Nakano T, Yoshimoto J, and Doya K (2013) A model-based prediction of the calcium responses in the striatal synaptic spines depending on the timing of cortical and dopaminergic inputs and post-synaptic spikes., Frontiers in Computational Neuroscience, 7:119 The dopamine-dependent plasticity of the cortico-striatal synapses is considered as the cellular mechanism crucial for reinforcement learning. The dopaminergic inputs and the calcium responses affect the synaptic plasticity by way of the signaling cascades within the synaptic spines. The calcium concentration within synaptic spines, however, is dependent on multiple factors including the calcium influx through ionotropic glutamate receptors, the intracellular calcium release by activation of metabotropic glutamate receptors, and the opening of calcium channels by EPSPs and back propagating action potentials. Furthermore, dopamine is known to modulate the efficacies of NMDA receptors, some of the calcium channels, and sodium and potassium channels that affect the back propagation of action potentials. Here we construct an electric compartment model of the striatal medial spiny neuron with a realistic morphology and predict the calcium responses in the synaptic spines with variable timings of the glutamatergic and dopaminergic inputs and the postsynaptic action potentials. The model was validated by reproducing the responses to current inputs and could predict the electric and calcium responses to glutamatergic inputs and back-propagating action potential in the proximal and distal synaptic spines during up and down states. We investigated the calcium responses by systematically varying the timings of the glutamatergic and dopaminergic inputs relative to the action potential and found that the calcium response and the subsequent synaptic potentiation is maximal when the dopamine input precedes glutamate input and action potential. The prediction is not consistent with the hypothesis that the dopamine input provides the reward prediction error for reinforcement learning. The finding suggests that there is an unknown learning mechanisms at the network level or an unknown cellular mechanism for calcium dynamics and signaling cascades. The model is based on the Wolf's model which is available from ModelDB (http://senselab.med.yale.edu/ModelDB/ShowModel.asp?model=112834). Please check their model for the basic instructions. In this text, we describe the main differences from Wolf's model and how to reproduce the figures in the paper. 1) The main modification of our model from Wolf's model. baseline_values.txt : parameters of the model damsg.mod : dopamine modulation mod files like "caL13.mod" : channel modules modulated by dopamine set_synapse*.hoc files : define connection between dopamine synapses and channels msp_template.hoc : morphology MGLU.mod : metabotropic glutamate receptor module ER.mod : intracellular calcium store module stim_files2 folder : input files of dopamine and glutamate with timing 2) How to reproduce the figures in the paper. First of all, to run the model on NEURON, just run mosinit.hoc on terminal. > nrngui mosinit.hoc To run simulations under conditions like up-state, in presence of channel blockers, and so on used in the paper, please edit "_control.hoc" and/or "_run_me.hoc" and run >xopen("./_control.hoc") >run() Figure 4 >xopen("_IVsaveplot.hoc") The subplot created for figure 4a should look like: Figure 6 >xopen("_plot_post02.hoc") figure 7 >xopen("_plot_pre_spine.hoc") To reproduce some conditions in Figure 5, 6 and 7, run >xopen("./_paper_condition.hoc") figure 8 and 9 >xopen("_timed_input_Glu.hoc") Figure 10, 11 and 12 >xopen("_timed_input_1AP_spine_post.hoc") About the file names generated by the simulation: After running a hoc file like "_plot_pre_spine.hoc", many data files are created in a data folder, for example "data_pre_spine0_mgfree.txt" and "data_c_pre_spine1_caTblock.txt" These file names contain the following: "c" indicates up-state, otherwise down-state. "pre" indicates presynaptic (glutamate) input. "spine0" and "spine1" indicate proximal and distal spines respectively. "mgfree" and "caTblock" are conditions. That is, "data_pre_spine0_mgfree.txt" means responses evoked presynaptic input at a proximal spine at down-state under Mg-free condition, and "data_c_pre_spine1_caTblock.txt" means responses evoked presynaptic input at distal spine at up-state under the blocking T-type calcium channels. Similarly, in the case of "spine0_pren005_DAp040.txt",ol "n" and "p" before the numbers are negative and positive timing of inputs. The numbers are the time difference (ms) from a postsynaptic spike. That is, "spine0_pren005_DAp040.txt" means responses to 5 ms following glutamate input and 40 ms preceding doapmine input to postsynaptic spike at a proximal spine. This text is written by Takashi Nakano Nov 6th, 2013 Updated Nov 22nd, 2013 20140307 Model updated to run with a new version of NEURON whose new compiler insists that the number of arguments in function calls match the number of arguments in the definition of the function. For this reason aip3, bip3 were removed from ER.mod jip3 function calls so that the calls match the number of arguments (8) in the function jip3 definition. This did not change the function of the code.