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An ACC–VTA–ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences

Nature Neuroscience volume 27, pages 272–285 (2024)Cite this article

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Abstract

The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACCGlu) projecting to the VTA indirectly inhibit dopaminergic neurons (VTADA) by activating local GABAergic interneurons (VTAGABA), and this effect is reinforced after nerve injury. VTADA neurons in turn project to the ACC and synapse to the initial ACCGlu neurons to convey feedback information from emotional changes. Thus, an ACCGlu–VTAGABA–VTADA–ACCGlu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term.

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Fig. 1: ACCGlu–VTAGABA–VTADA mediates anxiodepressive-like behavior and hyperalgesia in neuropathic pain.
Fig. 2: VTADA–ACC projection mediates feedback modulation of VTA-projecting ACCGlu neurons in neuropathic pain.
Fig. 3: ACC–VTA–ACC forms a positive-feedback loop.
Fig. 4: The ACC–VTA–ACC feedback loop mediates the persistence of neuropathic pain.
Fig. 5: Tuning down the ACC–VTA–ACC feedback loop leads to long-lasting restoration of hyperpathia and anxiodepressive-like behavior in neuropathic pain.
Fig. 6: D2R serves as a dual therapeutic target for persistent pain.
Fig. 7: Working model of the ACC–VTA–ACC positive-feedback loop in the chronicity of neuropathic pain.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

The present study did not use any customized code or mathematical algorithm.

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Acknowledgements

We thank M. Zhuo (Xi’an Jiaotong University, China) for CaMKIICre-transgenic mice and insightful comments, W. Zeng (Tsinghua University, China) for ThCre-transgenic mice, M. Luo (National Institute of Biological Sciences, China) for ThGFP-transgenic mice, Q. Yang (the Fourth Military Medical University) for optogenetics-coupled optical fiber photometry recordings, Y. Hao (Xi'an Jiaotong University, China) for assistance in confocal imaging, E. Wang (I-Harbour High School Affiliated to Xi'an Jiaotong University, China) for artwork and I.C. Bruce (Peking University) and C. Luo (the Fourth Military Medical University, China) for reading the manuscript. This work was supported by the National Natural Science Foundation of China (to C.W. (32171233, 31670843 and 31400708), X.K. (81974203), H.X. (81901308), Q.S. (32000704) and Y.C. (32300819)), the NIH–NINDS and NIDCR (to F.W., NS 091296 and DE 029946), the Natural Science Foundation of Shaanxi Province of China (to C.W. (2023-ZDLSF-23, 2021TD-37 and 2019JC-07), Q.S. (2020-JC-QN-1423) and N.D. (2023-JC-QN-0236)), the Natural Science Foundation of Sichuan Province of China (to X.K. (2020YJ0337) and H.X. (2020YJ0378)), the Sichuan Science and Technology Program (to X.K., 2022YFS0615), the Shaanxi Postdoc Funding (to H.X. (2023BSHTBZZ15), Y.C. (2023BSHYDZZ39) and C.Z. (2023BSHEDZZ67)) and the China Postdoctoral Science Foundation (to Q.S. (2018M640972) and N.D. (2022M712543)).

Author information

Author notes

  1. These authors contributed equally: Qian Song, Anqi Wei, Huadong Xu, Yuhao Gu.

Authors and Affiliations

  1. Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi’an Jiaotong University, Xi’an, China

    Qian Song, Anqi Wei, Huadong Xu, Yuhao Gu, Nan Dong, Chaowen Zheng, Xueting Duan, Yang Chen, Bianbian Wang, Jingxiao Huo, Jingyu Yao, Hao Wu, Hua Li, Xuanang Wu, Zexin Jing, Xiaoying Liu, Yuxin Yang, Shaoqin Hu, Anran Zhao & Changhe Wang

  2. Department of Neurology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Qian Song, Qiumin Qu & Changhe Wang

  3. Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease and the Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China

    Huadong Xu, Hongyan Wang, Xu Cheng, Yuhao Qin, Xinjiang Kang & Changhe Wang

  4. Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China

    Yong Jiang, Xinjiang Kang & Changhe Wang

  5. State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology; Peking-Tsinghua Center for Life Sciences; and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China

    Qinglong Wang, Min Gao, Suhua Sun & Zhuan Zhou

  6. College of Life Sciences, Liaocheng University, Liaocheng, China

    Yuxin Yang, Hongyan Wang & Xinjiang Kang

  7. Department of Human Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, the Fourth Military Medical University, Xi’an, China

    Tao Chen

  8. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Zuying Chai

  9. Department of Neural and Pain Sciences, School of Dentistry; Program in Neuroscience, Center to Advance Chronic Pain Research, University of Maryland, Baltimore, MD, USA

    Feng Wei

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  1. Qian Song
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  2. Anqi Wei
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Contributions

C.W., F.W., X.K. and Z.C. conceived the study and designed experiments with the help of Y.J., Q.Q., T.C. and Z.Z.; Q.S., A.W., H.X. and Y.G. designed studies and performed most experiments and data analysis; N.D., C.Z., X.D. and X.L. conducted some of the behavior experiments and data analysis; Q.W., M.G. and S.S. performed two-photon Ca2+ imaging and data analysis; Y.C. and B.W. performed some of the whole-cell patch and amperometric DA recording; J.H., J.Y., H. Wang., H.L. and X.W. performed some virus injections and stereotaxic surgery. Z.J., Y.Y. and S.H. performed some of the optogenetic behavior experiments; A.Z., H. Wu., X.C. and Y.Q. performed some of the immunochemistry experiments. C.W., A.W., F.W., X.K., Z.C. and Q.S. wrote the manuscript. All authors reviewed the manuscript and approved its submission.

Corresponding authors

Correspondence to Zuying Chai, Xinjiang Kang, Feng Wei or Changhe Wang.

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The authors declare no competing interests.

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Extended data

Extended Data Fig. 1 SNI mouse model shows pain and anxiodepression-like behaviors.

a, Statistics of thermal pain response of Sham and SNI mice (Sham, n = 7; SNI, n = 8 mice). b, Representative tracking maps in the OFT (upper) and EPM (lower) tests of Sham and SNI mice. c, Statistics of locomotion of Sham and SNI mice (Sham, n = 8; SNI, n = 8 mice). d-f, Statistics of the dark-light box (DLB, d), sucrose preference test (SPT, e), and forced swimming test (FST, f) of Sham (n = 7) and SNI (n = 8 for DLB, n = 7 for SPT and FST) mice. g, Sample traces (left) and statistics (right) of current injection-evoked APs of lateral VTADA neurons of TH-GFP mice 6 weeks after SNI (Sham, n = 8; SNI, n = 10 cells from 3 pairs of mice). h, Schematic of the CFE recordings of DA release in the NAc and the mPFC. Left, schematic of the CFE recording of DA release in the NAc. Right, schematic of the injection of Cre-dependent chemogenetic activation virus (DIO-hM3Dq) in the VTA of TH-Cre mice and CFE recording of DA release in the mPFC in response to CNO. i, Sample traces (Iamp and current integration) and statistics of DA release in response to CNO application (100 \({\rm{\mu }}\)M, 7 s) in the mPFC 6 weeks after SNI (Sham, n = 5; SNI, n = 6 slices from 3 pairs of mice). j, Statistics of OFT behavior of SNI (n = 7) versus Sham (n = 7) mice 7 days after SNI surgery. k, Statistics of VTADA neuron firing rate of SNI versus Sham mice 7 days after SNI surgery (Sham, n = 12 neurons from 3 mice; SNI, n = 11 neurons from 3 mice). The data are presented as the mean ± s.e.m. Unpaired Student’s t-test, *P < 0.05, **P < 0.01, ***P < 0.001. Detailed statistics information can be found in the Source Data.

Source data

Extended Data Fig. 2 VTADA neurons modulate hyperalgesia and anxiodepression-like behaviors in neuropathic pain.

a, Upper, schematic of the injection of Cre-dependent chemogenetic inhibition virus (GFP) into the lateral VTA of TH-Cre mice. Lower, representative trace of AP recording from VTADA neurons in response to CNO application. b, Representative micrograph showing the co-localization of GFP and TH-staining in the VTA. Scale bar, 500 μm. c–g, Statistics of mechanical (c) and thermal (d) pain, OFT (e), EPM (f), and DLB (g) behaviors of the chemogenetic inhibitory group and control mice (Von Frey, cold/hot plate, and OFT: Control, n = 9; hM4Di, n = 10; EPM: Control, n = 11; hM4Di, n = 10 mice; DLB: Control, n = 8; hM4Di, n = 10 mice). h, Left, schematic showing the injection of chemogenetic activation virus into the VTA of TH-Cre mice with SNI. Right, representative trace of AP recording of VTADA neurons in response to CNO application. i-o, Statistics of mechanical (i) and thermal (j) pain, OFT (k), EPM (l), DLB (m), SPT (n), and FST (o) behaviors of the chemogenetic excitatory group and control virus-injected mice with SNI (Von Frey: Control, n = 8; hM4Di, n = 8; Cold/Hot plate: Control n = 13, hM4Di n = 15; EPM: Control, n = 8; hM4Di, n = 8; OFT: Control, n = 9; hM4Di, n = 10 mice; DLB: Control n = 8; hM4Di n = 9 mice, SPT and FST: Control n = 7, hM4Di n = 7 mice). The data are presented as the mean ± s.e.m. Unpaired Student’s t-test, *P < 0.05, **P < 0.01, ***P < 0.001. Detailed statistics information can be found in the Source Data.

Source data

Extended Data Fig. 3 Inhibition of the ACCGlu–VTA projection relieves hyperalgesia and anxiety-like behaviors in neuropathic pain.

a,b, Schematic and representative micrograph showing the retrograde labeling of ACC neurons by injection of retrograde virus (mCherry) into the VTA. Scale bar, 300 μm. Statistics are shown on the right. c, Schematic of the injection of optogenetic inhibition virus (DIO-eNpHR) into the ACC and optical fiber delivery of L-stim (589-nm yellow light) in the VTA of SNI mice. d, e, Statistics of mechanical and thermal pain responses in the chemogenetic inhibitory and control groups. (Von Frey: Control, n = 8; NpHR, n = 8 mice; Cold/Hot plate, Control, n = 12; NpHR, n = 13 mice). f, Representative AP trace of a ACCGlu neuron in response to light stimulation (589 nm). g, h Statistics of OFT (e), and EPM (f) tests in the NpHR group and controls (OFT: Control, n = 11; NpHR, n = 11; EPM: Control, n = 10; NpHR, n = 10 mice). The data are presented as the mean ± s.e.m. Unpaired Student’s t-test, *P < 0.05, **P < 0.01, ***P < 0.001. Detailed statistics information can be found in the Source Data.

Source data

Extended Data Fig. 4 The ACCGlu–VTA projection mediates hyperalgesia and anxiodepressive-like behaviors in neuropathic pain.

a, Schematic showing the specific chemogenetic activation of ACCGlu neurons. b-h, Statistics of mechanical (b) and thermal (c) pain responses, OFT (d), and EPM (e), DLB (f), and CPA (conditioned place aversion, g,h) tests in the chemogenetic excitatory group and controls (Von Frey and Cold/Hot plate: Control, n = 14; hM3Dq, n = 13; OFT: Control, n = 14; hM3Dq, n = 13; EPM and DLB: Control, n = 12; hM3Dq, n = 12 mice; CPA: Control, n = 8; hM3Dq, n = 8 mice). i, Schematic showing the specific chemogenetic inhibtion of ACCGlu projection in the VTA in SNI mice. j, Statistics of thermal pain response in the chemogenetic inhibition and control groups (Control, n = 8; hM4Di, n = 8 mice). k, l, Statistics of EPM and CPP (conditioned place preference) tests in the chemogenetic inhibition and control groups (CPP = time in light side – time in dark side; Control, n = 8; hM4Di, n = 8 mice). m-q, Schematic and statistics of pain responses and anxiety-related behaviors of sham mice with (hM4Di) or without (Control) chemogenetic inhibition of ACCGlu-VTA projection (Control, n = 8; hM4Di, n = 8 mice). The data are presented as the mean ± s.e.m. Unpaired Student’s t-test, *P < 0.05, **P < 0.01, ***P < 0.001. Detailed statistics information can be found in the Source Data.

Source data

Extended Data Fig. 5 ACCGlu–innervated VTAGABA neurons mediate hyperalgesia and anxiety-like behaviors in neuropathic pain.

a, Left, schematic of the co-injection of CaMKII-Cre virus and the Cre-dependent anterograde trans-monosynaptic virus (rAAV-EF1α-DIO-EGFP-T2A-TK-WPRE-hGH, and H129ΔTK-ubc-tdTomato) into the ACC for the identification of ACCGlu-innervated neurons (GAD67-GFP) in the VTA. Right, representative micrograph showing the localization of anterograde virus (GFP and tdTomato) in ACCGlu neurons. Scale bar, 500 μm. b, Schematic and representative micrograph showing the specific expression of chemogenetic activation virus in ACCGlu neurons. c, Schematic of the injection of chemogenetic activation virus (VGAT1-DIO-hM3Dq) into the VTA and AAV2/1-Cre anterograde virus into the ACC. d-g, Statistics of mechanical (d) and thermal (e) pain responses, OFT (f), and EPM (g) tests following CNO application (0.5 mg/kg, i.p.) of mice receiving hM3Dq-expressing or control virus (Control, n = 8; hM3Dq, n = 8 mice). Behaviors were assessed 6 weeks after SNI. h-l, As in (c-g), except that AAV2/1-Cre anterograde virus was injected into the ACC and GAD67-DIO-hM4Di virus was injected into the VTA in SNI mice (n = 8 for each group). The data are presented as the mean ± s.e.m. Unpaired Student’s t-test, *P < 0.05, **P < 0.01. Detailed statistics information can be found in the Source Data.

Source data

Extended Data Fig. 6 VTADA-ACC projections inhibit VTA-projecting ACCGlu neurons via D2R.

a, Schematic and representative micrographs showing the retrograde labeling of VTADA neurons (TH-positive) by the injection of retrograde virus (mCherry) into the ACC. Scale bar, 150 μm. b, Sample traces (left) and statistics (right) showing the spontaneous action potential (AP) firing rate of VTADA neurons labelled by retrograde virus from the ACC of TH-GFP mice 6 weeks after SNI (Sham, n = 20; SNI, n = 20 cells from 4 pairs of mice). c, Schematic of the injection of anterograde (tdTomato) and retrograde (BFP) viruses into the VTA and CaMKII-GFP virus into the VTA of the TH-Cre mice. d, Representative micrograph showing tdTomato-positive neurons in the ACC (tdTomato-labeled ACCGlu neurons). Statistics of tdTomato-labeled glutamatergic (yellow) and non-glutamatergic (red) neurons in the ACC are shown on the right. e, Representative micrograph showing the tdTomato (anterograde) and BFP (retrograde) co-labeled neurons in the ACC. f, Schematic of the co-injection of retrograde virus (mCherry) and Cre-dependent chemogenetic activation virus (GFP) into the VTA of TH-Cre mice. g,h, Representative path-clamp recording traces and statistics of AP frequency of ACCGlu neurons in response to CNO application with or without (ACSF control, n = 23 cells from 4 mice) the treatment of haloperidol (an antagonist of D2R, n = 15 cells from 2 mice) or SCH23390 (an antagonist of D1R, n = 8 cells from 2 mice) in ACC slices. The data are presented as the mean ± s.e.m. Paired Student’s t-test, ***P < 0.001. Statistics are shown on the right. Scale bars, 150 μm. The data are presented as the mean ± s.e.m. Unpaired Student’s t-test, **P < 0.01. Detailed statistics information can be found in the Source Data.

Source data

Extended Data Fig. 7 The VTADA–ACC projection modulates anxiodepression-like behaviors and persistent pain.

a, Schematic of the injection of Cre-dependent chemogenetic inhibition virus into the VTA and CNO local administration in the ACC of TH-Cre mice. b-e, Statistics of thermal pain response, EPM, DLB and CPA in the chemogenetic inhibitory and control groups (Cold/Hot plate: Control, n = 10; hM4Di, n = 7; EPM: Control, n = 8; hM4Di, n = 8 mice; DLB: Control, n = 12; hM4Di, n = 11 mice; CPA: Control, n = 8; hM4Di, n = 8 mice). f–j, As in (a-e), except that Cre-dependent chemogenetic activation virus was injected into the VTA of SNI TH-Cre mice and CPP was used for the evaluation of behavior aversion (Control, n = 12; hM3Dq, n = 13 mice; CPP: Control, n = 8; hM4Di, n = 8 mice). k-o, Schematic and statistics of pain responses and anxiety-related behaviors of sham mice with (hM3Dq) or without (Control) chemogenetic activation of VTADA-ACC projection (Control, n = 8; hM3Dq, n = 8 mice). The data are presented as the mean ± s.e.m. Unpaired Student’s t-test, *P < 0.05, **P < 0.01, ***P < 0.001. Detailed statistics information can be found in the Source Data.

Source data

Extended Data Fig. 8 Synaptic connections within the ACCGlu–VTAGABA–VTADA–ACCGlu loop.

a, Schematic of virus injection for the functional connection of the ACCGlu–VTAGABA–VTADA–ACCGlu loop. The trans-monosynaptic anterograde-Cre/GFP virus is injected into the ACC to express Cre and GFP in the downstream VTAGABA neurons, which initiates the Cre-dependent retrograde trans-monosynaptic tracing rabies virus (DIO-TVA/RVG and RV-\(\Delta G\)-dsRed) and simultaniously turns on the Cre-dependent expression of WGA-Flpo (DIO-WGA-Flpo) that is trans-synaptically delivered into the downstream DA neurons to start the TH-driving Ch2R/mCherry expression. b, Immunofluorescence showing the co-localization of DsRed- and GFP-positive signals with GAD67 staining. The inset is enlarged on the right. Scale bar, 100 μm. c, Representative micrograph showing that TH-positive fibers densely surround the VTA-projecting ACCGlu neurons, which are labeled by the retrograde virus (DsRed). The inset is enlarged on the right. Scale bar, 40 μm. d, Schematic showing the effect of chemogenetic inhibition of VTADA terminals on VTA-projecting ACCGlu neurons in awake mice. e, Statistics showing the CNO effect on control virus-injected mice (n = 14 cells from 2 mice) as in (d). f, Statistics showing the effects of chemogenetic inhibition of VTADA terminals on VTA-projecting ACCGlu neurons in awake shame (n = 33 cells from 3 mice) vs SNI (n = 33 cells from 3 mice) mice. g, Schematic of virus injection for the functional connection of the ACCGlu–VTAGABA–VTADA–ACCGlu feedback loop. The Cre/GFP-carrying trans-monosynaptic anterograde virus is injected into the ACC to express Cre and GFP in the downstream VTAGABA neurons, which turns on the Cre-dependent expression of WGA-Flpo (DIO-WGA-Flpo) that is trans-synaptically delivered to the downstream DA neurons to start the Flpo-dependent Ch2R/mCherry expression driven by the TH-promoter. h, Statistics of cold/hot plate of the optogenetic activation group and control mice (Control, n = 8; ChR2, n = 8 mice). The data are presented as the mean ± s.e.m. Paired Student’s t-test for (e, f) and unpaired Student’s t-test for (h). n.s., P > 0.05, *P < 0.05, ***P < 0.001. Detailed statistics information can be found in the Source Data.

Source data

Extended Data Fig. 9 VTADA neuron excitation leads to a better performance in anxiety-like behaviors at the early stage after SNI surgery.

a, Schematic of the injection of Cre-dependent chemogenetic activation virus (GFP) into the VTA of TH-Cre mice, followed by the SNI surgery. b, Statistics of OFT behavior of chemogenetic activation (n = 7) and control (n = 7) groups 7 days after the SNI surgery. c, d, As in (a, b), except that CaMKII-Cre virus and Cre-dependent optical inhibitory virus were co-injected into the ACC and C57 mice were used (Control, n = 7; NpHR, n = 7). The data are presented as the mean ± s.e.m. Unpaired Student’s t-test, *P < 0.05, **P < 0.01. Detailed statistics information can be found in the Source Data.

Source data

Extended Data Fig. 10 Tuning down ACC–VTA–ACC feedback loop relieves hypersensitivity of thermal pain.

a, Statistics of thermal pain behaviors of SNI (nerve ligation removing) (n = 8 mice) vs sham (n = 7 mice), hM4Di vs control virus-injected (in the VTA) SNI mice (with nerve ligation removed), and hM3Dq vs control virus-injected (in the ACC) SNI mice (with nerve ligation removed) 3 weeks after repetitive CNO application (every second day for 2 weeks, n = 6 mice for each). b, Schematic of quinpirole local administration in the ACC (1 µg/µl, 200 nl) of SNI mice. c, Statistics of thermal pain behaviors of SNI mice following the local application of quinpirole vs saline (n = 7 mice for each). d, e, As in (b, c), except that haloperidol (50 µM, 200 nl) was applied in the VTA (saline, n = 7 mice; haloperidol, n = 8 mice). The data are presented as the mean ± s.e.m. Unpaired Student’s t-test, *P < 0.05, **P < 0.01. Detailed statistics information can be found in the Source Data.

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Song, Q., Wei, A., Xu, H. et al. An ACC–VTA–ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences. Nat Neurosci 27, 272–285 (2024). https://doi.org/10.1038/s41593-023-01519-w

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