Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Endocannabinoid interference blocks post-global cerebral ischemia depression through prefrontal cortico-amygdala projections

Neuropsychopharmacology volume 50, pages 1063–1074 (2025)Cite this article

Subjects

Abstract

Up to 45% of patients surviving from transient global cerebral ischemia (GCI) after cardiac arrest develop post-global cerebral ischemia depression (PGCID), but how to treat PGCID is clinically unknown. Here we find that cannabinoid type-1 receptor (CB1R) antagonists, CB1R knockout and endocannabinoid (eCB) synthesis inhibition block acute stress-induced PGCID. Application of acute stress to GCI mice increases CB1R activity from ventromedial prefrontal cortical (vmPFC) terminals synapsing with the basolateral amygdala (BLA) neurons, indicating the involvement of increased vmPFC-BLA synaptic eCB signaling in PGCID induction. This idea is supported by findings that optogenetic activation of CB1Rs in vmPFC-BLA projections mimics stress effects to induce PGCID, which is blocked by knock-down of eCB biosynthesis enzyme genes in vmPFC-BLA synapses. Interestingly, GCI mice show decreased mRNA expression of eCB degradation enzymes in vmPFCs without significant changes on mRNA expression of eCB biosynthesis and degradation enzymes in BLA cells. Thus, over-expression of eCB degradation enzymes in vmPFC cells innervating BLA neurons or activation of vmPFC-BLA projections blocks stress effects to induce PGCID. Our findings suggest that decreased eCB degradation and subsequent stress-increased eCB signaling in vmPFC-BLA circuits participate in the mechanism of PGCID, which can be treated clinically by eCB signaling interference systemically or in vmPFC-BLA circuits.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Endocannabinoid modulation of PGCID.
Fig. 2: Stress activates vmPFC-BLA synaptic CB1Rs in GCI mice and optical activation of these CB1Rs mimics stress effects to induce PGCID.
Fig. 3: Knockout of 2-AG biosynthesis Dagla genes in vmPFC-BLA synapses blocks PGCID.
Fig. 4: Overexpression of 2-AG hydrolase Magl genes in vmPFC-BLA projections blocks PGCID.
Fig. 5: Opto-activation/inhibition of vmPFC-BLA projections blocks/mimics stress effects to induce PGCID and diagram of PGCID mechanism.

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation. 2001;104:2158–63.

    Article  CAS  PubMed  Google Scholar 

  2. Bigham BL, Koprowicz K, Rea T, Dorian P, Aufderheide TP, Davis DP, et al. Cardiac arrest survival did not increase in the Resuscitation Outcomes Consortium after implementation of the 2005 AHA CPR and ECC guidelines. Resuscitation. 2011;82:979–83.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA. 2008;300:1423–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Segal N, di Pompéo C, Escutnaire J, Wiel E, Dumont C, Castra L, et al. Evolution of survival in cardiac arrest with age in elderly patients: is resuscitation a dead end? J Emerg Med. 2018;54:295–301.

    Article  PubMed  Google Scholar 

  5. Roine RO, Kajaste S, Kaste M. Neuropsychological sequelae of cardiac arrest. JAMA. 1993;269:237–42.

    Article  CAS  PubMed  Google Scholar 

  6. Wilder Schaaf KP, Artman LK, Peberdy MA, Walker WC, Ornato JP, Gossip MR, et al. Anxiety, depression, and PTSD following cardiac arrest: a systematic review of the literature. Resuscitation. 2013;84:873–7.

    Article  PubMed  Google Scholar 

  7. Metzger K, Gamp M, Tondorf T, Hochstrasser S, Becker C, Luescher T, et al. Depression and anxiety in relatives of out-of-hospital cardiac arrest patients: results of a prospective observational study. J Crit Care. 2019;51:57–63.

    Article  PubMed  Google Scholar 

  8. Yaow CYL, Teoh SE, Lim WS, Wang R, Han MX, Pek PP, et al. Prevalence of anxiety, depression, and post-traumatic stress disorder after cardiac arrest: A systematic review and meta-analysis. Resuscitation. 2022;170:82–91.

    Article  PubMed  Google Scholar 

  9. Raic M. Depression and heart diseases: leading health problems. Psychiatr Danub. 2017;29:770–7.

    PubMed  Google Scholar 

  10. de la Tremblaye PB, Linares NN, Schock S, Plamondon H. Activation of CRHR1 receptors regulates social and depressive-like behaviors and expression of BDNF and TrkB in mesocorticolimbic regions following global cerebral ischemia. Exp Neurol. 2016;284:84–97.

    Article  PubMed  Google Scholar 

  11. Yan B, Wang DY, Xing DM, Ding Y, Wang RF, Lei F, Du LJ. The antidepressant effect of ethanol extract of radix puerariae in mice exposed to cerebral ischemia reperfusion. Pharmacol Biochem Behav. 2004;78:319–25.

    Article  CAS  PubMed  Google Scholar 

  12. Yan B, He J, Xu H, Zhang Y, Bi X, Thakur S, et al. Quetiapine attenuates the depressive and anxiolytic-like behavioural changes induced by global cerebral ischemia in mice. Behav Brain Res. 2007;182:36–41.

    Article  CAS  PubMed  Google Scholar 

  13. Camargos QM, Silva BC, Silva DG, Toscano E, Oliveira B, Bellozi P, et al. Minocycline treatment prevents depression and anxiety-like behaviors and promotes neuroprotection after experimental ischemic stroke. Brain Res Bull. 2020;155:1–10.

    Article  CAS  PubMed  Google Scholar 

  14. Wang Y, Gu N, Duan T, Kesner P, Blaskovits F, Liu J, et al. Monoacylglycerol lipase inhibitors produce pro- or antidepressant responses via hippocampal CA1 GABAergic synapses. Mol Psychiatry. 2017;22:215–26.

    Article  CAS  PubMed  Google Scholar 

  15. Hill MN, Gorzalka BB. Pharmacological enhancement of cannabinoid CB1 receptor activity elicits an antidepressant-like response in the rat forced swim test. Eur Neuropsychopharmacol. 2005;15:593–9.

    Article  CAS  PubMed  Google Scholar 

  16. Bambico FR, Katz N, Debonnel G, Gobbi G. Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex. J Neurosci. 2007;27:11700–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X. Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Investig. 2005;115:3104–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhong P, Wang W, Pan B, Liu X, Zhang Z, Long JZ, et al. Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology. 2014;39:1763–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Alteba S, Mizrachi Zer-Aviv T, Tenenhaus A, Ben David G, Adelman J, Hillard CJ, et al. Antidepressant-like effects of URB597 and JZL184 in male and female rats exposed to early life stress. Eur Neuropsychopharmacol. 2020;39:70–86.

    Article  CAS  PubMed  Google Scholar 

  20. Han J, Kesner P, Metna-Laurent M, Duan T, Xu L, Georges F, et al. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell. 2012;148:1039–50.

    Article  CAS  PubMed  Google Scholar 

  21. Blankman JL, Cravatt BF. Chemical probes of endocannabinoid metabolism. Pharmacol Rev. 2013;65:849–71.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chevaleyre V, Takahashi KA, Castillo PE. Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci. 2006;29:37–76.

    Article  CAS  PubMed  Google Scholar 

  23. Katona I, Sperlágh B, Sík A, Käfalvi A, Vizi ES, Mackie K, Freund TF. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci. 1999;19:4544–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL. Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci. 2004;24:53–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mecca CM, Chao D, Yu G, Feng Y, Segel I, Zhang Z, et al. Dynamic change of endocannabinoid signaling in the medial prefrontal cortex controls the development of depression after neuropathic pain. J Neurosci. 2021;41:7492–508.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Jenniches I, Ternes S, Albayram O, Otte DM, Bach K, Bindila L, et al. Anxiety, Stress, and Fear Response in Mice With Reduced Endocannabinoid Levels. Biol Psychiatry. 2016;79:858–68.

    Article  CAS  PubMed  Google Scholar 

  27. Shen CJ, Zheng D, Li KX, Yang JM, Pan HQ, Yu XD, et al. Cannabinoid CB(1) receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior. Nat Med. 2019;25:337–49.

    Article  CAS  PubMed  Google Scholar 

  28. Steiner MA, Marsicano G, Wotjak CT, Lutz B. Conditional cannabinoid receptor type 1 mutants reveal neuron subpopulation-specific effects on behavioral and neuroendocrine stress responses. Psychoneuroendocrinology. 2008;33:1165–70.

    Article  CAS  PubMed  Google Scholar 

  29. Zhong H, Tong L, Gu N, Gao F, Lu Y, Xie RG, et al. Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice. J Clin Invest. 2017;127:2295–309.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Onken M, Berger S, Kristian T. Simple model of forebrain ischemia in mouse. J Neurosci Methods. 2012;204:254–61.

    Article  PubMed  Google Scholar 

  31. Charney, DS, Nestler EJ. Neurobiology of mental illness. New York: Oxford University Press; 2005.

  32. Hare BD, Shinohara R, Liu RJ, Pothula S, DiLeone RJ, Duman RS. Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects. Nat Commun. 2019;10:223.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Dong A, He K, Dudok B, Farrell JS, Guan W, Liput DJ, et al. A fluorescent sensor for spatiotemporally resolved imaging of endocannabinoid dynamics in vivo. Nat Biotechnol. 2022;40:787–98.

    Article  CAS  PubMed  Google Scholar 

  34. Shang H, Li P, Lin X, Cai Q, Li Z, Deng L, et al. Neuronal and astrocytic CB1R signaling differentially modulates goal-directed behavior and working memory by distinct temporal mechanisms. Neuropsychopharmacology. 2023;48:1520–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ran FA, Cong L, Yan WX, Scott DA, Gootenberg JS, Kriz AJ, et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature. 2015;520:186–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xie H, Tang L, He X, Liu X, Zhou C, Liu J, et al. SaCas9 requires 5’-NNGRRT-3’ PAM for sufficient cleavage and possesses higher cleavage activity than SpCas9 or FnCpf1 in human cells. Biotechnol J. 2018;13:1800080.

    Article  Google Scholar 

  37. Sun H, Fu S, Cui S, Yin X, Sun X, Qi X, et al. Development of a CRISPR-SaCas9 system for projection- and function-specific gene editing in the rat brain. Sci Adv. 2020;6:eaay6687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A. Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci. 2013;34:637–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci. 2018;19:833.

  40. Hill MN, Miller GE, Ho WS, Gorzalka BB, Hillard CJ. Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry. 2008;41:48–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Haring M, Guggenhuber S, Lutz B. Neuronal populations mediating the effects of endocannabinoids on stress and emotionality. Neuroscience. 2012;204:145–58.

    Article  CAS  PubMed  Google Scholar 

  42. Phelps EA, LeDoux JE. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron. 2005;48:175–87.

    Article  CAS  PubMed  Google Scholar 

  43. Buhle JT, Silvers JA, Wager TD, Lopez R, Onyemekwu C, Kober H, et al. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cereb Cortex. 2014;24:2981–90.

    Article  PubMed  Google Scholar 

  44. Kral TRA, Schuyler BS, Mumford JA, Rosenkranz MA, Lutz A, Davidson RJ. Impact of short- and long-term mindfulness meditation training on amygdala reactivity to emotional stimuli. Neuroimage. 2018;181:301–13.

    Article  PubMed  Google Scholar 

  45. Little JP, Carter AG. Synaptic mechanisms underlying strong reciprocal connectivity between the medial prefrontal cortex and basolateral amygdala. J Neurosci. 2013;33:15333–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. McGarry LM, Carter AG. Prefrontal Cortex Drives Distinct Projection Neurons in the Basolateral Amygdala. Cell Rep. 2017;21:1426–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Arruda-Carvalho M, Clem RL. Pathway-selective adjustment of prefrontal-amygdala transmission during fear encoding. J Neurosci. 2014;34:15601–9.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Bloodgood DW, Sugam JA, Holmes A, Kash TL. Fear extinction requires infralimbic cortex projections to the basolateral amygdala. Transl Psychiatry. 2018;8:60.

    Article  PubMed  PubMed Central  Google Scholar 

  49. McGinnis MM, Parrish BC, Chappell AM, Alexander NJ, McCool BA. Chronic Ethanol Differentially Modulates Glutamate Release from Dorsal and Ventral Prefrontal Cortical Inputs onto Rat Basolateral Amygdala Principal Neurons. eNeuro. 2020;7:ENEURO.0132-19.2019.

Download references

Funding

The Major program of Technological innovation 2030 “Brain science and brain-inspired research” (2021ZD0203002); Key Project from the National Natural Science Foundation of China (81830035); The Major program of National Natural Science Foundation of China (82090033); The Major Basic research program of Shandong Province Natural Science Foundation (ZR2019ZD35); National Natural Science Foundation of China (32371187,32000788); Natural Science Foundation of Shandong Province (ZR2024MH063).exte.

Author information

Author notes

  1. These authors contributed equally: Zhaoyuan Tu, Yao Ma.

Authors and Affiliations

  1. Mental Health Center, West China Hospital of Sichuan University, Chengdu, China

    Zhaoyuan Tu, Yao Ma & Xia Zhang

  2. Institute of Brain Function and Diseases, West China Hospital of Sichuan University, Chengdu, China

    Zhaoyuan Tu, Yao Ma & Xia Zhang

  3. Chinese Institute for Brain Research (CIBR), Beijing, China

    Huiping Shang & Xia Zhang

  4. Neuropsychiatry Research Institute, The Affiliated Hospital of Qingdao University, Qingdao, China

    Sha Zhao, Bao Xue, Yu Qu, Huamin Xu, Xufeng Xu & Xia Zhang

  5. Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China

    Jiangfan Chen

  6. State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China

    Yulong Li

  7. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Ji Hu

  8. Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, China

    Fang Gao

  9. School of Basic Medicine, Qingdao University, Qingdao, China

    Huamin Xu & Xufeng Xu

Authors
  1. Zhaoyuan Tu
    View author publications

    Search author on:PubMed Google Scholar

  2. Yao Ma
    View author publications

    Search author on:PubMed Google Scholar

  3. Huiping Shang
    View author publications

    Search author on:PubMed Google Scholar

  4. Sha Zhao
    View author publications

    Search author on:PubMed Google Scholar

  5. Bao Xue
    View author publications

    Search author on:PubMed Google Scholar

  6. Yu Qu
    View author publications

    Search author on:PubMed Google Scholar

  7. Jiangfan Chen
    View author publications

    Search author on:PubMed Google Scholar

  8. Yulong Li
    View author publications

    Search author on:PubMed Google Scholar

  9. Ji Hu
    View author publications

    Search author on:PubMed Google Scholar

  10. Fang Gao
    View author publications

    Search author on:PubMed Google Scholar

  11. Huamin Xu
    View author publications

    Search author on:PubMed Google Scholar

  12. Xufeng Xu
    View author publications

    Search author on:PubMed Google Scholar

  13. Xia Zhang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

XX, ZT, YM, FG, HX, HS, SZ, BX, YQ and NZ performed the research; XZ and XX analyzed data; XZ conceived the project and wrote the manuscript with the help of XX, JC, YL, and JH.

Corresponding authors

Correspondence to Xufeng Xu or Xia Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tu, Z., Ma, Y., Shang, H. et al. Endocannabinoid interference blocks post-global cerebral ischemia depression through prefrontal cortico-amygdala projections. Neuropsychopharmacol. 50, 1063–1074 (2025). https://doi.org/10.1038/s41386-024-02029-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41386-024-02029-4

Search

Advanced search

Quick links