Article Figures & Data
Figures
- Figure 1.
Quantification of firing rate and pattern of the VTA DA neurons in WT mice (black) after systemic deletion of β2-containing nAChRs (red) and their subsequent re-expression on VTA DA (green), on VTA GABA (blue), and on both neurons (purple). A, Mean firing frequency (in Hz) against %SWB for n = 38 and n = 39 individual cells in WT and β2 KO mice. Systemic deletion of β2-containing nAChR decreases both the DA neuron firing rate and bursting compared with WT (see also C and D). B, Various KO and re-expression cases that have been used to analyze the role of β2-containing nAChRs in the VTA (see Materials and Methods and C, D). C, Lentiviral re-expression of β2 subunit in the VTA of β2 KO mice using a ubiquitous mouse phosphoglycerate kinase (PGK) promoter (β2-Vec) restores firing rate and bursting (data modified from Naudé et al., 2016). D, Comparison of firing rate and bursting in WT (black), β2 KO mice (β2−/−, red), and mice with re-expression of β2 in a specific neuronal population. Cre recombinase-activated lentiviral expression vector was used to drive specific β2*-nAChR re-expression in DA or GABAergic neurons of the VTA of DAT Cre mice (β2 DA, green) and GAD67 Cre mice (β2 Gb, red; Data from Tolu et al., 2013). n.s., *p < 0.05; **p < 0.01; ***p < 0.001 as compared to chance level.
- Figure 2.
Comparison of the nicotine-elicited modifications of the firing rate (left) and %SWB (right) in VTA DA neurons in in two sets of experiments. A, β2 DA vector (green) and β2 Gb vector (blue) compared with wild-type (black) and β2−/− (red) mice (data modified from Tolu et al., 2013). B, β2-Vec (purple) compared with wild-type (black) and β2−/− (red) mice (data modified from Naudé et al., 2016). Vertical dashed line indicates the nicotine injection.
- Figure 3.
Schematic of the model. A, Afferent inputs and microcircuitry of the VTA. B, Time course of the nicotine concentration and subsequent activation and desensitization of nAChRs. C, Temporal profile of ACh input and subsequent activation of nAChRs. D, State transitions of the nAChRs.
- Figure 4.
The rate and regularity of the DA neuron firing receiving asynchronous synaptic Glu and GABA inputs. A, Glu raster. B, GABA raster. C, Activation of the GABAR on the DA neuron. D, Activation of the NMDAR on the DA neuron. E, The voltage of the DA neuron. Note the high regularity of DA neuron firing.
- Figure 5.
Quantification of the spontaneous firing of simulated DA neurons. A, Bar plot representation of the mean basal firing rate, represented as the mean ± SEM, WT case (black), KO (red), β2-containing nAChRs on DA neurons (green), the nAChRs on GABA neurons (blue), and the nAChRs on DA and GABA neurons (purple). B, and mean %SWB. B, Bar plot representation of the mean %SWB, represented as the mean ± SEM, KO (red), the nAChRs on DA neurons (green), the nAChRs on GABA neurons (blue), and the nAChRs on DA and GABA neurons (purple). C, Example voltage traces of simulated DA neurons under four different conditions, indicated in A and B. Colors of the voltage traces match the colors of the bars. Inclusion of nAChR-mediated ACh current to GABA neurons significantly increased DA neuron firing and bursting in a manner similar to the experiment (Tolu et al., 2013). See Extended Data Figure 6-1 for parametric analysis.
- Figure 6.
Nicotine-elicited changes in firing rate and burstiness of simulated DA neuron. A, Raster plots of DA neuron firing in response to nicotine, KO (red), β2-containing nAChRs on DA neurons (green), the nAChRs on GABA neurons (blue), the nAChRs on DA and GABA neurons (purple), and WT case (black). B, C, Nicotine-elicited changes in firing rate (B) and %SWB (C) of simulated DA neurons in response to nicotine. The vertical black line shows the onset of the nicotinic input. There is no change in DA neurons firing or bursting in response to nicotine if both DA and GABA neurons lack the receptors (red). Nicotine increases DA neuron firing if β2-nAChR is added only to the DA neuron (green). Oppositely, it decreases DA neuron firing and bursting if β2-nAChR is added only to GABA neurons (blue). Interestingly, nicotine increases DA neuron firing and bursting if β2-nAChRs are added to both neurons (purple). Nicotine elicits an even greater response in the WT-like case, because of the nicotine-elicited increase in the frequency of Glu inputs to the DA neurons (black). See Extended Data Figure 6-1 for parametric analysis.
- Figure 7.
Bursty pulsatile cholinergic input transiently synchronizes GABA neurons. Synchronous GABA input evokes additional DA spikes and increases DA neuron burstiness. A, Raster of Glu neurons. B, ACh input. C, Raster of VTA GABA neurons. D, E, The cumulative activation variable of the GABAR current on DA neurons without (red) and with (blue) ACh input. F, The activation variable of the NMDAR current on the DA neuron. Note the lack of significant variations. G, H, Voltages of the DA neurons in the cases where they receive GABAR activation from D or E, respectively. Note that there is a greater number of spikes grouped in bursts when the nAChR is added to the GABA neurons (blue).
Tables
Parameter Description DA neuron GABA neuron Amplitude of Ach input 5 μM 10 μM Amplitude of Nic input 0.5 μM 0.5 μM w Potency of Nic to evoke response 3 3 GABAR conductance 2.5 mS/cm2 NMDAR conductance 4 mS/cm2 0 mS/cm2 Leak conductance 0.03 mS/cm2 0.05 + 0.05(rnd-0.5) mS/cm2 - Table 2
ACh receptor maximal conductance used to reproduce different KO re-expression cases
Parameter KO Re-expression on DA Re-expression on GABA Re-expression on both, WT case 0 5 mS/cm2 0 10 mS/cm2 0 0 4 mS/cm2 1.5 mS/cm2
Figure 6-1
Parametric analysis of DA neuron responses to ACh and nicotinic inputs for different maximal conductances of nAChR current (mimicking different levels of expression of nAChRs) on GABA neurons. The range of low nAChR conductances on GABA neurons shows good correspondence with the experimental data. Download Figure 6-1, TIF file.
Table 1-1
Model parameters. Download Table 1-1, DOCX file.
Figure 5-1
Parametric analysis of DA neuron responses to ACh and nicotinic inputs for different maximal conductances of nAChR current (mimicking different levels of expression of nAChRs) on DA neurons. The range of low nAChR conductances shows a good correspondence with the experimental data. Download Figure 5-1, TIF file.
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