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Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior

Nature Neuroscience volume 20, pages 438–448 (2017)Cite this article

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A Corrigendum to this article was published on 26 July 2017

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Abstract

Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABAB receptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABAB receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.

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Figure 1: Optogenetic stimulation of NAc D1 terminals elicits GABAB activation in VTA dopamine neurons.
Figure 2: NAc inputs preferentially inhibit VTA GABA and dopamine neurons through separate postsynaptic receptors.
Figure 3: NAc inputs form synapses onto cell bodies and dendrites of dopamine neurons.
Figure 4: NAc inputs and local GABA interneurons activate separate receptor populations in dopamine neurons.
Figure 5: Presynaptic inhibition of NAc inputs, but not VTA GABA inputs, by adenosine A1 receptors.
Figure 6: NAc inputs inhibit dopamine neuron firing at multiple frequencies through activation of GABABRs.
Figure 7: Deletion of GABABRs from dopamine neurons increases cocaine-induced locomotion.

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  • 27 March 2017

    In the version of this article initially published, the y-axis scale in Figure 4c was labeled 0–150 instead of 0–300, the gray data points in Figure 6g were duplicates of the black data points in Figure 6f, and the error bars were missing from the green trace in Figure 7e. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank members of the Bonci lab for insightful discussions and careful reading of the manuscript. We thank the NIDA Histology Core for help with in situ hybridization experiments, B. Sadacca for help with statistical analysis, K. Deisseroth (Stanford University) for the generation of optogenetic constructs, and B. Lowell (Beth Israel Deaconess Medical Center) for Dyn-Cre and VGAT-Cre transgenic mice. This work was supported by the Intramural Research Program at the National Institute on Drug Abuse.

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Authors and Affiliations

  1. Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA

    Nicholas J Edwards, Hugo A Tejeda, Marco Pignatelli, Shiliang Zhang, Ross A McDevitt, Jocelyn Wu, Marisela Morales & Antonello Bonci

  2. Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA

    Caroline E Bass

  3. Department of Biomedicine, Pharmazentrum, University of Basel, Basel, Switzerland

    Bernhard Bettler

  4. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Antonello Bonci

  5. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Antonello Bonci

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Contributions

N.J.E., A.B., H.A.T., R.A.M., M.M.and M.P. designed the experiments. N.J.E. performed electrophysiological and behavioral experiments. J.W. determined virus localizations and S.Z. performed electron microscopy experiments. B.B. provided critical reagents. N.J.E. analyzed the data. N.J.E. and A.B. wrote the paper with contributions from all of the other authors.

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Correspondence to Antonello Bonci.

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Integrated supplementary information

Supplementary Figure 1 Localization of virus injections.

(a) Schematic showing the approximate center of AAV-DIO-ChR2-YFP injection sites in the NAc of Dyn-cre mice (n=8 mice, 16 injections; caudate/putamen, CPu; nucleus accumbens core, NAcC; nucleus accumbens shell, NAcSh). (b) Representative GABAB oIPSCs at different stimution frequencies.

Supplementary Figure 2 D2 MSNs project to the ventral pallidum, but not directly to the VTA.

(a) Schematic of experimental protocol. Cre-dependent ChR2-YFP was injected into the VTA of A2A-cre mice and whole-cell patch-clamp recordings were performed in VTA dopamine and GABA neurons and in ventral pallidal neurons. (b) Summary data of light-evoked GABAA oIPSCs in voltage clamp recordings (Vm=-70 mV) of VTA dopamine (blue), VTA GABA (red), and ventral pallidal neurons (purple; n=10, 8, and 11 cells; one-way ANOVA, F(28)=8.606, p<0.01). (c) Representative traces of light-evoked GABAA IPSCs in VTA dopamine (blue), VTA GABA (red) and ventral pallidal neurons (purple). Data are shown as mean ± s.e.m.

Supplementary Figure 3 GABABRs are strongly expressed in dopamine neurons throughout the midbrain.

(a) Wide-field image showing TH immunoreactivity (brown) and GABAB1 in situ (black; scale bar, 300 μm). (b) TH neurons co-express GABAB1 mRNA (scale bar, 25 μm). (c) Percentage of TH neurons co-expressing GABAB1 mRNA in the substantia nigra pars compacta (SNc) and VTA (n=3 mice, 4 sections per mouse, p=0.68, t(4)=0.4504). (d) Percentage of GABAB1+ cells that do not express TH (n=3 mice, 4 sections per mouse, p=0.30, t(4)=1.191). All data are shown as mean ± s.e.m.

Supplementary Figure 4 Amplitudes of GABAA oIPSCs correlate with electrophysiological properties of GABA neurons and amplitudes of GABAB oIPSCs correlate with electrophysiological properties of dopamine neurons.

(a-c) Example traces demonstrating the AP width (a), firing rate (b), and h-current (c) of a representative GABA (red) and dopamine (blue) neuron. (d) Correlation of GABAA oIPSCs with AP width (n=45 cells, 6 mice). (e) Correlation of GABAA oIPSCs with firing rate (n=45 cells, 6 mice). (f) Correlation of GABAA oIPSCs with h-current (n=45 cells, 6 mice). (g) Correlation of GABAB oIPSCs with AP width (n=64 cells, 12 mice). (h) Correlation of GABAB oIPSCs with firing rate (n=64 cells, 12 mice). (i) Correlation of GABAB oIPSCs with h-current (n=64 cells, 12 mice).

Supplementary Figure 5 Nucleus accumbens inputs preferentially activate GABABRs in dopamine neurons and GABAARs in GABA neurons.

(a) Horizontal brain section containing biocytin-filled cells – two TH+ cells and two TH- cells (scale bar, 60 μm). (b) Representative GABAB oIPSCs from the cells shown in (a). (c) Summary data of GABAB oIPSCs in TH+ and TH- neurons (Vm=-55 mV; n=8 and 10 cells, respectively, 6 mice; unpaired t-test, p<0.01, t(16)=5.502). (d,e) Example (d) and summary (e) of GABAA oIPSCs in VTA dopamine (blue) and GABA (red) neurons using K-gluconate internal solution (Vm=-55 mV; n=15 and 12 cells respectively, 4 mice each, unpaired t-test, p<0.01, t(25)=7.808). (f,g) Example (f) and summary (g) of GABAB oIPSCs in VTA dopamine and GABA neurons (Vm=-55 mV; n=16 and 11 cells respectively, 4 mice each, unpaired t-test, p<0.01, t(25)=7.989). All data are shown as mean ± s.e.m.

Supplementary Figure 6 Evidence for synaptic release of GABA onto GABAB receptors.

(a) Time to onset (10% max current) of GABAB IPSCs while GABA (1M) was iontophoretically released (open circles) at different distances from the soma compared to the time to onset of electrically-evoked GABAB eIPSCs (closed circle, n=9 and 10 cells). (b) Experimental schematic for (c-e). GABAA oIPSCs were evoked in voltage clamp recordings (-70 mV) of VTA GABA neurons. (c) Representative traces of normalized NAc→VTA GABAA oIPSCs in normal artificial cerebrospinal fluid (aCSF) versus dextran-incubated slices. (d) Summary of time to onset for GABAA oIPSCs from normal ACSF versus dextran-incubated slices (n= 8 cells, two-tailed t-test, t(14)=0.18, p=0.86). (e) Summary of time to maximum current for GABAA oIPSCs from normal ACSF versus dextran-incubated slices (n= 8 cells, two-tailed t-test, t(14)=1.85, p=0.09). (f) Experimental schematic for (g-i). GABAB oIPSCs were evoked during voltage clamp recordings (-55 mV) of VTA dopamine neurons. (g) Representative traces of normalized NAc→VTA GABAB oIPSCs onto dopamine neurons in normal aCSF versus dextran-incubated slices. (h) Summary of time to onset for GABAB oIPSCs from normal ACSF versus dextran-incubated slices (n= 9 cells, two-tailed t-test, t(16)=0.32, p=0.75). (i) Summary of time to maximum current for GABAB oIPSCs from normal ACSF versus dextran-incubated slices (n=9 cells, two-tailed t-test, t(16)=0.58, p=0.55). (j) Representative iontophoretic GABAB current before and after dextran application. (k) Time to peak amplitude of iontophoretic GABAB current before and after dextran (n=3 cells, paired t-test, t(2)=7.647, p<0.05). (l) Peak amplitude of iontophoretic currents at different distances from the cell, normalized to the peak amplitude at 0 μm (n=7 cells each, two-way ANOVA, F(4,60)=2.723, p<0.05). (m) Decay time from the peak of iontophoretic currents (n=7 cells each, two-way ANOVA, F(4,55)=9.985, p<0.05) All data are shown as mean ± s.e.m.

Supplementary Figure 7 Nucleus accumbens inputs inhibit dopamine neurons via GABABRs.

(a) Experimental schematic, stimulating NAc→VTA terminals and recording tonic firing in cell-attached mode from VTA dopamine neurons. (b-f) Effect of optical stimulation of NAc→VTA terminals on the normalized firing rate of dopamine cells at various frequencies (1, 2, 5, 10, or 20 Hz). Optical stimulation inhibited dopamine cell firing during baseline (blue, n=10 cells and 4 mice) and during GABAA blockade with picrotoxin (100 μM, grey, n=8 cells and 4 mice), but not during GABAB blockade with CGP 35348 (100 μM, black, n=8 cells and 4 mice). Data are shown as mean ± s.e.m.

Supplementary Figure 8 VTA GABA neurons inhibit dopamine neurons via GABAARs.

(a) Experimental schematic, stimulating VTA GABA neurons and recording tonic firing in cell-attached mode from VTA dopamine neurons. (b-f) Effect of optical stimulation of VTA GABA neurons on the normalized firing rate of dopamine cells at various frequencies (1, 2, 5, 10, or 20 Hz). Optical stimulation inhibited dopamine cell firing during baseline (red, n=10 cells and 4 mice) and during GABAB blockade with CGP 35348 (100 μM, black, n=11 cells and 5 mice), but not during GABAA blockade with picrotoxin (100 μM, grey, n=11 cells and 5 mice). Data are shown as mean ± s.e.m.

Supplementary Figure 9 Deletion of GABABRs from dopamine neurons does not affect general or morphine-induced locomotion.

(a) Summary of locomotor activity in a 30 min open-field test for AAV-Control versus AAV-TH-iCre mice (n=8 mice each, unpaired t-test, t(7)=0.3768, p=0.71). (b) Summary of time spent in the center during the open-field test for AAV Control versus AAV TH-iCre mice (n=8 mice each, unpaired t-test, t(7)=0.88, p=0.40). (c) Locomotor activity in 15 min bins after 10 mg/kg morphine injection. (d) Locomotor activity in 15 min bins after 30 mg/kg morphine injection. All data are shown as mean ± s.e.m.

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Edwards, N., Tejeda, H., Pignatelli, M. et al. Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior. Nat Neurosci 20, 438–448 (2017). https://doi.org/10.1038/nn.4482

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