// CN model used in Saak V Ovsepian, Volker Steuber, Marie Le // Berre, Liam O'Hara, Valerie B O'Leary, and J. Oliver Dolly // (2013). A Defined Heteromeric KV1 Channel Stabilizes the // Intrinsic Pacemaking and Regulates the Efferent Code of Deep // Cerebellar Nuclear Neurons to Thalamic Targets. Journal of // Physiology (epub ahead of print). // // written by Johannes Luthman, modified by Volker Steuber // // parameters for the simulation that replicates Figure 9A,B // in Ovsepian et al. (2013) strdef strTemp // Set (optionally) prefix for the output file names. The following will be suffixed // automatically: compartment recorded from, number of seconds simulated, ".dat". // Ovsepian simulation: use this prefix to record extent of Kdr block //Kdrblock = 1.3 //strFilePrefix = "Kdr130" //have moved this to the main simulation file randomiserSeed = 1 runTime = 8100 // ms /* Set synaptic input rates (Hz). The default of the model is to receive 40 Hz inhibitory and 20 Hz excitatory input.*/ inhibitoryHz = 0//40 excitatoryHz = 0//20 // Set whether to record membrane potential and current traces, and if so, during // which intervals to record. (The somatic spike times are saved by default) // For each interval, give the number of milliseconds into the simulation to start // and stop the recording. // A non-instantiated vector error occurs if nExtraVars = 0, so to not record any // traces, set tTraceStop[0] = 0. nStepsSaveTrace = 1 double tTraceStart[nStepsSaveTrace] double tTraceStop[nStepsSaveTrace] tTraceStart[0] = 3000 tTraceStop[0] = 8000 vInit = -70 dt = 0.025 secondorder = 1 // Set the recording interval. recInterval = 0.100 // ms // Set current injection parameters SOMACIP1DEL = 0.0 SOMACIP1DUR = 0.0 SOMACIP1AMP = 0.0 SOMACIP2DEL = 0.0 SOMACIP2DUR = 0.0 SOMACIP2AMP = 0.0 AXISCIPDEL = 0.0 AXISCIPDUR = 0.0 AXISCIPAMP = 0.0 // Set the number of excitatory and inhibitory (Purkinje cell) synapses. EXCSOMASYNAPSES = 50 EXCDENDSYNAPSES = 100 EXCTOTALSYNAPSES = 100//EXCSOMASYNAPSES + EXCDENDSYNAPSES INHSOMASYNAPSES = 100//50 INHDENDSYNAPSES = 100//400 INHTOTALSYNAPSES = 200//INHSOMASYNAPSES + INHDENDSYNAPSES // Set convergence of Purkinje cells to the DCN. PCtoDCNconvergence = 450 nDCNsynsPerPC = int(INHTOTALSYNAPSES / PCtoDCNconvergence) // Set parameters of the synaptic inputs. // If noise below is set to 0 (to get fully regular inputs), and the number of GABA inputs // (PCtoDCNconvergence) is set to less than 450, then NEURON sometimes gives this error: // "internal error: Source delay is > NetCon delay" // The problem is corrected by setting noise to 1e-19 (1e-20 brings back the // error). noiseFractionExcSyn = 1 // max=1 noiseFractionInhSyn = 1 // min=1e-19 if PCtoDCNconvergence<450 (see explanation above), max=1 // Set the gamma distribution of the inputs. // The default value of 3 for gammaOrderPC is based on the values of 2.8 (for patterns) // and 3.4 (whole train) in Shin SL, Rotter S, Aertsen A, De Schutter E (2007) // Stochastic description of complex and simple spike firing in cerebellar Purkinje cells. // Eur J Neurosci 25:785-794. gammaOrderExc = 3 gammaOrderPC = 3 // refractory periods of the inputs (ms) refractoryPeriodExc = 1 refractoryPeriodPC = 2 // set useGABAsyndep to 1 (default) to use mech DCNsynGABA.mod, 0 to use DCNsyn.mod // to instantiate the GABA synapses, with the former giving short-term // depression as in Shin et al 2007 (PLOSone issue 5, e485) useGABAsyndep = 1 // Define the length of the synaptic transmission delay (ms) in the PC-DCN synapse // and its jitter (standard deviation). gabaTransDelay = 2 gabaTransDelaySD = 0 // Set the temperature of the simulation. The model has been titrated to reproduce // in vivo like firing at celsius = 37.0 (default), while the original GENESIS // DCN model was constructed with temp = 32 deg celsius. celsius = 32.0//37.0 TempOrigDCN = 32.0 // Temperature adjustments // TempAnchisi = the temperature in the middle of the given range of room temperature // recording in Anchisi D, Scelfo B, Tempia F (2001) Postsynaptic currents in deep // cerebellar nuclei. J Neurophysiol 85:323-331. TempAnchisi = 24.0 Q10channelGating = 3.0 // Middle of experimentally shown range (2-4) of ion channel gating, // see Hille 3rd ed (2001), p.51. Q10synapseGating = 2.0 // (Silver et al., 1996; Otis and Mody, 1992) Synaptic Q10s are given // for GABA and excitatory synapses in Otis and Mody (1992), and Silver et al. (1996), // respectively (full references below), with both giving Q10s in the region of 2. Q10conductances = 1.4 // The middle of the range (1.2-1.5) given in Hille 3rd ed (2001) // for ion channel conductances (p.51). Also, eg Milburn et al (1995) // Receptors Channels 3:201-211: “The conductance increases steeply with temperature, // with Q10 ranging from 1.4 to 1.5”. However, also note Cao XJ, Oertel D (2005) // J Neurophysiol 94:821-832. They get the results that some conductances have a // Q10 of 2 while other channel conductances don’t change at all by changing // temp (Q10=1). Q10CaConc = 2.0 // Guesswork: I assume that calcium concentration changes due to a // combination of diffusion (Q10 of ca 1.4) and pumping action (Q10 of enzymatic // reactions = ca 3) QdTsynapseTausAnchisi = Q10synapseGating^((celsius - TempAnchisi) / 10.0) QdTconductanceAnchisi = Q10conductances^((celsius - TempAnchisi) / 10.0) QdTchannelGating = Q10channelGating^((celsius - TempOrigDCN) / 10.0) QdTsynapseTaus = Q10synapseGating^((celsius - TempOrigDCN) / 10.0) QdTconductances = Q10conductances^((celsius - TempOrigDCN) / 10.0) QdTCaConc = Q10CaConc^((celsius - TempOrigDCN) / 10.0) // Synaptic conductances gGABA = 0.1*11700e-6*QdTconductances tauRiseGABA = 0.25 / QdTsynapseTaus // From Dieter Jaeger's code cn6c_const_dj4.g tauFallGABA = 2.1 / QdTsynapseTaus // Telgkamp P, Padgett DE, Ledoux VA, Woolley CS, Raman IM (2004) // Maintenance of high-frequency transmission at purkinje to cerebellar nuclear // synapses by spillover from boutons with multiple release sites. Neuron 41:113-126. // For the following excitatory synaptic conductances, I'm using the high input gain // level of Steuber, V., N. W. Schultheiss, et al. (2010). "Determinants of synaptic // integration and heterogeneity in rebound firing explored with data-driven models of // deep cerebellar nucleus cells." J Comput Neurosci. // [= AMPA 200 pS, NMDA peak conductance (fast + slow) 172 pS (114+57)] // The time constants are from Anchisi D, Scelfo B, Tempia F (2001) Postsynaptic currents // in deep cerebellar nuclei. J Neurophysiol 85:323-331. gAMPA = 0.07*3250e-6 //*QdTconductanceAnchisi tauRiseAMPA = 0.5 / QdTsynapseTausAnchisi tauFallAMPA = 7.1 / QdTsynapseTausAnchisi gfNMDA = 0.07*6000e-6 //*QdTconductanceAnchisi tauRisefNMDA = 5 / QdTsynapseTausAnchisi tauFallfNMDA = 20.2 / QdTsynapseTausAnchisi MgFactorfNMDA = 0.002 gammafNMDA = 0.109 gsNMDA = 0.07*6000e-6 //*QdTconductanceAnchisi tauRisesNMDA = 5 / QdTsynapseTausAnchisi tauFallsNMDA = 136.4 / QdTsynapseTausAnchisi MgFactorsNMDA = 0.25 gammasNMDA = 0.057 // Passive electrical parameters. RA = 235.3 // ohm * cm CM = 1.57 // microfarad / cm2 CMMYEL = CM/100 PASSCOND = 2.81e-5*QdTconductances // S/cm2 passive conductance PASSCONDMYEL = PASSCOND / 2.81 // passive conductance of the axon SHELLTHICK = 0.2 // micrometers, the thickness of the calcium-containing shell // defined by CaConc.mod. // Reversal potentials in mV SodiumRevPot = 71 PotassiumRevPot = -90 GABARevPot = -75 ExcitSynRevPot = 0 hRevPot = -45 TNCrevPot = -35 CCaO = 2.0 // mM CCaI = 50e-6 // mM (= 50nM) TempK = celsius + 273.15 RbyF = 8.6154e-5 carev = 139 //RbyF/2.0 * TempK * (log (CCaO/CCaI)) //GCaLVAs = 1.5e-4*QdTconductances//4.5//3.5 GCaLVAs = 3.5e-4*QdTconductances//4.5//3.5 GCaLVApd = 2*GCaLVAs GCaLVAdd = 2*GCaLVAs // Non-synaptic channel conductances gNaFsoma = 2.5e-2*QdTconductances gNaFaxHill = 2*gNaFsoma gNaFaxIniSeg = 2*gNaFsoma gNaFpDend = 0.4*gNaFsoma //gNaPsoma = 8e-4*QdTconductances gNaPsoma = 2e-4*QdTconductances gfKdrsoma = 1.5e-2*QdTconductances*Kdrblock gfKdraxHill = 2*gfKdrsoma*Kdrblock gfKdraxIniSeg = 2*gfKdrsoma*Kdrblock gfKdrpDend = 0.6*gfKdrsoma*Kdrblock gsKdrsoma = 1.25e-2*QdTconductances*Kdrblock gsKdraxHill = 2*gsKdrsoma*Kdrblock gsKdraxIniSeg = 2*gsKdrsoma*Kdrblock gsKdrpDend = 0.6*gsKdrsoma*Kdrblock gSKsoma = 2.2e-4*QdTconductances gSKpDend = 0.3*gSKsoma gSKdDend = 0.3*gSKsoma permCaLVAsoma = 2.33*1.77e-5*QdTconductances permCaLVAdend = 2*permCaLVAsoma permCaHVAsoma = 7.5e-6*QdTconductances permCaHVAdend = permCaHVAsoma / 1.5 tauCaConcSoma = 70/QdTCaConc kCaCaConcSoma = 3.45e-7 kCaCaConcDend = 1.04e-6 //gHsoma = 2e-4*QdTconductances gHsoma = .5e-4*QdTconductances gHpDend = 2*gHsoma gHdDend = 3*gHsoma gTNCsoma = 3e-5*QdTconductances //3e-5 6e-4 6e-4 //gTNCsoma = 3e-4*QdTconductances gTNCaxHill = 3.5e-5*QdTconductances gTNCaxIniSeg = 3.5e-5*QdTconductances gTNCpDend = 0.2*gTNCsoma /* ///////////////////////////////////////////////////// /// REFERENCES /// //////////////////////////////////////////////////////// @@@ Excitatory inputs @@@ (Gauck and Jaeger, 2003) say: "The mean activation rate of excitatory inputs was set to 20 Hz in accordance with in vivo recordings (Eccles et al., 1972; Cazin et al., 1980; van Kan et al., 1993; Gamlin and Clarke, 1995; Matsuzaki and Kyuhou, 1997). No difference between mossy and climbing fiber inputs has been described in the DCN, and we simulate only one homogenous group of excitatory inputs." @@@ Inhibitory inputs (from Purkinje cells) @@@ (Savio and Tempia, 1985): spontaneous firing of single spikes = 36.15/s (± 17.04 SD) in awake rats. (wistar 180-240 grams, a size I believe corresponds to almost adult size (Stratton et al., 1988) gives a spontaneous simple spike firing rate of normal awake rats of 35 ± 5.1 spikes/sec, (with SE), and “average complex spike rate, 1.3 spikes/sec”. The age was P20-28. (LeDoux and Lorden, 2002) give a mean of ca 41 Hz SS frequency in 19.5±0.8 days old awake rats. Max PC firing rate: 260 Hz in axonal recordings: Monsivais P, Clark BA, Roth A, Hausser M (2005) Determinants of action potential propagation in cerebellar Purkinje cell axons. J Neurosci 25:464-472. @@@ Other references in the code @@@ Gauck V, Jaeger D (2003) The contribution of NMDA and AMPA conductances to the control of spiking in neurons of the deep cerebellar nuclei. J Neurosci 23:8109-8118. LeDoux MS, Lorden JF (2002) Abnormal spontaneous and harmaline-stimulated Purkinje cell activity in the awake genetically dystonic rat. Exp Brain Res 145:457-467. Savio T, Tempia F (1985) On the Purkinje cell activity increase induced by suppression of inferior olive activity. Exp Brain Res 57:456-463. Stratton SE, Lorden JF, Mays LE, Oltmans GA (1988) Spontaneous and harmaline-stimulated Purkinje cell activity in rats with a genetic movement disorder. J Neurosci 8:3327-3336. Otis TS, Mody I (1992) Modulation of decay kinetics and frequency of GABAA receptor-mediated spontaneous inhibitory postsynaptic currents in hippocampal neurons. Neuroscience 49:13-32. Silver RA, Colquhoun D, Cull-Candy SG, Edmonds B (1996) Deactivation and desensitization of non-NMDA receptors in patches and the time course of EPSCs in rat cerebellar granule cells. J Physiol 493:167-173.