Cannabidiol prevents depressive-like behaviors through the modulation of neural stem cell differentiation

Abstract

Chronic stress impairs radial neural stem cell (rNSC) differentiation and adult hippocampal neurogenesis (AHN), whereas promoting AHN can increase stress resilience against depression. Therefore, investigating the mechanism of neural differentiation and AHN is of great importance for developing antidepressant drugs. The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to be effective against depression. However, whether CBD can modulate rNSC differentiation and hippocampal neurogenesis is unknown. Here, by using the chronic restraint stress (CRS) mouse model, we showed that hippocampal rNSCs mostly differentiated into astrocytes under stress conditions. Moreover, transcriptome analysis revealed that the FoxO signaling pathway was involved in the regulation of this process. The administration of CBD rescued depressive-like symptoms in CRS mice and prevented rNSCs overactivation and differentiation into astrocyte, which was partly mediated by the modulation of the FoxO signaling pathway. These results revealed a previously unknown neural mechanism for neural differentiation and AHN in depression and provided mechanistic insights into the antidepressive effects of CBD.

Keywords

cannabidiol / depression / radial neural stem cells / neurogenesis

References

[1] Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci 2016; 17(8): 497–511

[2] Flint J, Kendler KS. The genetics of major depression. Neuron 2014; 81(3): 484–503

[3] Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002; 34(1): 13–25

[4] Micheli L, Ceccarelli M, D’Andrea G, Tirone F. Depression and adult neurogenesis: positive effects of the antidepressant fluoxetine and of physical exercise. Brain Res Bull 2018; 143: 181–193

[5] Anacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility—linking memory and mood. Nat Rev Neurosci 2017; 18(6): 335–346

[6] Sun L, Sun Q, Qi J. Adult hippocampal neurogenesis: an important target associated with antidepressant effects of exercise. Rev Neurosci 2017; 28(7): 693–703

[7] Toda T, Parylak SL, Linker SB, Gage FH. The role of adult hippocampal neurogenesis in brain health and disease. Mol Psychiatry 2019; 24(1): 67–87

[8] Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 2011; 476(7361): 458–461

[9] Mirescu C, Gould E. Stress and adult neurogenesis. Hippocampus 2006; 16(3): 233–238

[10] Jung S, Choe S, Woo H, Jeong H, An HK, Moon H, Ryu HY, Yeo BK, Lee YW, Choi H, Mun JY, Sun W, Choe HK, Kim EK, Yu SW. Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits. Autophagy 2020; 16(3): 512–530

[11] Anacker C, Luna VM, Stevens GS, Millette A, Shores R, Jimenez JC, Chen B, Hen R. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature 2018; 559(7712): 98–102

[12] Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 2014; 55(6): 791–802

[13] Campos AC, Fogaça MV, Sonego AB, Guimarães FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res 2016; 112: 119–127

[14] Linge R, Jiménez-Sánchez L, Campa L, Pilar-Cuéllar F, Vidal R, Pazos A, Adell A, Díaz Á. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology 2016; 103: 16–26

[15] Pisanti S, Malfitano AM, Ciaglia E, Lamberti A, Ranieri R, Cuomo G, Abate M, Faggiana G, Proto MC, Fiore D, Laezza C, Bifulco M. Cannabidiol: state of the art and new challenges for therapeutic applications. Pharmacol Ther 2017; 175: 133–150

[16] Scuderi C, Filippis DD, Iuvone T, Blasio A, Steardo A, Esposito G. Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders. Phytother Res 2009; 23(5): 597–602

[17] Berardi A, Schelling G, Campolongo P. The endocannabinoid system and post traumatic stress disorder (PTSD): from preclinical findings to innovative therapeutic approaches in clinical settings. Pharmacol Res 2016; 111: 668–678

[18] Micale V, Di Marzo V, Sulcova A, Wotjak CT, Drago F. Endocannabinoid system and mood disorders: priming a target for new therapies. Pharmacol Ther 2013; 138(1): 18–37

[19] Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, Witztum J, Shaver DC, Rosenthal DL, Alway EJ, Lopez K, Meng Y, Nellissen L, Grosenick L, Milner TA, Deisseroth K, Bito H, Kasai H, Liston C. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science 2019; 364(6436): eaat8078

[20] Huang L, Xi Y, Peng Y, Yang Y, Huang X, Fu Y, Tao Q, Xiao J, Yuan T, An K, Zhao H, Pu M, Xu F, Xue T, Luo M, So KF, Ren C. A visual circuit related to habenula underlies the antidepressive effects of light therapy. Neuron 2019; 102(1): 128–142.e8

[21] Wang Y, Chen ZP, Hu H, Lei J, Zhou Z, Yao B, Chen L, Liang G, Zhan S, Zhu X, Jin F, Ma R, Zhang J, Liang H, Xing M, Chen XR, Zhang CY, Zhu JN, Chen X. Sperm microRNAs confer depression susceptibility to offspring. Sci Adv 2021; 7(7): eabd7605

[22] Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 2018; 554(7692): 317–322

[23] Fernandez DC, Fogerson PM, Lazzerini Ospri L, Thomsen MB, Layne RM, Severin D, Zhan J, Singer JH, Kirkwood A, Zhao H, Berson DM, Hattar S. Light affects mood and learning through distinct retina-brain pathways. Cell 2018; 175(1): 71–84.e18

[24] Chen ZP, Zhang XY, Peng SY, Yang ZQ, Wang YB, Zhang YX, Chen X, Wang JJ, Zhu JN. Histamine H1 receptor contributes to vestibular compensation. J Neurosci 2019; 39(3): 420–433

[25] Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA, Fishell G, Koulakov A, Enikolopov G. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 2011; 8(5): 566–579PMID:21549330

[26] Sierra A, Martín-Suárez S, Valcárcel-Martín R, Pascual-Brazo J, Aelvoet SA, Abiega O, Deudero JJ, Brewster AL, Bernales I, Anderson AE, Baekelandt V, Maletić-Savatić M, Encinas JM. Neuronal hyperactivity accelerates depletion of neural stem cells and impairs hippocampal neurogenesis. Cell Stem Cell 2015; 16(5): 488–503

[27] Huang T, Xu T, Wang Y, Zhou Y, Yu D, Wang Z, He L, Chen Z, Zhang Y, Davidson D, Dai Y, Hang C, Liu X, Yan C. Cannabidiol inhibits human glioma by induction of lethal mitophagy through activating TRPV4. Autophagy 2021; 25: 1–15

[28] Fiksdal A, Hanlin L, Kuras Y, Gianferante D, Chen X, Thoma MV, Rohleder N. Associations between symptoms of depression and anxiety and cortisol responses to and recovery from acute stress. Psychoneuroendocrinology 2019; 102: 44–52

[29] Dong J, Pan YB, Wu XR, He LN, Liu XD, Feng DF, Xu TL, Sun S, Xu NJ. A neuronal molecular switch through cell-cell contact that regulates quiescent neural stem cells. Sci Adv 2019; 5(2): eaav4416

[30] Kaplan JS, Stella N, Catterall WA, Westenbroek RE. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci USA 2017; 114(42): 11229–11234

[31] Tunc-Ozcan E, Peng CY, Zhu Y, Dunlop SR, Contractor A, Kessler JA. Activating newborn neurons suppresses depression and anxiety-like behaviors. Nat Commun 2019; 10(1): 3768

[32] Eisch AJ, Petrik D. Depression and hippocampal neurogenesis: a road to remission? Science 2012; 338(6103): 72–75

[33] Peng L, Bonaguidi MA. Function and dysfunction of adult hippocampal neurogenesis in regeneration and disease. Am J Pathol 2018; 188(1): 23–28

[34] Fogaça MV, Campos AC, Coelho LD, Duman RS, Guimarães FS. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: role of neurogenesis and dendritic remodeling. Neuropharmacology 2018; 135: 22–33

[35] Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci 2012; 367(1607): 3364–3378

[36] Campos AC, Ortega Z, Palazuelos J, Fogaça MV, Aguiar DC, Díaz-Alonso J, Ortega-Gutiérrez S, Vázquez-Villa H, Moreira FA, Guzmán M, Galve-Roperh I, Guimarães FS. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol 2013; 16(6): 1407–1419

[37] Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis. Lancet Psychiatry 2019; 6(7): 601–609

[38] Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 2010; 159(1): 122–128

[39] Lages YVM, Rossi AD, Krahe TE, Landeira-Fernandez J. Effect of chronic unpredictable mild stress on the expression profile of serotonin receptors in rats and mice: a meta-analysis. Neurosci Biobehav Rev 2021; 124: 78–88

[40] Hill JD, Zuluaga-Ramirez V, Gajghate S, Winfield M, Persidsky Y. Activation of GPR55 increases neural stem cell proliferation and promotes early adult hippocampal neurogenesis. Br J Pharmacol 2018; 175(16): 3407–3421

RIGHTS & PERMISSIONS

Higher Education Press