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A thalamic input to the nucleus accumbens mediates opiate dependence

Nature volume 530, pages 219–222 (2016)Cite this article

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Abstract

Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use1,2,3, and the nucleus accumbens is important for orchestrating both processes4,5. While multiple inputs to the nucleus accumbens regulate reward6,7,8,9, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction.

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Figure 1: In vivo optical activation of the PVT→NAc pathway evokes behavioural aversion.
Figure 2: The PVT→NAc pathway is required for expression of aversive withdrawal symptoms.
Figure 3: Morphine-induced potentiation at the PVT→D2–MSN synapses.
Figure 4: In vivo optogenetic LTD induction restores normal transmission at PVT→D2-MSN synapses and suppresses withdrawal symptoms.

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Acknowledgements

We thank R. C. Malenka, K. Shen, L. Luo, T. R. Clandinin and members of the Chen laboratory for comments on the manuscript. We thank M. Asaad, J. Charalel and X. Sun for tracing and behaviour experiments. This work was supported by grants from The Whitehall Foundation, the Ajinomoto innovation alliance program, the Terman Scholarship and start-up funding from Stanford University. G.N. is supported by a training grant from the National Institute on Drug Abuse (5T32DA035165-02).

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Authors and Affiliations

  1. Department of Biology, Stanford University, Stanford, 94305, California, USA

    Yingjie Zhu, Carl F. R. Wienecke, Gregory Nachtrab & Xiaoke Chen

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  1. Yingjie Zhu
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  2. Carl F. R. Wienecke
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  3. Gregory Nachtrab
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  4. Xiaoke Chen
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Contributions

X.K.C. conceived the study. Y.J.Z., G.N. and X.K.C. designed the experiments. Y.J.Z. and C.F.R.W. conducted experiments. Y.J.Z. and X.K.C. analysed data. G.N., Y.J.Z. and X.K.C. wrote the manuscript, and all authors participated in the revision of the manuscript.

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Correspondence to Xiaoke Chen.

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Extended data figures and tables

Extended Data Figure 1 Retrograde tracing with rabies virus labels brain areas innervating the NAc and naloxone-precipitated opiate withdrawal induces c-Fos expression in the PVT.

a, Representative images show the injection site in the medial shell of the NAc, and retrograde labelling with mCherry in the ventral hippocampus (vHipp), prelimbic cortex (PrL) and basolateral amygdala (BLA). b, Representative images show retrograde labelling with mCherry in the PVT, ranging from Bregma −0.4 to −2.2 mm. c, Distribution of the density of retrogradely labelled neurons in the PVT (n = 7). d, Representative images show c-Fos expression in the PVT induced by naloxone-precipitated opiate withdrawal. e, Distribution of the density of c-Fos expressing neurons in the PVT (n = 5). Area of the PVT at different anterior–posterior coordinates are determined on the basis of the brain atlas published by Allen Institute for Brain Science (available from http://mouse.brain-map.org/experiment/thumbnails/100142143?image_type=atlas). Scale bars, 500 μm. Mean ± s.e.m.

Extended Data Figure 2 Optogenetic targeting of glutamatergic transmission between the PVT and the NAc.

a, A confocal image shows ChR2–eYFP- (enhanced yellow fluorescent protein) expressing terminals from the PVT in the medial shell of the NAc. Inset, injection site in the PVT. Scale bars, 500 μm. b, Example traces (left) and quantification (right) of action potential firing evoked by light stimulation at different frequencies in ChR2-expressing PVT neurons (n = 7). Scale bar, 25 mV, 250 ms. c, Example traces (left) and quantification (right) of photo-evoked EPSCs recorded from the NAc before and after superfusion of CNQX (10 μM, n = 6). Scale bar, 50 pA, 25 ms. Wilcoxon signed-rank test. *P < 0.05. Mean ± s.e.m.

Extended Data Figure 3 Optogenetic activation of the PVT input evoked feed–forward inhibition onto MSNs in the NAc.

a, In situ hybridization with GAD1 (http://mouse.brain-map.org/gene/show/14191), GAD2 (http://mouse.brain-map.org/experiment/show/79591669) and vGlut2 (http://mouse.brain-map.org/experiment/show/73818754) in the PVT (©2014 Allen Institute for Brain Science). b, c, Superfusion of a GABAA receptor antagonist (picrotoxin, 100 μM) selectively blocked IPSCs (b) (n = 4), whereas superfusion of an AMPAR antagonist (CNQX, 10 μM) blocked both IPSCs and EPSCs (c) (n = 5). Scale bar, 400 pA, 30 ms. d, Example trace (left) and quantification (right) of the onset latency for photo-evoked IPSCs and EPSCs in the same neuron (n = 20). Scale bar, 400 pA, 10 ms. Wilcoxon signed-rank test. ***P < 0.001. e, Averaged amplitude of photo-evoked IPSCs in D1-MSNs (n = 11) and D2-MSNs (n = 14). Mann–Whitney U-test, P = 0.67. Mean ± s.e.m.

Extended Data Figure 4 Location of ChR2, ArchT and hM4Di expression in the PVT.

a, Schematics showing the PVT and its surrounding brain nucleus from anterior to posterior locations. 3V, third ventricle; MD, mediodorsal thalamus; CM, central middle thalamus; DG, dentate gyrus; Hb, habenula; IMD, intermediodorsal thalamus. b, Overlay of ChR2–YFP expression in 21 mice, including 13 mice in Fig. 1d and 8 mice in Fig. 4g, h. c, Overlay of ArchT–YFP expression in 18 mice, including 10 mice in Fig. 2d and 8 mice in Extended Data Fig. 7c. d, Overlay of hM4Di–mCherry expression in 16 mice, including 8 mice in Fig. 2g and 8 mice in Extended Data Fig. 7d. Intensity of red colour is proportional to the number of mice expressing virus in the marked area.

Extended Data Figure 5 Dose–response analysis of naloxone-precipitated withdrawal symptoms.

Concentration of naloxone was determined by 2 × 2 factorial design. Different doses of naloxone (0, 1, 5, 10 mg per kg body weight) were injected in chronic saline- (blue) or morphine- (red) treated mice. Behavioural signs of withdrawal including jump (a), rearing (b) and tremor (c) were recorded for 20 min immediately after naloxone injection. CPA (d) tests were performed 24 h after withdrawal. One-way ANOVA followed by Tukey’s test. Jumping: morphine + naloxone group F(3,36) = 9.93, P < 0.0001; rearing: saline + naloxone group F(3,36) = 7.07, P < 0.01; morphine + naloxone group F(3,36) = 22.98, P < 0.0001; tremor: saline + naloxone group F(3,29) = 3.74, P < 0.05; morphine + naloxone group F(3,36) = 40.48, P < 0.0001; CPA: saline + naloxone group F(3,29) = 2.67, P = 0.066; morphine + naloxone group F(3,36) = 9.93, P < 0.0001; P values for post-hoc Tukey’s test are indicated on each comparison pair. Mean ± s.e.m.

Extended Data Figure 6 Opiate withdrawal induced c–Fos expression in the PVTNAc projection neurons.

a, Example confocal image shows expression of c-Fos in a small number of PVTNAc projection neurons after injection of saline into chronic morphine treated mice. Left: scale bar, 100 μm. Right: magnified image shows the boxed area; scale bar, 50 μm. b, Quantification of CTB- (left) and c-Fos- (right) positive cells per square millimetre after injection of saline (white bar, n = 5) or naloxone (grey bar, n = 6) into chronic morphine-treated mice. c, Example confocal images show that spontaneous withdrawal from morphine (bottom) but not saline (top) treatment increases the expression of c-Fos in PVTNAc projection neurons. Left: scale bar, 100 μm. Right: magnified image shows the boxed area; scale bar, 50 μm. d, Quantification of CTB- (left) and c-Fos- (middle) positive cells per square millimetre and percentage of PVTNAc projection neurons (right) expressing c-Fos induced by spontaneous withdrawal from morphine (grey bar, n = 4) or saline (white bar, n = 4). Mann–Whitney U-test. *P < 0.05, **P < 0.01. Mean ± s.e.m.

Extended Data Figure 7 The PVT→NAc pathway is required for expression of behavioural aversion to footshock and LiCl injection.

a, Confocal images show robust expression of c-Fos (red) in the PVTNAc projection neurons (green) after footshock (top) and LiCl injection (bottom). Left: scale bar, 100 μm. Right: magnified image shows the boxed area; scale bar, 50 μm. b, Quantification of CTB- (left) and c-Fos- (middle) positive cells per square millimetre and percentage of PVTNAc projection neurons (right) expressing c-Fos induced by footshock (white bar, n = 4) or LiCl injection (grey bar, n = 4). c, Light stimulation suppressed the expression of footshock-induced CPA in ArchT- (n = 8) but not eGFP- (n = 8) expressing mice. d, Local infusion of CNO reduced the expression of LiCl-induced CPA in hM4Di- (n = 8) but not eGFP- (n = 8) expressing mice. Mann–Whitney U-test. *P < 0.05, **P < 0.01. Mean ± s.e.m.

Extended Data Figure 8 Effects of chronic morphine treatment and in vivo optogenetic LTD induction on the strength of AMPAR and NMDAR current in MSNs receiving input from the PVT or BLA.

a, b, In the PVT→NAc pathway, chronic morphine treatment specifically increases AMPAR but not NMDAR current on D2-MSNs (saline/morphine, n = 13/16 cells) but not D1-MSNs (saline/morphine, n = 14/14 cells). Two-way ANOVA (AMPAR: F(1,53) = 5.24, P < 0.05; NMDAR: F(1,53) = 0.04, P = 0.83) followed by Tukey’s test. **P < 0.01. c, d, In the BLA→NAc pathway, chronic morphine treatment increases both AMPAR current (c) and NMDAR current (d) on D1-MSNs (saline/morphine, n = 14/13 cells) but not D2-MSNs (saline/morphine, n = 13/12 cells). Two-way ANOVA (AMPAR: F(1,51) = 7.06, P < 0.05; NMDAR: F(1,51) = 0.35, P = 0.55) followed by Tukey’s test. *P < 0.05. e, Chronic morphine treatment has no effect on the AMPAR/NMDAR ratio in either D1-MSNs or D2-MSNs in the BLA→NAc pathway. Two-way ANOVA (F(1,51) = 7.06, P < 0.05). f, g, In the PVT→NAc pathway, in vivo optogenetic stimulation (4 ms, 1 Hz, 900 pulses) in morphine-treated mice specifically decreases AMPAR but not NMDAR current in D2-MSNs (morphine/morphine + 1 Hz, n = 16/17 cells) but not D1-MSNs (morphine/morphine + 1 Hz, n = 14/14 cells). Two-way ANOVA (AMPAR: F(1,57) = 4.24, P = 0.04; NMDAR: F(1,57) = 0.01, P = 0.92) followed by Tukey’s test. *P < 0.05. Mean ± s.e.m.

Extended Data Figure 9 Chronic morphine treatment and in vivo optogenetic LTD induction does not affect paired-pulse ratio of MSNs receiving PVT input.

a, b, Example traces (a) and quantification (b) of paired-pulse ratio of photo-evoked EPSCs in D1- and D2-MSNs. An escalating regimen of morphine treatment and in vivo optogenetic stimulation (4 ms, 1 Hz, 900 pulses) in morphine-treated mice had no obvious effect on the paired-pulse ratio of MSNs receiving PVT input (two-way ANOVA, F(2,35) = 0.02, P = 0.97). D1-MSNs: saline/morphine/morphine + 1 Hz, n = 9/7/6; D2-MSNs: saline/morphine/morphine + 1 Hz, n = 7/6/6. Scale bars, 200 pA, 50 ms. Mean ± s.e.m.

Extended Data Table 1 Statistical analysis for Figs 1–4
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Zhu, Y., Wienecke, C., Nachtrab, G. et al. A thalamic input to the nucleus accumbens mediates opiate dependence. Nature 530, 219–222 (2016). https://doi.org/10.1038/nature16954

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