Expression of c-FOS in neurons of the brain in different itch model mice

王清珍 吴欣然 毛娥 沈俊君 王爽 田苗 寇珍珍

doi:10.16098/j.issn.0529-1356.2026.04.002

PDF(1576 KB)

Acta Anatomica Sinica ›› 2026, Vol. 57 ›› Issue (4) : 400-409. DOI: 10.16098/j.issn.0529-1356.2026.04.002

Neurobiology

Expression of c-FOS in neurons of the brain in different itch model mice

WANG Qing-zhen^1,2, WU Xin-ran^1,2, MAO E², SHEN Jun-jun², WANG Shuang^1,2, TIAN Miao^{2 *}, KOU Zhen-zhen^{1,2 *}

Author information +

History +

Abstract

Objective To compare the differences in c-Fos protein expression in various brain nuclei of acute itch model mice induced by histamine(His) and chloroquine(CQ), the chronic itch model induced by 1-fluoro-2,4-dinitrofluorobenzene (DNFB), and the chronic kidney disease-associated pruritus (CKD-aP) model, and to explore the common central nervous system nuclei mediating different types of itch stimuli. Methods Mice were divided into His, CQ, DNFB, CKD-aP groups, and respective control groups, with six mice in each group. Immunohistochemical staining was used to label c-FOS protein throughout the brain, followed by quantitative analyses. Results Compared with the control group, c-FOS expression increased in the left/right ventrolateral/medial olivary nucleus (LVPO/MVPO), thalamic reticular nucleus (Re), paraventricular thalamic nucleus (PVT), lateral pallidum (LPB), inferior colliculus (IC), pontine nucleus (Pn), and superior colliculus (SC) showed increased c-FOS expression (P<0.05) compared to the control group, with a higher proportion of c-FOS/ neuronal nuclei（NeuN）double-labeled neurons among NeuN-positive neurons (P<0.05); In the DNFB group, c-FOS expression increased in Pn and SC compared to the control group (P<0.0001), and the proportion of c-FOS/NeuN double-labeled neurons among NeuN-positive neurons was elevated (P<0.001). However, no significant increase in c-FOS protein was observed in LVPO/MVPO, Re, PVT, LPB, or IC; In the CKD-aP group, c-FOS expression increased in the SC compared to the control group (P<0.001), and the proportion of c-FOS/NeuN double-labeled neurons among NeuN-positive neurons was elevated (P<0.0001). However, no significant increase in c-FOS protein was observed in the LVPO/MVPO, Re, PVT, LPB, IC, or Pn. Conclusion Acute itch activates the LVPO/MVPO, PVT, Re, IC, LPB, Pn, and SC; DNFB-induced chronic itch activates the Pn and SC; CKD-aP activates the SC. The SC can be activated by acute itch, chronic itch, and systemic disease-related itch, suggesting that the SC may serve as a common downstream center mediating multiple types of itch.

Key words

Acute itch

/ Chronic kidney disease-associated pruritus;Chronic itch / Histamine-dependent pruritus / Non-histamine-dependent pruritus / Immunohistochemistry / Mouse

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

WANG Qing-zhen, WU Xin-ran, MAO E, SHEN Jun-jun, WANG Shuang, TIAN Miao, KOU Zhen-zhen. Expression of c-FOS in neurons of the brain in different itch model mice[J]. Acta Anatomica Sinica. 2026, 57(4): 400-409 https://doi.org/10.16098/j.issn.0529-1356.2026.04.002

References

[1] Balaji SK, Khuwaja WM, Hossain ML, et al. Neuroimmune interactions between itch neurons and skin microbes [J]. Semin Immunol, 2025, 78: 101933.

[2] Ferreira BR, Katamanin OM, Jafferany M, et al. Psychodermatology of chronic pruritus: an overview of the link between itch and distress [J]. Dermatol Ther (Heidelb), 2024, 14(7): 1799-1809.

[3] Han L, Ma C, Liu Q, et al. A subpopulation of nociceptors specifically linked to itch [J]. Nat Neurosci, 2013, 16(2): 174-182.

[4] Yassky D, Kim BS. Mouse models of itch [J]. J Invest Dermatol, 2024, 144(12): 2634-2644.

[5] Liu Q, Tang Z, Surdenikova L, et al. Sensory neuron-specific gpcr mrgprs are itch receptors mediating chloroquine-induced pruritus [J]. Cell, 2009, 139(7): 1353-1365.

[6] Dermatology Branch of the Chinese Medical Doctor Association. Guidelines for the management of chronic pruritus（2024 Edition）[J]. Chinese Journal of Dermatology, 2024,57(5)：387-399. （in Chinese）

中国医师协会皮肤科医师分会. 慢性瘙痒管理指南（2024版）[J]. 中华皮肤科杂志，2024，57（5）：387-399.

[7] Xu ZH, Zhang JC, Chen K, et al. Mechanisms of the pd-1/pd-l1 pathway in itch: from acute itch model establishment to the role in chronic itch in mouse [J]. Eur J Pharmacol, 2023, 960: 176128.

[8] Kaya E, Mcdonald G, Gallagher R. Managing pruritus in advanced chronic disease [J]. J Palliat Med, 2024, 27(12): 1666-1671.

[9] Yoshimura Y, Fujii A. Topical beta-hydroxybutyrate suppresses allergic dermatitis via hcrk2-camkk-ampk-mediated barrier protection [J]. Biochem Biophys Res Commun, 2025, 791: 152931.

[10] Rose L, Schneider C, Stock C, et al. Extended dnfb-induced contact hypersensitivity models display characteristics of chronic inflammatory dermatoses [J]. Exp Dermatol, 2012, 21(1): 25-31.

[11] Diepgen TL, Ofenloch RF, Bruze M, et al. Prevalence of contact allergy in the general population in different European regions [J]. Br J Dermatol, 2016, 174(2): 319-329.

[12] Lambert J. Itch in allergic contact dermatitis [J]. Front Allergy, 2021, 2: 702488.

[13] Zhai S, Chen L, Liu H, et al. Skin barrier: new therapeutic targets for chronic kidney disease-associated pruritus- a narrative review [J]. Int J Dermatol, 2024, 63(11): 1513-1521.

[14] Lu PH, Tai YC, Yu MC, et al. Western and complementary alternative medicine treatment of uremic pruritus: a literature review [J]. Tzu Chi Med J, 2021, 33(4): 350-358.

[15] Marcello M, Marturano D, Ronco C, et al. The role of blood purification therapies in the treatment of chronic kidney disease-associated pruritus: a systematic review [J]. Clin Kidney J, 2024, 17(9): sfae266.

[16] Wang YY, Wu Y, Yu KW, et al. Ginsenoside rg1 promotes non-rapid eye movement sleep via inhibition of orexin neurons of the lateral hypothalamus and corticotropin-releasing hormone neurons of the paraventricular hypothalamic nucleus [J]. J Integr Med, 2024, 22(6): 719-728.

[17] Lara Aparicio SY, Laureani Fierro AJ, Aranda Abreu GE, et al. Current opinion on the use of c-fos in neuroscience [J]. NeuroSci, 2022, 3(4): 687-702.

[18] Liljencrantz J, Pitcher MH, Low LA, et al. Comment on “molecular and neural basis of contagious itch behavior in mice” [J]. Science, 2017, 357(6347): eaan4749.

[19] Kuraishi Y, Nagasawa T, Hayashi K, et al. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice [J]. Eur J Pharmacol, 1995, 275(3): 229-233.

[20] Palkar R, Ongun S, Catich E, et al. Cooling relief of acute and chronic itch requires trpm8 channels and neurons [J]. J Invest Dermatol, 2018, 138(6): 1391-1399.

[21] Kanemaru-Kawazoe A, Funahashi H, Kogoh Y, et al. Role of orexin receptors in histamine- and chloroquine-induced pruriceptive processing [J]. Neurosci Res, 2025, 219: 104952.

[22] Chen X, Zhu C, Zhang Y, et al. Antipruritic effect of ethyl acetate extract from fructus cnidii in mice with 2,4-dinitrofluorobenzene-induced atopic dermatitis [J]. Evid Based Complement Alternat Med, 2020, 2020: 6981386.

[23] Li JN. Morphological and functional study on the involvement of the neural pathway of the spinal cord brachiocephalic nucleus thalamus midline/parietal nucleus group in the transmission and regulation of itch information [D]. Xi’an: Air Force Medical University, 2022. (in Chinese)

李佳妮. 脊髓-臂旁核-丘脑中线/板内核群神经通路参与痒信息传递和调控的形态学和机能学研究[D]. 西安：中国人民解放军空军军医大学, 2022.

[24] Yang Y, Sun Y, Zhu C, et al. Allantoin induces pruritus by activating mrgprd in chronic kidney disease [J]. J Cell Physiol, 2023, 238(4): 813-828.

[25] Qu D, Zhu Y, Guo Z, et al. Scorpion polypeptide bmk it2 alleviates epileptic seizures and neuronal pyroptosis by regulating sodium channel nav1.6 [J]. J Ethnopharmacol, 2026, 356: 120849.

[26] Sun YG. Central neural circuits underlying itch sensation [J]. Nat Rev Neurosci, 2025, 26(12): 765-777.

[27] Shor EK, Freeman DA. The paraventricular thalamus serves as a nexus in the regulation of stress and immunity [J]. Brain Behav Immun, 2021, 95: 36-44.

[28] Hauer BE, Pagliardini S, Dickson CT. The reuniens nucleus of the thalamus has an essential role in coordinating slow-wave activity between neocortex and hippocampus [J]. eNeuro, 2019, 6(5): ENEURO.0365-19.2019.

[29] Liu M, Wang Y, Jiang L, et al. Research progress of the inferior colliculus: from neuron, neural circuit to auditory disease [J]. Brain Res, 2024, 1828: 148775.

[30] Sherin JE, Shiromani PJ, Mccarley RW, et al. Activation of ventrolateral preoptic neurons during sleep [J]. Science, 1996, 271(5246): 216-219.

[31] Francois A, Low SA, Sypek EI, et al. A brainstem-spinal cord inhibitory circuit for mechanical pain modulation by gaba and enkephalins [J]. Neuron, 2017, 93(4): 822-839.e6.

[32] Angeles Fernandez-Gil M, Palacios-Bote R, Leo-Barahona M, et al. Anatomy of the brainstem: a gaze into the stem of life [J]. Semin Ultrasound CT MR, 2010, 31(3): 196-219.

[33] Chen C, Niehaus JK, Dinc F, et al. Neural circuit basis of placebo pain relief [J]. Nature, 2024, 632(8027): 1092-1100.

[34] Mason P. Central mechanisms of pain modulation [J]. Curr Opin Neurobiol, 1999, 9(4): 436-441.

[35] Glennon CM, Nigwekar SU, Kroshinsky D, et al. Skin disorders in kidney disease: core curriculum 2026 [J]. Am J Kidney Dis, 2026, 87(1): 102-114.

[36] Basso MA, Bickford ME, Cang J. Unraveling circuits of visual perception and cognition through the superior colliculus [J]. Neuron, 2021, 109(6): 918-937.

[37] Huang X, Liu X, Xu X, et al. Multisensory integration in the mouse ventral visual thalamus mediates stress coping via locus coeruleus-related circuits [J]. Neuron, 2026, 114(2): 307-324.e7.

[38] Jeong KY, Kang JH. Investigation of the pruritus-induced functional activity in the rat brain using manganese-enhanced mri [J]. J Magn Reson Imaging, 2015, 42(3): 709-716.