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Lateral habenula induces cognitive and affective dysfunctions in mice with neuropathic pain via an indirect pathway to the ventral tegmental area

Neuropsychopharmacology volume 50, pages 1039–1050 (2025)Cite this article

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Abstract

Neuropathic pain, which has become a major public health concern, is frequently accompanied by the deterioration of affective behavior and cognitive function. However, the brain circuitry underlying these changes is poorly understood. Therefore, we aimed to identify in a mouse model the converging circuit that influences the sensory, affective, and cognitive consequences of neuropathic pain. The lateral habenula (LHb) and ventral tegmental area (VTA) have been confirmed to play critical roles in the regulation of pain, cognition, and depression. Given the essential role of the LHb in depression and cognition, we attempted to clarify how neural circuitry involving the LHb integrates pain-related information. Our data confirmed that the VTA receives projections from the LHb, but our results suggest that inhibition of this direct pathway has no effect on the behavior of mice with chronic neuropathic pain. The rostromedial tegmental nucleus (RMTg), a GABAergic structure believed to underlie the transient inhibition of DAergic neurons in the VTA, received glutamatergic inputs from the LHb and projected strongly to the VTA. Furthermore, our data suggest that a projection from LHb glutamatergic neurons to RMTg GABAergic neurons in the VTA, constituting an indirect LHbGlu → RMTgGABA → VTADA pathway, participates in peripheral nerve injury-induced nociceptive hypersensitivity, depressive-like behavior, and cognitive dysfunction. Ex vivo extracellular recordings of LHb neurons showed that the proportion of burst-firing cells in the LHb was significantly increased in indirect projections rather than in direct projections. This may explain the functional discrepancies between direct and indirect projections of the LHb to the VTA. Collectively, our study identifies a pivotal role of the LHbGlu → RMTgGABA → VTADA pathway in processing pain. This pathway may offer new therapeutic targets to treat neuropathic pain and its associated depressive-like and cognitive impairments.

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Fig. 1: Short- and long-term changes in sensory, affective, and cognitive test results of male mice with neuropathic pain.
Fig. 2: Chemogenetic inhibition of LHb neurons increases mechanical and thermal pain thresholds and alleviates depressive-like and cognitive impairments.
Fig. 3: The direct LHb→VTA pathway does not affect the behavior of mice with chronic neuropathic pain while the indirect LHb→RMTg→VTA pathway controls pain-induced depressive-like and cognitive impairments in mice.
Fig. 4: Dissection of the direct LHb→VTA and indirect LHb→RMTg→VTA pathways.
Fig. 5: Increased LHb burst firing in the indirect pathway is associated with pain-induced depressive-like and cognitive impairments in mice.

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All data are present in the main text or the Supplementary Materials. Additional data to support the findings of this study are available from the corresponding author upon request.

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References

  1. Komboz F, Mehsein Z, Kobaïter-Maarrawi S, Chehade HD, Maarrawi J. Epidural posterior insular stimulation alleviates neuropathic pain manifestations in rats with spared nerve injury through endogenous opioid system. Neuromodulation. 2022;26:1602–1611.

  2. Devor M. Sodium channels and mechanisms of neuropathic pain. J Pain. 2006;7:S3–12.

    Article  CAS  PubMed  Google Scholar 

  3. Moriarty O, McGuire BE, Finn DP. The effect of pain on cognitive function: a review of clinical and preclinical research. Prog Neurobiol. 2011;93:385–404.

    Article  PubMed  Google Scholar 

  4. Malfliet A, Coppieters I, Van Wilgen P, Kregel J, De Pauw R, Dolphens M, et al. Brain changes associated with cognitive and emotional factors in chronic pain: a systematic review. Eur J Pain. 2017;21:769–86.

    Article  CAS  PubMed  Google Scholar 

  5. Alba-Delgado C, Llorca-Torralba M, Horrillo I, Ortega JE, Mico JA, Sánchez-Blázquez P, et al. Chronic pain leads to concomitant noradrenergic impairment and mood disorders. Biol Psychiatry. 2013;73:54–62.

    Article  CAS  PubMed  Google Scholar 

  6. May A. Chronic pain may change the structure of the brain. Pain. 2008;137:7–15.

    Article  PubMed  Google Scholar 

  7. Hu H, Cui Y, Yang Y. Circuits and functions of the lateral habenula in health and in disease. Nat Rev Neurosci. 2020;21:277–95.

    Article  CAS  PubMed  Google Scholar 

  8. Proulx CD, Hikosaka O, Malinow R. Reward processing by the lateral habenula in normal and depressive behaviors. Nat Neurosci. 2014;17:1146–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci. 2004;5:483–94.

    Article  CAS  PubMed  Google Scholar 

  10. Hikosaka O. The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci. 2010;11:503–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gu HW, Zhang GF, Liu PM, Pan WT, Tao YX, Zhou ZQ, et al. Contribution of activating lateral hypothalamus-lateral habenula circuit to nerve trauma-induced neuropathic pain in mice. Neurobiol Dis. 2023;182:106155.

    Article  CAS  PubMed  Google Scholar 

  12. Rossi MA, Basiri ML, Liu Y, Hashikawa Y, Hashikawa K, Fenno LE, et al. Transcriptional and functional divergence in lateral hypothalamic glutamate neurons projecting to the lateral habenula and ventral tegmental area. Neuron. 2021;109:3823–37.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang C, Chen M, Qin C, Qu X, Shen X, Liu S. Lateral hypothalamic orexin neurons mediate the reward effects of pain relief induced by electroacupuncture. Front Mol Neurosci. 2022;15:812035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen M, Ma S, Liu H, Dong Y, Tang J, Ni Z, et al. Brain region-specific action of ketamine as a rapid antidepressant. Science. 2024;385:eado7010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dai D, Li W, Chen A, Gao XF, Xiong L. Lateral habenula and its potential roles in pain and related behaviors. ACS Chem Neurosci. 2022;13:1108–18.

    Article  CAS  PubMed  Google Scholar 

  16. Kiening K, Sartorius A. A new translational target for deep brain stimulation to treat depression. EMBO Mol Med. 2013;5:1151–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xin J, Shan W, Li J, Yu H, Zuo Z. Activation of the lateral habenula-ventral tegmental area neural circuit contributes to postoperative cognitive dysfunction in mice. Adv Sci. 2022;9:e2202228.

    Article  Google Scholar 

  18. Engelhard B, Finkelstein J, Cox J, Fleming W, Jang HJ, Ornelas S, et al. Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons. Nature. 2019;570:509–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Morales M, Margolis EB. Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nat Rev Neurosci. 2017;18:73–85.

    Article  CAS  PubMed  Google Scholar 

  20. Guang-Fen Z, Jie G, Jian-Jun Y. The lateral Habenula: role in chronic pain and depression. Translational perioperative and pain medicine. 2020;7:271–278.

  21. Markovic T, Pedersen CE, Massaly N, Vachez YM, Ruyle B, Murphy CA, et al. Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior. Nat Neurosci. 2021;24:1601–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Geisler S, Andres KH, Veh RW. Morphologic and cytochemical criteria for the identification and delineation of individual subnuclei within the lateral habenular complex of the rat. J Comp Neurol. 2003;458:78–97.

    Article  PubMed  Google Scholar 

  23. Ji H, Shepard PD. Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABA(A) receptor-mediated mechanism. J Neurosci. 2007;27:6923–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bourdy R, Barrot M. A new control center for dopaminergic systems: pulling the VTA by the tail. Trends Neurosci. 2012;35:681–90.

    Article  CAS  PubMed  Google Scholar 

  25. Lu YG, Wang L, Chen JL, Zhu J, Meng XY, You ZD, et al. Projections from lateral habenular to tail of ventral tegmental area contribute to inhibitory effect of stress on morphine-induced conditioned place preference. Brain Res. 2019;1717:35–43.

    Article  CAS  PubMed  Google Scholar 

  26. Batalla A, Homberg JR, Lipina TV, Sescousse G, Luijten M, Ivanova SA, et al. The role of the habenula in the transition from reward to misery in substance use and mood disorders. Neurosci Biobehav Rev. 2017;80:276–85.

    Article  CAS  PubMed  Google Scholar 

  27. Herkenham M, Nauta WJ. Efferent connections of the habenular nuclei in the rat. J Comp Neurol. 1979;187:19–47.

    Article  CAS  PubMed  Google Scholar 

  28. Gonçalves L, Sego C, Metzger M. Differential projections from the lateral habenula to the rostromedial tegmental nucleus and ventral tegmental area in the rat. J Comp Neurol. 2012;520:1278–300.

    Article  PubMed  Google Scholar 

  29. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317–22.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang CK, Wang P, Ji YY, Zhao JS, Gu JX, Yan XX, et al. Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain. Sci China Life Sci. 2024;67:67–82.

    Article  CAS  PubMed  Google Scholar 

  31. Wilcox KS, Gutnick MJ, Christoph GR. Electrophysiological properties of neurons in the lateral habenula nucleus: an in vitro study. J Neurophysiol. 1988;59:212–25.

    Article  CAS  PubMed  Google Scholar 

  32. Cui Y, Yang Y, Ni Z, Dong Y, Cai G, Foncelle A, et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature. 2018;554:323–7.

    Article  CAS  PubMed  Google Scholar 

  33. Wagner F, Weiss T, Veh RW. Electrophysiological properties of neurons and synapses in the lateral habenular complex (LHb). Pharmacol Biochem Behav. 2017;162:38–45.

    Article  CAS  PubMed  Google Scholar 

  34. Huang L, Xi Y, Peng Y, Yang Y, Huang X, Fu Y, et al. A visual circuit related to habenula underlies the antidepressive effects of light therapy. Neuron. 2019;102:128–42.e8.

    Article  CAS  PubMed  Google Scholar 

  35. Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain. 2000;87:149–58.

    Article  PubMed  Google Scholar 

  36. Llorca-Torralba M, Suárez-Pereira I, Bravo L, Camarena-Delgado C, Garcia-Partida JA, Mico JA, et al. Chemogenetic silencing of the locus coeruleus-basolateral amygdala pathway abolishes pain-induced anxiety and enhanced aversive learning in rats. Biol Psychiatry. 2019;85:1021–35.

    Article  CAS  PubMed  Google Scholar 

  37. Baker PM, Jhou T, Li B, Matsumoto M, Mizumori SJ, Stephenson-Jones M, et al. The lateral habenula circuitry: reward processing and cognitive control. J Neurosci. 2016;36:11482–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Björklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci. 2007;30:194–202.

    Article  PubMed  Google Scholar 

  39. Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 2010;68:815–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lammel S, Lim BK, Ran C, Huang KW, Betley MJ, Tye KM, et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature. 2012;491:212–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Flores-García M, Rizzo A, Garçon-Poca MZ, Fernández-Dueñas V, Bonaventura J. Converging circuits between pain and depression: the ventral tegmental area as a therapeutic hub. Front Pharmacol. 2023;14:1278023.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Xia SH, Hu SW, Ge DG, Liu D, Wang D, Zhang S, et al. Chronic pain impairs memory formation via disruption of neurogenesis mediated by mesohippocampal brain-derived neurotrophic factor signaling. Biol Psychiatry. 2020;88:597–610.

    Article  PubMed  Google Scholar 

  43. Ungless MA, Magill PJ, Bolam JP. Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science. 2004;303:2040–2.

    Article  CAS  PubMed  Google Scholar 

  44. Yang H, de Jong JW, Cerniauskas I, Peck JR, Lim BK, Gong H, et al. Pain modulates dopamine neurons via a spinal-parabrachial-mesencephalic circuit. Nat Neurosci. 2021;24:1402–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Brischoux F, Chakraborty S, Brierley DI, Ungless MA. Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc Natl Acad Sci USA. 2009;106:4894–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. de Jong JW, Afjei SA, Pollak Dorocic I, Peck JR, Liu C, Kim CK, et al. A neural circuit mechanism for encoding aversive stimuli in the mesolimbic dopamine system. Neuron. 2019;101:133–51.e7.

    Article  PubMed  Google Scholar 

  47. Han Y, Ai L, Song L, Zhou Y, Chen D, Sha S, et al. Midbrain glutamatergic circuit mechanism of resilience to socially transferred allodynia in male mice. Nat Commun. 2024;15:4947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lammel S, Ion DI, Roeper J, Malenka RC. Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron. 2011;70:855–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Qi J, Zhang S, Wang HL, Wang H, de Jesus Aceves Buendia J, Hoffman AF, et al. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons. Nat Commun. 2014;5:5390.

    Article  CAS  PubMed  Google Scholar 

  50. Stamatakis AM, Jennings JH, Ung RL, Blair GA, Weinberg RJ, Neve RL, et al. A unique population of ventral tegmental area neurons inhibits the lateral habenula to promote reward. Neuron. 2013;80:1039–53.

    Article  CAS  PubMed  Google Scholar 

  51. Root DH, Mejias-Aponte CA, Qi J, Morales M. Role of glutamatergic projections from ventral tegmental area to lateral habenula in aversive conditioning. J Neurosci. 2014;34:13906–10.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Root DH, Mejias-Aponte CA, Zhang S, Wang HL, Hoffman AF, Lupica CR, et al. Single rodent mesohabenular axons release glutamate and GABA. Nat Neurosci. 2014;17:1543–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jhou TC, Geisler S, Marinelli M, Degarmo BA, Zahm DS. The mesopontine rostromedial tegmental nucleus: a structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol. 2009;513:566–96.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Sun Y, Cao J, Xu C, Liu X, Wang Z, Zhao H. Rostromedial tegmental nucleus-substantia nigra pars compacta circuit mediates aversive and despair behavior in mice. Exp Neurol. 2020;333:113433.

    Article  CAS  PubMed  Google Scholar 

  55. Yang SH, Yang E, Lee J, Kim JY, Yoo H, Park HS, et al. Neural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice. Nat Commun. 2023;14:2435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lisman JE. Bursts as a unit of neural information: making unreliable synapses reliable. Trends Neurosci. 1997;20:38–43.

    Article  CAS  PubMed  Google Scholar 

  57. Cerniauskas I, Winterer J, de Jong JW, Lukacsovich D, Yang H, Khan F, et al. Chronic stress induces activity, synaptic, and transcriptional remodeling of the lateral habenula associated with deficits in motivated behaviors. Neuron. 2019;104:899–915.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Figee M, Riva-Posse P, Choi KS, Bederson L, Mayberg HS, Kopell BH. Deep brain stimulation for depression. Neurotherapeutics. 2022;19:1229–45.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by STI2030-Major Projects (2021ZD0203100), Grants from the National Natural Science Foundation of China (No.82471244; No.82271257; No.82071228), Postgraduate Research & Practice Innovation Program of Jiangsu Province (No. KYCX23_3001), and Open Competition Grant from Xuzhou Medical University (JBGS202202).

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  1. These authors contributed equally: Yue-ying Liu, Ke Wu.

Authors and Affiliations

  1. NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou, China

    Yue-ying Liu, Ke Wu, Yu-ting Dong, Ru Jia, Xing-han Chen, An-yu Ge, Jun-li Cao & Yong-mei Zhang

  2. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China

    Yue-ying Liu, Ke Wu, Yu-ting Dong, Ru Jia, Xing-han Chen, An-yu Ge, Jun-li Cao & Yong-mei Zhang

  3. Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China

    Yue-ying Liu, Ke Wu, Yu-ting Dong, Ru Jia, Xing-han Chen, An-yu Ge, Jun-li Cao & Yong-mei Zhang

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Contributions

Conceptualization, YYL and YMZ; Methodology, YYL, KW and YTD; Investigation, YYL, XHC, AYG and RJ; Writing—Original Draft, YYL and YMZ; Supervision, YMZ and JLC.

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Correspondence to Jun-li Cao or Yong-mei Zhang.

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Liu, Yy., Wu, K., Dong, Yt. et al. Lateral habenula induces cognitive and affective dysfunctions in mice with neuropathic pain via an indirect pathway to the ventral tegmental area. Neuropsychopharmacol. 50, 1039–1050 (2025). https://doi.org/10.1038/s41386-025-02084-5

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