstop1 (ms)) {
	LOCAL s
	if (t <= GAPstart1) { GAP1 = 1}
	else if (t >= GAPstart1 && t <= GAPstop1) {GAP1 = 10}					: During the Gap, apply lamda2*2
	else  {	GAP1 = 1}
}
FUNCTION unirand() {    : uniform random numbers between 0 and 1
        unirand = scop_random()
}