The potential role of bone-derived factor ucOCN in the anti-depressive effects of exercise

doi:10.3724/SP.J.1042.2022.00375

Abstract

Abstract:

Depression is a major problem in the modern society. The pathogenesis of depression is a research hotspot in the field of neuroscience. The proved mechanisms of depression include monoamine neurotransmitter hypothesis, gene-environment interaction, neurogenesis, neuroplasticity, immune activation and suppression, etc. With the deepening of research, the roles of "brain-gut interaction", "muscle-brain crosstalk", and adipocytokines in the sports antidepressant field has been discovered. As an endocrine organ, the role of bone tissue in anti-depressive exercise remains to be revealed. Based on this, this research innovatively explores the biological effects and mechanisms of uncarboxylated osteocalcin (ucOCN) in exercise anti-depression from the perspective of “bone-brain crosstalk”, and further reveals the relationship between bone endocrine activity and the molecular regulation of sports antidepressant. ucOCN is a specific non-collagen protein secreted by osteoblasts (OB). After entering the blood, it acts on the hippocampus, cingulate gyrus and other brain tissues, and triggers a cascade reaction through targeting cell membrane receptors to regulate neurodevelopment, neuroplasticity and bone endocrine-nerve response system. Exercise promotes the secretion of ucOCN and has a significant antidepressant effect, but there are few studies focusing on the molecular mechanism. Based on integrated biological theory and bone endocrine function, through analysis of current research, we found several mechanisms by which ucOCN mediating exercise antidepressant. Firstly, ucOCN regulates neurotransmitters expression: exercise induces high expression of ucOCN which inhibits γ-amino groups butyric acid (GABA) expression to improve depression-like behavior. Secondly, ucOCN regulates neuroendocrine secretion: ucOCN activates the HPA axis to promote adrenocorticotropic hormone (ACTH), mineralocorticoid, cortisol and other secretions to improve depression-like behavior. In addition, ucOCN also activates G protein-coupled receptors 158 (Gpr158)/brain-derived neurotrophic factor (BDNF) pathway to promote neurotransmitter secretion and further regulate depression occurring. Thirdly, ucOCN regulates neuroimmunity: ucOCN activates the ERK and STAT pathways and down-regulates the expression of IL-6 and IL-8 in the hippocampus, and then through malondialdehyde (MDA)/super up-regulation of superoxide dismutase (SOD)/nuclear factor erythroid-derived 2-like 2(Nrf2)/heme oxygenase 1(HO1) pathway to increase expression of VGF and BDNF, which further improve depression-like behaviors. Taken together, these results provide a solid theoretical basis for the mechanism of ucOCN in sports anti-depression. We also provides new research directions and ideas for sports anti-depression, and provide a new perspective for enriching the biological mechanism network of sports brain.

Key words: undercarboxylated osteocalcin, bone, brain, exercise, depression

CLC Number:

B845

CHEN XiangHe, LI WenXiu, LIU Bo, YIN RongBin. The potential role of bone-derived factor ucOCN in the anti-depressive effects of exercise[J]. Advances in Psychological Science, 2022, 30(2): 375-388.

Figures/Tables 2

References 96

[1]	陈蓉. (2019). 有氧运动对慢性应激抑郁小鼠肌、脑PGC-1α/FNDC5/BDNF通路的影响 (硕士学位论文). 湖南师范大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CMFD201902&filename=1019671533.nh
[2]	崔冬雪. (2005). 游泳锻炼对实验性抑郁症大鼠神经内分泌及行为学的影响 (博士学位论文). 华东师范大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CDFD9908&filename=2005086214.nh
[3]	崔建梅, 王卓琳, 郭燕兰, 李中华, 于芳, 李洪涛, 苏晓云. (2020). 自愿转轮运动对慢性应激大鼠焦虑及抑郁样行为、前额叶皮质炎症因子及NGF/TrkA信号通路的影响. 天津体育学院学报, 35(3), 321-327.doi: 10.13297/j.cnki.issn1005-0000.2020.03.012 doi: 10.13297/j.cnki.issn1005-0000.2020.03.012
[4]	杜远. (2019). 运动对抑郁症患者症状、认知功能及γ-氨基丁酸影响的研究 (硕士学位论文). 山东大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CMFD202001&filename=1020013505.nh
[5]	郭雨欣, 邢国刚. (2012). 抑郁症的生物学机制研究进展. 中国神经精神疾病杂志, 38(1), 57-60.
[6]	胡亮, 韩雨晴. (2019). 运动抗抑郁的神经生物学机制研究新进展. 陕西师范大学学报(自然科学版). 47(3), 9-20+125. doi: 10.15983/j.cnki.jsnu.2019.03.232 doi: 10.15983/j.cnki.jsnu.2019.03.232
[7]	刘文彬, 刘微娜, 漆正堂. (2018). 神经营养因子介导运动的抗抑郁作用. 体育科学, 38(10), 54-66. doi: 10.16469/ j.css.201810007 doi: 10.16469/ j.css.201810007
[8]	罗佳. (2019). 有氧运动对CUMS诱导的抑郁小鼠骨骼肌miRNA/PGC-1α/KATs通路的影响研究 (硕士学位论文). 湖南师范大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CMFD201902&filename=1019671532.nh
[9]	牛望, 李茜, 蒋若天. (2020). 胶质细胞在术后认知功能障碍发生发展中的研究进展. 生物医学工程学杂志, 37(4), 708-713+720.
[10]	丘玥, 王之遥, 黄宇光. (2016). 神经病理性疼痛的补体相关神经免疫机制的研究进展. 中国疼痛医学杂志, 22(3), 214-218.
[11]	屈红林. (2019). 有氧运动对CUMS抑郁小鼠炎性因子的影响及改善内源性H₂S信号通路调控机制研究 (博士学位论文). 湖南师范大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CDFDLAST2020&filename=1019672967.nh
[12]	单畅. (2019). 骨钙素和NAD在神经退行性疾病中的作用(博士学位论文). 上海交通大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CDFDLAST2020&filename=1020619276.nh
[13]	石旺清, 郑关毅, 陈晓东, 朱元贵, 张静, 江琼. (2013). 大鼠脑缺血/再灌注后bFGF和GAP-43的表达与神经再生. 中国应用生理学杂志, 29(1), 63-67+98-100. doi: 10.13459/j.cnki.cjap.2013.01.023 doi: 10.13459/j.cnki.cjap.2013.01.023
[14]	王新发. (2017). 骨钙素对小鼠星型胶质细胞周期调控作用的初步研究 (硕士学位论文). 重庆医科大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CMFD201801&filename=1017844417.nh
[15]	夏杰, 刘微娜, 漆正堂, 季浏. (2017). PGC-1α介导的“肌脑Crosstalk”与运动的抗抑郁机制--基于整合生物学的反思与展望. 上海体育学院学报, 41(4), 57-64. doi: 10.16099/j.sus.2017.04.010 doi: 10.16099/j.sus.2017.04.010
[16]	校欢. (2020). PDE9-cGMP-PKG在天麻素促进脑缺血后海马神经发生中的作用 (硕士学位论文). 重庆医科大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CMFD202002&filename=1020765079.nh
[17]	许静, 房辉, 李玉凯, 张丹丹, 张谷月, 田骆冰, ... 周莉. (2016). 2型糖尿病男性患者血清羧化不全骨钙素水平与抑郁状态的相关性研究. 中国现代医学杂志, 26(11), 127-131.
[18]	薛香莉, 刘微娜, 漆正堂, 娄淑杰. (2019). 基于“脑-肠互动”理论探究脑肠肽在运动抗抑郁中的作用机制. 体育科学, 39(12), 76-85. doi: 10.16469/j.css.201912008 doi: 10.16469/j.css.201912008
[19]	袁萍. (2020). Notch信号途径对未成熟脑惊厥持续状态后海马神经发生和癫痫形成的调控作用 (博士学位论文). 重庆医科大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CDFDLAST2021&filename=1020764528.nh
[20]	张波. (2019). 不同运动方式改善CUMS大鼠抑郁症状的血浆代谢组学机制研究 (硕士学位论文). 山西大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CMFD202001&filename=1019247331.nh
[21]	周婵娟. (2016). 骨钙素与抑郁症临床及机制的初步研究(博士学位论文). 重庆医科大学. https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=CDFDLAST2017&filename=1017843350.nh
[22]	aan het Rot, M., Collins, K. A., Murrough, J. W., Perez, A. M., Reich, D. L., Charney, D. S., & Mathew, S. J. (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biological Psychiatry, 67(2), 139-145. https://doi.org/10.1016/j.biopsych.2009.08.038 doi: 10.1016/j.biopsych.2009.08.038 URL
[23]	Abd El-Kader, S. M., & Al-Jiffri, O. H. (2016). Exercise alleviates depression related systemic inflammation in chronic obstructive pulmonary disease patients. African Health Sciences, 16(4), 1078-1088. https://doi.org/10.4314/ahs.v16i4.25 doi: 10.4314/ahs.v16i4.25 URL pmid: 28479901
[24]	Algaidi, S. A., Eldomiaty, M. A., Elbastwisy, Y. M., Almasry, S. M., Desouky, M. K., & Elnaggar, A. M. (2019). Effect of voluntary running on expression of myokines in brains of rats with depression. International Journal of Immunopathology and Pharmacology, 33, https://doi.org/10.1177/2058738419833533
[25]	Andolina, D., Maran, D., Viscomi, M. T., & Puglisi-Allegra, S. (2014). Strain-dependent variations in stress coping behavior are mediated by a 5-HT/GABA interaction within the prefrontal corticolimbic system. The International Journal of Neuropsychopharmacology, 18(3), https://doi.org/10.1093/ijnp/pyu074
[26]	Baudry, A., Mouillet-Richard, S., Schneider, B., Launay, J. M., & Kellermann, O. (2010). miR-16 targets the serotonin transporter: A new facet for adaptive responses to antidepressants. Science, 329(5998), 1537-1541. https://doi.org/10.1126/science.1193692 doi: 10.1126/science.1193692 URL pmid: 20847275
[27]	Bessa, J. M., Ferreira, D., Melo, I., Marques, F., Cerqueira, J. J., Palha, J. A., Almeida, O. F., & Sousa, N. (2009). The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Molecular Psychiatry, 14(8), 764-739. https://doi.org/10.1038/mp.2008.119 doi: 10.1038/mp.2008.119 URL pmid: 18982002
[28]	Bremner, J. D., Randall, P., Scott, T. M., Bronen, R. A., Seibyl, J. P., Southwick, S. M., Delaney, R. C., McCarthy, G., Charney, D. S., & Innis, R. B. (1995). MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. The American Journal of Psychiatry, 152(7), 973-981. https://doi.org/10.1176/ajp.152.7.973 doi: 10.1176/ajp.152.7.973 URL
[29]	Cavalheri, V., Burtin, C., Formico, V. R., Nonoyama, M. L., Jenkins, S., Spruit, M. A., & Hill, K. (2019). Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer. The Cochrane Database of Systematic Reviews, 6(6), CD009955. https://doi.org/10.1002/14651858.CD009955.pub3
[30]	Czéh, B., Welt, T., Fischer, A. K., Erhardt, A., Schmitt, W., Müller, M. B., Toschi, N., Fuchs, E., & Keck, M. E. (2002). Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation: Effects on stress hormone levels and adult hippocampal neurogenesis. Biological Psychiatry, 52(11), 1057-1065. https://doi.org/10.1016/s0006-3223(02)01457-9 doi: 10.1016/S0006-3223(02)01457-9 URL
[31]	David, D. J., Samuels, B. A., Rainer, Q., Wang, J. W., Marsteller, D., Mendez, I., Drew, M., Craig, D. A., Guiard, B. P., Guilloux, J. P., Artymyshyn, R. P., Gardier, A. M., Gerald, C., Antonijevic, I. A., Leonardo, E. D., & Hen, R. (2009). Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron, 62(4), 479-493. https://doi.org/10.1016/j.neuron.2009.04.017 doi: 10.1016/j.neuron.2009.04.017 URL
[32]	de Toni, L., Guidolin, D., de Filippis, V., Peterle, D., Rocca, M. S., di Nisio, A., de Rocco Ponce, M., & Foresta, C. (2019). SHBG141-161 Domain-Peptide Stimulates GPRC6A-Mediated Response in Leydig and β-Langerhans cell lines. Scientific Reports, 9(1), 19432. https://doi.org/10.1038/s41598-019-55941-x
[33]	Ding, X. F., Li, Y. H., Chen, J. X., Sun, L. J., Jiao, H. Y., Wang, X. X., & Zhou, Y. (2017). Involvement of the glutamate/glutamine cycle and glutamate transporter GLT-1 in antidepressant-like effects of Xiao Yao san on chronically stressed mice. BMC Complementary and Alternative Medicine, 17(1), 326. https://doi.org/10.1186/s12906-017-1830-0
[34]	Duman, R. S. (2004). Depression: A case of neuronal life and death?. Biological Psychiatry, 56(3), 140-145. https://doi.org/10.1016/j.biopsych.2004.02.033 doi: 10.1016/j.biopsych.2004.02.033 URL
[35]	Edvinsson, Å., Hoyer, A., Hansson, M., Kallak, T. K., Sundström-Poromaa, I., Skalkidou, A., & Lager, S. (2020). Placental glucocorticoid receptors are not affected by maternal depression or SSRI treatment. Upsala Journal of Medical Sciences, 125(1), 30-36. https://doi.org/10.1080/03009734.2019.1702126 doi: 10.1080/03009734.2019.1702126 URL pmid: 31960733
[36]	Eyre, H., & Baune, B. T. (2012). Neuroplastic changes in depression: A role for the immune system. Psychoneuroendocrinology, 37(9), 1397-1416. https://doi.org/10.1016/j.psyneuen.2012.03.019 doi: 10.1016/j.psyneuen.2012.03.019 URL
[37]	Eyre, H. A., Papps, E., & Baune, B. T. (2013). Treating depression and depression-like behavior with physical activity: An immune perspective. Frontiers in Psychiatry, 4, 3. https://doi.org/10.3389/fpsyt.2013.00003
[38]	Fordahl, S. C., & Jones, S. R. (2017). High-Fat-Diet-Induced Deficits in Dopamine Terminal Function Are Reversed by Restoring Insulin Signaling. ACS Chemical Neuroscience, 8(2), 290-299. https://doi.org/10.1021/acschemneuro.6b00308 doi: 10.1021/acschemneuro.6b00308 URL pmid: 27966885
[39]	Frye, C. A., & Walf, A. A. (2009). Depression-like behavior of aged male and female mice is ameliorated with administration of testosterone or its metabolites. Physiology & Behavior, 97(2), 266-269. https://doi.org/10.1016/j.physbeh.2009.02.022 doi: 10.1016/j.physbeh.2009.02.022 URL
[40]	Gerber, M., Imboden, C., Beck, J., Brand, S., Colledge, F., Eckert, A., Holsboer-Trachsler, E., Pühse, U., & Hatzinger, M. (2020). Effects of Aerobic Exercise on Cortisol Stress Reactivity in Response to the Trier Social Stress Test in Inpatients with Major Depressive Disorders: A Randomized Controlled Trial. Journal of Clinical Medicine, 9(5), 1419. https://doi.org/10.3390/jcm9051419 doi: 10.3390/jcm9051419 URL
[41]	Gould, T. D., & Manji, H. K. (2005). Glycogen synthase kinase-3: A putative molecular target for lithium mimetic drugs. Neuropsychopharmacology, 30(7), 1223-1237. https://doi.org/10.1038/sj.npp.1300731 URL pmid: 15827567
[42]	Gu, P. Y., Yu, F., Jin, S., Yang, Q., Su, J., Chen, Y., Zhao, L., & Hu, S. L. (2017). Analysis of serum undercarboxylated osteocalcin level in rats with type 2 diabetes mellitus and the correlation with cognitive impairment. Experimental and Therapeutic Medicine, 14(3), 2603-2607. https://doi.org/10.3892/etm.2017.4838 doi: 10.3892/etm.2017.4838 URL
[43]	Halassa, M. M., Florian, C., Fellin, T., Munoz, J. R., Lee, S. Y., Abel, T., Haydon, P. G., & Frank, M. G. (2009). Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron, 61(2), 213-219. https://doi.org/10.1016/j.neuron.2008.11.024 doi: 10.1016/j.neuron.2008.11.024 URL
[44]	Hansen, R. R., & Malcangio, M. (2013). Astrocytes--multitaskers in chronic pain. European Journal of Pharmacology, 716(1-3), 120-128. https://doi.org/10.1016/j.ejphar.2013.03.023 doi: 10.1016/j.ejphar.2013.09.001 URL
[45]	Hare, B. D., Beierle, J. A., Toufexis, D. J., Hammack, S. E., & Falls, W. A. (2014). Exercise-associated changes in the corticosterone response to acute restraint stress: Evidence for increased adrenal sensitivity and reduced corticosterone response duration. Neuropsychopharmacology, 39(5), 1262-1269. https://doi.org/10.1038/npp.2013.329 doi: 10.1038/npp.2013.329 URL
[46]	Hegberg, N. J., Hayes, J. P., & Hayes, S. M. (2019). Exercise intervention in PTSD: A narrative review and rationale for implementation. Frontiers in Psychiatry, 10, 133. https://doi.org/10.3389/fpsyt.2019.00133 doi: 10.3389/fpsyt.2019.00133 URL pmid: 30949075
[47]	Holmin, S., Söderlund, J., Biberfeld, P., & Mathiesen, T. (1998). Intracerebral inflammation after human brain contusion. Neurosurgery, 42(2), 291-298. https://doi.org/10.1097/00006123-199802000-00047 URL pmid: 9482179
[48]	Huang, T. H., Lin, J. C., Ma, M. C., Yu, T., & Chen, T. C. (2020). Acute responses of bone specific and related markers to maximal eccentric exercise of the knee extensors and flexors in young men. Journal of Musculoskeletal & Neuronal Interactions, 20(2), 206-215.
[49]	Jun, C., Choi, Y., Lim, S. M., Bae, S., Hong, Y. S., Kim, J. E., & Lyoo, I. K. (2014). Disturbance of the glutamatergic system in mood disorders. Experimental Neurobiology, 23(1), 28-35. https://doi.org/10.5607/en.2014.23.1.28 doi: 10.5607/en.2014.23.1.28 URL
[50]	Kettenmann, H., Kirchhoff, F., & Verkhratsky, A. (2013). Microglia: New roles for the synaptic stripper. Neuron, 77(1), 10-18. https://doi.org/10.1016/j.neuron.2012.12.023 doi: 10.1016/j.neuron.2012.12.023 URL pmid: 23312512
[51]	Khrimian, L., Obri, A., Ramos-Brossier, M., Rousseaud, A., Moriceau, S., Nicot, A. S., Mera, P., Kosmidis, S., Karnavas, T., Saudou, F., Gao, X. B., Oury, F., Kandel, E., & Karsenty, G. (2017). Gpr158 mediates osteocalcin's regulation of cognition. The Journal of Experimental Medicine, 214(10), 2859-2873. https://doi.org/10.1084/jem.20171320 doi: 10.1084/jem.20171320 URL pmid: 28851741
[52]	Knoblach, S. M., & Faden, A. I. (1998). Interleukin-10 improves outcome and alters proinflammatory cytokine expression after experimental traumatic brain injury. Experimental Neurology, 153(1), 143-151. https://doi.org/10.1006/exnr.1998.6877 URL pmid: 9743576
[53]	Kohut, M. L., McCann, D. A., Russell, D. W., Konopka, D. N., Cunnick, J. E., Franke, W. D., Castillo, M. C., Reighard, A. E., & Vanderah, E. (2006). Aerobic exercise, But not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults. Brain, Behavior, and Immunity, 20(3), 201-209. https://doi.org/10.1016/j.bbi.2005.12.002 doi: 10.1093/brain/20.1-2.201 URL
[54]	Kowiański, P., Lietzau, G., Czuba, E., Waśkow, M., Steliga, A., & Moryś, J. (2018). BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity. Cellular and Molecular Neurobiology, 38(3), 579-593. https://doi.org/10.1007/s10571-017-0510-4 doi: 10.1007/s10571-017-0510-4 URL
[55]	Krishnan, V., Han, M. H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., Laplant, Q., Graham, A., Lutter, M., Lagace, D. C., Ghose, S., Reister, R., Tannous, P., Green, T. A., Neve, R. L., Chakravarty, S., Kumar, A., Eisch, A. J., Self, D. W., Lee, F. S., … Nestler, E. J. (2007). Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell, 131(2), 391-404. https://doi.org/10.1016/j.cell.2007.09.018 doi: 10.1016/j.cell.2007.09.018 URL
[56]	Lee, J. M., Kim, T. W., Park, S. S., Kim, C. J., Shin, M. S., Lee, S. J., Kim, S. H., & Baek, S. S. (2019). Wnt signaling pathway is implicated in the alleviating effect of treadmill exercise on maternal separation-induced depression. Journal of Exercise Rehabilitation, 15(2), 200-205. https://doi.org/10.12965/jer.1938148.074 doi: 10.12965/jer.1938148.074 URL
[57]	Lian, H., Yang, L., Cole, A., Sun, L., Chiang, A. C., Fowler, S. W., Shim, D. J., Rodriguez-Rivera, J., Taglialatela, G., Jankowsky, J. L., Lu, H. C., & Zheng, H. (2015). NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease. Neuron, 85(1), 101-115. https://doi.org/10.1016/j.neuron.2014.11.018 doi: 10.1016/j.neuron.2014.11.018 URL
[58]	Liang, Y., Tan, A., Liang, D., Yang, X., Liao, M., Gao, Y., Jiang, Y., Yao, Z., Lin, X., Lu, Z., Wu, C., Zhang, S., Hu, Y., Qin, X., Mo, Z., Li, H., & Zhang, H. (2016). Low osteocalcin level is a risk factor for impaired glucose metabolism in a Chinese male population. Journal of Diabetes Investigation, 7(4), 522-528. https://doi.org/10.1111/jdi.12439 doi: 10.1111/jdi.2016.7.issue-4 URL
[59]	Lin, X., Patil, S., Gao, Y. G., & Qian, A. (2020). The Bone Extracellular Matrix in Bone Formation and Regeneration. Frontiers in Pharmacology, 11, 757. https://doi.org/10.3389/fphar.2020.00757 doi: 10.3389/fphar.2020.00757 URL
[60]	Liu, C., Zhu, R., Liu, H., Li, L., Chen, B., Jia, Q., Wang, L., Ma, R., Tian, S., Wang, M., Fu, M., Niu, J., Orekhov, A. N., Gao, S., Zhang, D., & Zhao, B. (2018). Aqueous extract of mori folium exerts bone protective effect through regulation of calcium and redox homeostasis via PTH/VDR/CaBP and AGEs/RAGE/Nox4/NF-κB signaling in diabetic rats. Frontiers in Pharmacology, 9, 1239. https://doi.org/10.3389/fphar.2018.01239 doi: 10.3389/fphar.2018.01239 URL
[61]	Liu, Q. S., Xu, Q., Arcuino, G., Kang, J., & Nedergaard, M. (2004). Astrocyte-mediated activation of neuronal kainate receptors. Proceedings of the National Academy of Sciences of the United States of America, 101(9), 3172-3177. https://doi.org/10.1073/pnas.0306731101
[62]	López, A. J., Kramár, E., Matheos, D. P., White, A. O., Kwapis, J., Vogel-Ciernia, A., Sakata, K., Espinoza, M., & Wood, M. A. (2016). Promoter-specific effects of DREADD modulation on hippocampal synaptic plasticity and memory formation. The Journal of Neuroscience, 36(12), 3588-3599. https://doi.org/10.1523/JNEUROSCI.3682-15.2016 doi: 10.1523/JNEUROSCI.3682-15.2016 URL
[63]	Mar, A. D., Nick, O., Jan-Paul, B., Arul, R. N., Barbara, B., Irina, P., … Joseph, M. M. (2020). Mon-722 cross-species glucocorticoid-sensitive posterior dentate gyrus gene network: Developing a polygenic score associated to susceptibility to depression after early life adversity exposure in humans. Journal of the Endocrine Society, 4(Supplement_1).
[64]	McIntyre, R. S., Soczynska, J. K., Konarski, J. Z., Woldeyohannes, H. O., Law, C. W., Miranda, A., Fulgosi, D., & Kennedy, S. H. (2007). Should depressive syndromes be reclassified as "metabolic syndrome type II"?. Annals of Clinical Psychiatry, 19(4), 257-264. https://doi.org/10.1080/10401230701653377 URL pmid: 18058283
[65]	Millar, S. A., Anderson, S. I., & O'Sullivan, S. E. (2019). Osteokines and the vasculature: A review of the in vitro effects of osteocalcin, fibroblast growth factor-23 and lipocalin-2. PeerJ, 7, e7139. https://doi.org/10.7717/peerj.7139 doi: 10.7717/peerj.7139 URL
[66]	Millar, S. A., Zala, I., Anderson, S. I., & O'Sullivan, S. E. (2020). Osteocalcin does not influence acute or chronic inflammation in human vascular cells. Journal of Cellular Physiology, 235(4), 3414-3424. https://doi.org/10.1002/jcp.29231 doi: 10.1002/jcp.v235.4 URL
[67]	Muhammad, S. I., Maznah, I., Mahmud, R., Zuki, A. B., & Imam, M. U. (2013). Upregulation of genes related to bone formation by γ-amino butyric acid and γ-oryzanol in germinated brown rice is via the activation of GABAB-receptors and reduction of serum IL-6 in rats. Clinical Interventions in Aging, 8, 1259-1271. https://doi.org/10.2147/CIA.S45943 doi: 10.2147/CIA.S45943 URL pmid: 24098073
[68]	Napoli, N., Strollo, R., Paladini, A., Briganti, S. I., Pozzilli, P., & Epstein, S. (2014). The alliance of mesenchymal stem cells, bone, and diabetes. International Journal of Endocrinology, 2014, 690783. https://doi.org/10.1155/2014/690783
[69]	Nella, A. A., Mallappa, A., Perritt, A. F., Gounden, V., Kumar, P., Sinaii, N., Daley, L. A., Ling, A., Liu, C. Y., Soldin, S. J., & Merke, D. P. (2016). A phase 2 study of continuous subcutaneous hydrocortisone infusion in adults with congenital adrenal hyperplasia. The Journal of Clinical Endocrinology and Metabolism, 101(12), 4690-4698. https://doi.org/10.1210/jc.2016-1916 doi: 10.1210/jc.2016-1916 URL
[70]	Obri, A., Khrimian, L., Karsenty, G., & Oury, F. (2018). Osteocalcin in the brain: From embryonic development to age-related decline in cognition. Nature Reviews Endocrinology, 14(3), 174-182. https://doi.org/10.1038/nrendo.2017.181 doi: 10.1038/nrendo.2017.181 URL
[71]	Okbay Güneş, A., Alikaşifoğlu, M., Şen Demirdöğen, E., Erginöz, E., Demir, T., Kucur, M., & Ercan, O. (2017). The relationship of disordered eating attitudes with stress level, bone turnover markers, and bone mineral density in obese adolescents. Journal of Clinical Research in Pediatric Endocrinology, 9(3), 237-245. https://doi.org/10.4274/jcrpe.3794 doi: 10.4274/jcrpe.3794 URL pmid: 28196789
[72]	Oury, F., Ferron, M., Huizhen, W., Confavreux, C., Xu, L., Lacombe, J., Srinivas, P., Chamouni, A., Lugani, F., Lejeune, H., Kumar, T. R., Plotton, I., & Karsenty, G. (2015). Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. The Journal of Clinical Investigation, 125(5), 2180. https://doi.org/10.1172/JCI81812
[73]	Oury, F., Khrimian, L., Denny, C. A., Gardin, A., Chamouni, A., Goeden, N., Huang, Y. Y., Lee, H., Srinivas, P., Gao, X. B., Suyama, S., Langer, T., Mann, J. J., Horvath, T. L., Bonnin, A., & Karsenty, G. (2013). Maternal and offspring pools of osteocalcin influence brain development and functions. Cell, 155(1), 228-241. doi: 10.1016/j.cell.2013.08.042 URL
[74]	Pang, T. Y., Du, X., Catchlove, W. A., Renoir, T., Lawrence, A. J., & Hannan, A. J. (2013b). Positive environmental modification of depressive phenotype and abnormal hypothalamic-pituitary-adrenal axis activity in female C57BL/6J mice during abstinence from chronic ethanol consumption. Frontiers in Pharmacology, 4, 93. https://doi.org/10.3389/fphar.2013.00093
[75]	Pang, T. Y., Renoir, T., Du, X., Lawrence, A. J., & Hannan, A. J. (2013a). Depression-related behaviours displayed by female C57BL/6J mice during abstinence from chronic ethanol consumption are rescued by wheel-running. The European Journal of Neuroscience, 37(11), 1803-1810. https://doi.org/10.1111/ejn.12195 doi: 10.1111/ejn.2013.37.issue-11 URL
[76]	Rentz, J., Winberg, J., Swardfager, W., & Mitchell, J. (2020). Sat-293 osteocalcin and exercise improve mood and cognition in female mice with high-fat diet induced type 2 diabetes. Journal of the Endocrine Society, 4(Supplement_1).
[77]	Rubin, R. T., Poland, R. E., Lesser, I. M., Winston, R. A., & Blodgett, A. L. (1987). Neuroendocrine aspects of primary endogenous depression. I. Cortisol secretory dynamics in patients and matched controls. Archives of General Psychiatry, 44(4), 328-336. https://doi.org/10.1001/archpsyc.1987.01800160032006 URL pmid: 3566455
[78]	Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., Belzung, C., & Hen, R. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301(5634), 805-809. https://doi.org/10.1126/science.1083328 URL pmid: 12907793
[79]	Saxton, J. M., Scott, E. J., Daley, A. J., Woodroofe, M., Mutrie, N., Crank, H., Powers, H. J., & Coleman, R. E. (2014). Effects of an exercise and hypocaloric healthy eating intervention on indices of psychological health status, hypothalamic-pituitary-adrenal axis regulation and immune function after early-stage breast cancer: A randomised controlled trial. Breast Cancer Research, 16(2), R39. https://doi.org/10.1186/bcr3643
[80]	Shan, C., Ghosh, A., Guo, X. Z., Wang, S. M., Hou, Y. F., Li, S. T., & Liu, J. M. (2019). Roles for osteocalcin in brain signalling: Implications in cognition- and motor-related disorders. Molecular Brain, 12(1), 23. https://doi.org/10.1186/s13041-019-0444-5 doi: 10.1186/s13041-019-0444-5 URL
[81]	Shobana, A., Danae, D., Sundeep, K., Matthew, D., & Irina, B. (2019). Sat-366 the impact of mild autonomous cortisol secretion on bone metabolism. Journal of the Endocrine Society, 3(Supplement_1).
[82]	Stepanichev, M., Dygalo, N. N., Grigoryan, G., Shishkina, G. T., & Gulyaeva, N. (2014). Rodent models of depression: Neurotrophic and neuroinflammatory biomarkers. BioMed Research International, 2014, 932757. https://doi.org/10.1155/2014/932757 doi: 10.1155/2014/932757 URL pmid: 24999483
[83]	Sutton, L. P., Orlandi, C., Song, C., Oh, W. C., Muntean, B. S., Xie, K., Filippini, A., Xie, X., Satterfield, R., Yaeger, J., Renner, K. J., Young, S. M., Jr, Xu, B., Kwon, H., & Martemyanov, K. A. (2018). Orphan receptor GPR158 controls stress-induced depression. eLife, 7, e33273. https://doi.org/10.7554/eLife.33273 doi: 10.7554/eLife.33273 URL
[84]	Tsikirai, T. M., Ramirez, F., & Nedley, N. (2020). Light and exercise therapy improves depression in women with premenstrual syndrome. Journal of the Endocrine Society, 4(S1), SUN-006. doi: 10.1210/jendso/bvaa046.1929 URL
[85]	Vella, A., & Kumar, R. (2013). Osteocalcin and the Regulation of Glucose Metabolism. Clinical Reviews in Bone and Mineral Metabolism, 11(1), 11-16. https://doi.org/10.1007/s12018-012-9126-x doi: 10.1007/s12018-012-9126-x URL
[86]	Vollmayr, B., Simonis, C., Weber, S., Gass, P., & Henn, F. (2003). Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. Biological Psychiatry, 54(10), 1035-1040. https://doi.org/10.1016/s0006-3223(03)00527-4 URL pmid: 14625145
[87]	Wolf, D., Klasen, M., Eisner, P., Zepf, F. D., Zvyagintsev, M., Palomero-Gallagher, N., Weber, R., Eisert, A., & Mathiak, K. (2018). Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks. Brain Structure & Function, 223(7), 3327-3345. https://doi.org/10.1007/s00429-018-1693-2
[88]	Woodruff, T. M., Ager, R. R., Tenner, A. J., Noakes, P. G., & Taylor, S. M. (2010). The role of the complement system and the activation fragment C5a in the central nervous system. Neuromolecular Medicine, 12(2), 179-192. https://doi.org/10.1007/s12017-009-8085-y doi: 10.1007/s12017-009-8085-y URL pmid: 19763906
[89]	Yu, H., Li, H., Liu, X., Du, X., & Deng, B. (2020). Levels of serum S100B are associated with cognitive dysfunction in patients with type 2 diabetes. Aging, 12(5), 4193-4203. https://doi.org/10.18632/aging.102873 doi: 10.18632/aging.v12i5 URL
[90]	Zanos, P., Highland, J. N., Stewart, B. W., Georgiou, P., Jenne, C. E., Lovett, J., Morris, P. J., Thomas, C. J., Moaddel, R., Zarate, C. A.,Jr, & Gould, T. D. (2019). (2R, 6R)-hydroxynorketamine exerts mGlu2 receptor- dependent antidepressant actions. Proceedings of the National Academy of Sciences of the United States of America, 116(13), 6441-6450. https://doi.org/10.1073/pnas.1819540116
[91]	Zhang, J., Malik, A., Choi, H. B., Ko, R. W., Dissing-Olesen, L., & MacVicar, B. A. (2014). Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron, 82(1), 195-207. https://doi.org/10.1016/j.neuron.2014.01.043 doi: 10.1016/j.neuron.2014.01.043 URL
[92]	Zhang, J., Narr, K. L., Woods, R. P., Phillips, O. R., Alger, J. R., & Espinoza, R. T. (2013). Glutamate normalization with ECT treatment response in major depression. Molecular Psychiatry, 18(3), 268-270. https://doi.org/10.1038/mp.2012.46 doi: 10.1038/mp.2012.46 URL pmid: 22565784
[93]	Zhao, C., Ma, H., Yang, L., & Xiao, Y. (2016). Long-term bicycle riding ameliorates the depression of the patients undergoing hemodialysis by affecting the levels of interleukin-6 and interleukin-18. Neuropsychiatric Disease and Treatment, 13, 91-100. https://doi.org/10.2147/NDT.S124630 doi: 10.2147/NDT URL
[94]	Zhao, J., Ying, L., Liu, Y., Liu, N., Tu, G., Zhu, M., Wu, Y., Xiao, B., Ye, L., Li, J., Guo, F., Zhang, L., Wang, H., & Zhang, L. (2019). Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens. Theranostics, 9(23), 7051-7071. https://doi.org/10.7150/thno.34655 doi: 10.7150/thno.34655 URL
[95]	Zhao, T., Ding, Y., Li, M., Zhou, C., & Lin, W. (2019). Silencing lncRNA PVT1 inhibits activation of astrocytes and increases BDNF expression in hippocampus tissues of rats with epilepsy by downregulating the Wnt signaling pathway. Journal of Cellular Physiology, 234(9), 16054-16067. https://doi.org/10.1002/jcp.28264 doi: 10.1002/jcp.v234.9 URL
[96]	Zoch, M. L., Clemens, T. L., & Riddle, R. C. (2016). New insights into the biology of osteocalcin. Bone, 82, 42-49. https://doi.org/10.1016/j.bone.2015.05.046 doi: 10.1016/j.bone.2015.05.046 URL

发生机制	介导/调控的分子机制及基因、蛋白活动
调节神经递质	a. 5-HTTLPR短等位基因在慢性应激下易患抑郁; b. ucOCN下调NMDA表达, AMPAR表达↑, 谷氨酸、BDNF↑, GABA↓, 快速抗抑郁; c. Gpr158影响MF-CA1区神经远树突结构和功能调控抑郁发生;
调节神经内分泌	a. 敲除ucOCN后, GC↑, 引发抑郁样行为; b. 血清ucOCN↓, 激活HPA轴, ACTH和皮质醇↑, 抑制海马对HPA轴的负反馈调节; c. 敲除ucOCN后, GPRC6A失活, 胰岛素↓, 激活海马区炎症反应和IR, Ezrin表达↓。
介导神经免疫机制	a. 应激状态下, CRH↑, 交感神经系统和HPA轴激活, 抑制正常免疫反应; b. NF-κB激活C3参与抑郁发生; c. NF-κB激活后, C3释放↑, 作用于神经细胞上的C3受体; NF-κB/C3/C3aR途径参与神经内钙电流调节, 突触后电流↑, 并受AMPAR调节影响抑郁发生; d. 缺失ucOCN, ATP不能正常合成, IP3Rs2和囊泡胶质细胞诱导ATP缺陷, 抑郁小鼠模型内测P2X2受体介导ATP抗抑郁; e. ucOCN作用于炎症AKT/mTOR/NF-κB途径和星型胶质细胞调控抑郁发生; f. ucOCN直接作用于IL-6、IL-8、IL-1β表达, 影响HPA轴调控抑郁发生。 g. ucOCN上调PVT1表达, 抑制TNF-α、IL-1β、IL-6作用于PKC后上调BDNF, TUNEL数量↓, 激活AKT/ mTOR途径并调节Aβ相关蛋白表达, 改善抑郁样行为; h. 体外实验, ucOCN通过AKT/mTOR途径保护Aβ-42损伤PC12细胞实现上述效果。
调节神经再生	a. 骨中Runx2↓, ucOCN↓, 认知功能损; b. ucOCN敲除后, 神经元数量减少, 再生能力下降, 抑郁易发生。

发生机制	介导/调控的分子机制及基因、蛋白活动
调节神经递质	a. 5-HTTLPR短等位基因在慢性应激下易患抑郁; b. ucOCN下调NMDA表达, AMPAR表达↑, 谷氨酸、BDNF↑, GABA↓, 快速抗抑郁; c. Gpr158影响MF-CA1区神经远树突结构和功能调控抑郁发生;
调节神经内分泌	a. 敲除ucOCN后, GC↑, 引发抑郁样行为; b. 血清ucOCN↓, 激活HPA轴, ACTH和皮质醇↑, 抑制海马对HPA轴的负反馈调节; c. 敲除ucOCN后, GPRC6A失活, 胰岛素↓, 激活海马区炎症反应和IR, Ezrin表达↓。
介导神经免疫机制	a. 应激状态下, CRH↑, 交感神经系统和HPA轴激活, 抑制正常免疫反应; b. NF-κB激活C3参与抑郁发生; c. NF-κB激活后, C3释放↑, 作用于神经细胞上的C3受体; NF-κB/C3/C3aR途径参与神经内钙电流调节, 突触后电流↑, 并受AMPAR调节影响抑郁发生; d. 缺失ucOCN, ATP不能正常合成, IP3Rs2和囊泡胶质细胞诱导ATP缺陷, 抑郁小鼠模型内测P2X2受体介导ATP抗抑郁; e. ucOCN作用于炎症AKT/mTOR/NF-κB途径和星型胶质细胞调控抑郁发生; f. ucOCN直接作用于IL-6、IL-8、IL-1β表达, 影响HPA轴调控抑郁发生。 g. ucOCN上调PVT1表达, 抑制TNF-α、IL-1β、IL-6作用于PKC后上调BDNF, TUNEL数量↓, 激活AKT/ mTOR途径并调节Aβ相关蛋白表达, 改善抑郁样行为; h. 体外实验, ucOCN通过AKT/mTOR途径保护Aβ-42损伤PC12细胞实现上述效果。
调节神经再生	a. 骨中Runx2↓, ucOCN↓, 认知功能损; b. ucOCN敲除后, 神经元数量减少, 再生能力下降, 抑郁易发生。