Synaptic Dysfunction in the Anterior Cingulate Cortex Underlies Pain‐Anxiety Comorbidity in a Mandibular Asymmetry Mouse Model

Zhaoyichun Zhang; Yanran Zhang; Jialin Si; Honghui Mao; Feng He; Jin Ning; Guaiguai Ma; Xiaohua Chen; Haoxiang Xiao; Yuanyuan Zhu; Haifeng Zhang; Yifan Lu; Qian Liu; Meng Nian; Shiquan Sun; Shibin Yu; Shengxi Wu; Ze Fan; Zuolin Jin; Jing Huang

doi:10.1002/advs.202509509

journal article·2025-12Open access

Synaptic Dysfunction in the Anterior Cingulate Cortex Underlies Pain‐Anxiety Comorbidity in a Mandibular Asymmetry Mouse Model

Zhaoyichun Zhang, Yanran Zhang, Jialin Si, Honghui Mao, Feng He, Jin Ning, Guaiguai Ma, Xiaohua Chen, Haoxiang Xiao, Yuanyuan Zhu, Haifeng Zhang, Yifan Lu, Qian Liu, Meng Nian, Shiquan Sun, Shibin Yu, Shengxi Wu, Ze Fan, Zuolin Jin, Jing Huang

Advanced Science· Volume 12· Issue 46

Publisher page Open full text

Source abstract

Abstract

Abstract Structural craniofacial abnormalities, particularly mandibular asymmetry (MA), are increasingly recognized as key drivers of orofacial pain and emotional comorbidities, although the underlying neural mechanisms remain unclear. This study aims to develop a preclinical MA model to investigate the dynamic interplay between craniofacial structural defects and neurobehavioral dysfunction. Longitudinal behavioral phenotyping including von Frey filaments test as well as open field and elevated plus maze tests reveals progressive sensory hypersensitivity and anxiety‐like behaviors, with computational ethology revealing subtle but consistent alterations in the naturalistic behaviors. Whole‐brain activity mapping reveal hyperactivation in the anterior cingulate cortex (ACC), whereas multi‐omics profiling reveal cell type‐specific transcriptional changes and synaptic reorganization within this region. Functional investigation including sparse labeling, electrophysiology, western blotting, and chemogenetics demonstrate that the ACC modulation regulated both pain and anxiety. These findings establish a causal association between structural craniofacial defects and maladaptive neural circuit remodeling, with the ACC emerging as a critical therapeutic target. The study provides a comprehensive framework for understanding how anatomical abnormalities translate into persistent neurological dysfunction and offers new avenues for mechanistically informed intervention.

Source: crossref · Quality: baseline

Research context

OpenAlex topics: Pain Mechanisms and Treatments · Neuropeptides and Animal Physiology · Musculoskeletal pain and rehabilitation

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi Clinical Research Center for Oral Diseases Department of Orthondotics School of Stomatology The Fourth Military Medical University Xi'an 710032 China

Department of Neurobiology Basic Medical Science Academy The Fourth Military Medical University Xi'an 710032 China

State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi Clinical Research Center for Oral Diseases Department of Pediatric Dentistry School of Stomatology The Fourth Military Medical University Xi'an 710032 China

State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi International Joint Research Center for Oral Diseases Department of Oral Anatomy and Physiology School of Stomatology The Fourth Military Medical University Xi'an 710032 China

Center for Single‐Cell Omics and Health School of Public Health Xi'an Jiaotong University Xi'an 710061 China

State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture Department of Anesthesiology School of Stomatology The Fourth Military Medical University Xi'an 710032 China

Funding

National Natural Science Foundation of China · Fourth Military Medical University

References (66)

Show source-provided references

1. 10.3390/ijerph1909541510.3390/ijerph19095415 ↗

2. 10.1016/j.jpain.2013.03.01110.1016/j.jpain.2013.03.011 ↗

3. 10.1093/ejo/cji07310.1093/ejo/cji073 ↗

4. 10.1007/s00784-020-03756-w10.1007/s00784-020-03756-w ↗

5. 10.1186/s40510-022-00445-010.1186/s40510-022-00445-0 ↗

6. Singh B. P. · Cochrane Database Syst. Rev. · 2024 · 9

7. 10.1248/bpb.b18-0044210.1248/bpb.b18-00442 ↗

8. 10.1016/j.pain.2010.09.03010.1016/j.pain.2010.09.030 ↗

9. 10.1002/ar.2358710.1002/ar.23587 ↗

10. 10.3389/fncel.2022.84113310.3389/fncel.2022.841133 ↗

11. 10.1016/j.jpsychores.2018.02.00210.1016/j.jpsychores.2018.02.002 ↗

12. 10.1038/s41368-023-00241-410.1038/s41368-023-00241-4 ↗

13. 10.3389/fpsyt.2022.81000810.3389/fpsyt.2022.810008 ↗

14. 10.1111/j.1365-2842.2010.02074.x10.1111/j.1365-2842.2010.02074.x ↗

15. 10.3390/ijms25201130610.3390/ijms252011306 ↗

16. 10.1016/j.jpain.2009.06.01210.1016/j.jpain.2009.06.012 ↗

17. Fregoso G. · Pain Physician · 2019 · 22 · 479

18. 10.3390/ijms2013313010.3390/ijms20133130 ↗

19. 10.1038/nrn.2016.16210.1038/nrn.2016.162 ↗

20. 10.1016/j.pain.2013.11.00810.1016/j.pain.2013.11.008 ↗

21. 10.1155/2015/17401310.1155/2015/174013 ↗

22. 10.1038/s41593-023-01519-w10.1038/s41593-023-01519-w ↗

23. Bäckryd E. · Lakartidningen · 2023 · 120

24. 10.1371/journal.pone.009430010.1371/journal.pone.0094300 ↗

25. 10.1148/rg.26305509110.1148/rg.263055091 ↗

26. 10.1016/j.tins.2016.01.00610.1016/j.tins.2016.01.006 ↗

27. 10.1186/s13041-021-00849-910.1186/s13041-021-00849-9 ↗

28. 10.1038/s41380-024-02419-610.1038/s41380-024-02419-6 ↗

29. 10.1016/j.neuroimage.2013.10.06710.1016/j.neuroimage.2013.10.067 ↗

30. 10.3389/fncel.2018.0047010.3389/fncel.2018.00470 ↗

31. 10.7150/thno.11113010.7150/thno.111130 ↗

32. 10.1515/sjpain-2019-013110.1515/sjpain-2019-0131 ↗

33. 10.4103/ejd.ejd_11_1710.4103/ejd.ejd_11_17 ↗

34. 10.1080/15548627.2019.160664710.1080/15548627.2019.1606647 ↗

35. 10.1016/j.joca.2020.12.01610.1016/j.joca.2020.12.016 ↗

36. 10.1016/j.lfs.2024.12291310.1016/j.lfs.2024.122913 ↗

37. 10.1038/s41368-020-00095-010.1038/s41368-020-00095-0 ↗

38. 10.1016/j.physbeh.2019.02.02410.1016/j.physbeh.2019.02.024 ↗

39. 10.3389/fncel.2022.99534510.3389/fncel.2022.995345 ↗

40. 10.1016/j.jpain.2024.10475610.1016/j.jpain.2024.104756 ↗

41. 10.1111/joor.1352610.1111/joor.13526 ↗

42. 10.3389/fneur.2020.58912510.3389/fneur.2020.589125 ↗

43. 10.2147/JPR.S36279310.2147/JPR.S362793 ↗

44. 10.1038/s41398-024-03122-410.1038/s41398-024-03122-4 ↗

45. 10.1016/j.conb.2018.04.01910.1016/j.conb.2018.04.019 ↗

46. 10.1016/j.tics.2021.01.00110.1016/j.tics.2021.01.001 ↗

47. 10.1007/s00702-019-02071-310.1007/s00702-019-02071-3 ↗

48. 10.1016/j.neuropharm.2021.10874910.1016/j.neuropharm.2021.108749 ↗

49. 10.1038/nrn.2016.6810.1038/nrn.2016.68 ↗

50. 10.1016/j.celrep.2021.10941110.1016/j.celrep.2021.109411 ↗

51. 10.1177/174480691878394310.1177/1744806918783943 ↗

52. 10.1523/JNEUROSCI.3195-17.201810.1523/JNEUROSCI.3195-17.2018 ↗

53. 10.1017/S031716710005190810.1017/S0317167100051908 ↗

54. Martucci K. T. · Anesthesiology · 2018

55. 10.4196/kjpp.2017.21.5.48710.4196/kjpp.2017.21.5.487 ↗

56. 10.1111/j.1526-4610.2011.01998.x10.1111/j.1526-4610.2011.01998.x ↗

57. 10.1212/WNL.000000000000739610.1212/WNL.0000000000007396 ↗

58. Chen Q. Y. · Molecular Pain · 2018 · 1410.1177/1744806918798406 ↗

59. 10.1523/JNEUROSCI.3502-04.200410.1523/JNEUROSCI.3502-04.2004 ↗

60. 10.1016/j.neuron.2023.10.02710.1016/j.neuron.2023.10.027 ↗

61. Deseure K. R. · JoVE · 2024

62. 10.1038/s41467-021-22970-y10.1038/s41467-021-22970-y ↗

63. O.Le Moëne M.Larsson eNeuro2023 10 ENEURO.0349.10.1523/ENEURO.0349-22.2022 ↗

64. 10.1126/sciadv.adf546410.1126/sciadv.adf5464 ↗

65. Xiao H. · Adv. Sci.(Weinheim, Baden‐Wurttemberg, Germany) · 2024 · 11

66. 10.1038/s41380-022-01707-310.1038/s41380-022-01707-3 ↗