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.
Molecular Psychiatry (2022 )Cite this article
Opioids are the frontline analgesics for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH), which significantly contributes to dose escalation and consequently opioid overdose. Neuronal malplasticity in pain circuits has been the predominant proposed mechanism of OIH expression. Although glial cells are known to become reactive in OIH animal models, their biological contribution to OIH remains to be defined and their activation mechanism remains to be elucidated. Here, we show that reactive astrocytes (a.k.a. astrogliosis) are critical for OIH development in both male and female mice. Genetic reduction of astrogliosis inhibited the expression of OIH and morphine-induced neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We found that Wnt5a is a neuron-to-astrocyte signal that is required for morphine-induced astrogliosis. Conditional knock-out of Wnt5a in neurons or its co-receptor ROR2 in astrocytes blocked not only morphine-induced astrogliosis but also OIH and NCP. Furthermore, we showed that the Wnt5a-ROR2 signaling-dependent astrogliosis contributes to OIH via inflammasome-regulated IL-1β. Our results reveal an important role of morphine-induced astrogliosis in OIH pathogenesis and elucidate a neuron-to-astrocyte intercellular Wnt signaling pathway that controls the astrogliosis.
This is a preview of subscription content, access via your institution
Get full journal access for 1 year
All prices are NET prices. VAT will be added later in the checkout. Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Colvin LA, Bull F, Hales TG. Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet 2019;393:1558–68.
Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995;62:259–74.
CAS PubMed Article Google Scholar
Dumas EO, Pollack GM. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 2008;10:537–51.
CAS PubMed PubMed Central Article Google Scholar
Corder G, Tawfik VL, Wang D, Sypek EI, Low SA, Dickinson JR, et al. Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nat Med. 2017;23:164.
CAS PubMed PubMed Central Article Google Scholar
Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci: Off J Soc Neurosci. 1994;14:2301–12.
Angst Martin S, Clark JD. Opioid-induced Hyperalgesia: A Qualitative Systematic Review. Anesthesiology 2006;104:570–87.
CAS PubMed Article Google Scholar
Chu LF, Angst MS, Clark D. Opioid-induced Hyperalgesia in Humans: Molecular Mechanisms and Clinical Considerations. Clin J Pain. 2008;24:479–96. 1097/AJP.1090b1013e31816b31812f31843
Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011;14:145–61.
Roeckel L-A, Le Coz G-M, Gavériaux-Ruff C, Simonin F. Opioid-induced hyperalgesia: Cellular and molecular mechanisms. Neuroscience 2016;338:160–82.
CAS PubMed Article Google Scholar
Drdla R, Gassner M, Gingl E, Sandkühler J. Induction of Synaptic Long-Term Potentiation After Opioid Withdrawal. Science 2009;325:207–10.
CAS PubMed Article Google Scholar
Ferrini F, Trang T, Mattioli T-AM, Laffray S, Del’Guidice T, Lorenzo L-E, et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis. Nat Neurosci. 2013;16:183.
CAS PubMed PubMed Central Article Google Scholar
Liu X, Liu BL, Yang Q, Zhou X, Tang SJ. Microglial ablation does not affect opioid-induced hyperalgesia in rodents. Pain 2022;163:508–17.
CAS PubMed Article Google Scholar
Berta T, Liu YC, Xu ZZ, Ji RR. Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice. Neuroscience 2013;247(Supplement C):376–85.
CAS PubMed Article Google Scholar
Sanna MD, Ghelardini C, Galeotti N. Activation of JNK pathway in spinal astrocytes contributes to acute ultra-low-dose morphine thermal hyperalgesia. Pain 2015;156:1265–75.
CAS PubMed Article Google Scholar
Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 2009;32:421–31.
CAS PubMed Article Google Scholar
Ji R-R, Donnelly CR, Nedergaard M. Astrocytes in chronic pain and itch. Nat Rev Neurosci. 2019;20:667–85.
CAS PubMed PubMed Central Article Google Scholar
Barres BA. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 2008;60:430–40.
CAS PubMed Article Google Scholar
Khakh BS, Sofroniew MV. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci. 2015;18:942–52.
CAS PubMed PubMed Central Article Google Scholar
Allen NJ, Eroglu C. Cell Biology of Astrocyte-Synapse Interactions. Neuron 2017;96:697–708.
CAS PubMed PubMed Central Article Google Scholar
Lines J, Martin ED, Kofuji P, Aguilar J, Araque A. Astrocytes modulate sensory-evoked neuronal network activity. Nat Commun. 2020;11:3689.
CAS PubMed PubMed Central Article Google Scholar
Bush TG, Savidge TC, Freeman TC, Cox HJ, Campbell EA, Mucke L, et al. Fulminant Jejuno-Ileitis following Ablation of Enteric Glia in Adult Transgenic Mice. Cell 1998;93:189.
CAS PubMed Article Google Scholar
Miyoshi H, Ajima R, Luo CT, Yamaguchi TP, Stappenbeck TS. Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury. Science 2012;338:108–13.
CAS PubMed PubMed Central Article Google Scholar
Zhu Y, Romero MI, Ghosh P, Ye Z, Charnay P, Rushing EJ, et al. Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev. 2001;15:859–76.
CAS PubMed PubMed Central Article Google Scholar
Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet. 1999;23:99.
CAS PubMed Article Google Scholar
Ho H-YH, Susman MW, Bikoff JB, Ryu YK, Jonas AM, Hu L, et al. Wnt5a–Ror–Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc Natl Acad Sci. 2012;109:4044–51.
CAS PubMed PubMed Central Article Google Scholar
Garcia ADR, Doan NB, Imura T, Bush TG, Sofroniew MV. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat Neurosci. 2004;7:1233.
CAS PubMed Article Google Scholar
Callahan BL, Gil AS, Levesque A, Mogil JS Modulation of mechanical and thermal nociceptive sensitivity in the laboratory mouse by behavioral state. J Pain. 2008; 9:174–84.
Andrews N, Loomis S, Blake R, Ferrigan L, Singh L, McKnight AT. Effect of gabapentin-like compounds on development and maintenance of morphine-induced conditioned place preference. Psychopharmacol (Berl). 2001;157:381–7.
Bae C, Wang J, Shim HS, Tang S-J, Chung JM, La J-H. Mitochondrial superoxide increases excitatory synaptic strength in spinal dorsal horn neurons of neuropathic mice. Mol Pain. 2018;14:1744806918797032.
CAS PubMed PubMed Central Article Google Scholar
Lee KY, Bae C, Lee D, Kagan Z, Bradley K, Chung JM, et al. Low-intensity, Kilohertz Frequency Spinal Cord Stimulation Differently Affects Excitatory and Inhibitory Neurons in the Rodent Superficial Dorsal Horn. Neuroscience 2020;428:132–9.
CAS PubMed Article Google Scholar
Zhang D, Wei Y, Liu J, Chen H, Li J, Zhu T, et al. Single-nucleus transcriptomic atlas of spinal cord neuron in human. bioRxiv. 2021: 2021.2009.2028.462103.
Zhang D, Wei Y, Liu J, Yang Y, Ou M, Chen Y, et al. Single-nucleus transcriptomic analysis reveals divergence of glial cells in peripheral somatosensory system between human and mouse. bioRxiv. 2022: 2022.2002.2015.480622.
Li X, Angst MS, Clark JD. A murine model of opioid-induced hyperalgesia. Brain Res Mol Brain Res. 2001;86:56–62.
CAS PubMed Article Google Scholar
Stoicea N, Russell D, Weidner G, Durda M, Joseph NC, Yu J, et al. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin. Front Pharm. 2015;6:104.
Song P, Zhao ZQ. The involvement of glial cells in the development of morphine tolerance. Neurosci Res. 2001;39:281–6.
CAS PubMed Article Google Scholar
Hutchinson MR, Lewis SS, Coats BD, Rezvani N, Zhang Y, Wieseler JL, et al. Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences. Neuroscience 2010;167:880–93.
CAS PubMed Article Google Scholar
Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 1999;23:297–308.
CAS PubMed Article Google Scholar
Punnakkal P, von Schoultz C, Haenraets K, Wildner H, Zeilhofer HU. Morphological, biophysical and synaptic properties of glutamatergic neurons of the mouse spinal dorsal horn. J Physiol. 2014;592:759–76.
CAS PubMed PubMed Central Article Google Scholar
Todd AJ. Identifying functional populations among the interneurons in laminae I-III of the spinal dorsal horn. Mol Pain. 2017;13:1744806917693003.
PubMed PubMed Central Article Google Scholar
Yuan S, Shi Y, Tang SJ Wnt Signaling in the Pathogenesis of Multiple Sclerosis-Associated Chronic Pain. J Neuroimmune Pharmacology 2012; https://doi.org/10.1007/s11481-012-9370-3.
Yuan S, Ji G, Li B, Andersson T, Neugebauer V, Tang S-J. A Wnt5a signaling pathway in the pathogenesis of HIV-1 gp120-induced pain. Pain 2015;156:1311–9.
CAS PubMed PubMed Central Article Google Scholar
Simonetti M, Kuner R. Spinal Wnt5a Plays a Key Role in Spinal Dendritic Spine Remodeling in Neuropathic and Inflammatory Pain Models and in the Proalgesic Effects of Peripheral Wnt3a. J Neurosci: Off J Soc Neurosci. 2020;40:6664–77.
Li B, Shi Y, Shu J, Gao J, Wu P, Tang S-J. Wingless-type Mammary Tumor Virus Integration Site Family, Member 5A (Wnt5a) Regulates Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Glycoprotein 120 (gp120)-induced Expression of Pro-Inflammatory Cytokines via the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) and c-Jun N-terminal Kinase (JNK) Signaling Pathways. J Biol Chem. 2013;288:13610–9.
CAS PubMed PubMed Central Article Google Scholar
Shi Y, Yuan S, Li B, Wang J, Carlton S, Chung K, et al. Regulation of Wnt signaling by nociceptive input in animal models. Mol Pain. 2012;8:47.
CAS PubMed PubMed Central Article Google Scholar
Li Y, Li B, Wan X, Zhang W, Zhong L, Tang S-J. NMDA receptor activation stimulates transcription-independent rapid wnt5a protein synthesis via the MAPK signaling pathway. Mol Brain. 2012;5:1.
PubMed PubMed Central Article Google Scholar
Chen J, Park CS, Tang SJ. Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation. J Biol Chem. 2006;281:11910–6.
CAS PubMed Article Google Scholar
Shi Y, Yuan S, Tang S-J. Morphine and HIV-1 gp120 cooperatively promote pathogenesis in the spinal pain neural circuit. Mol Pain. 2019;15:1744806919868380.
CAS PubMed PubMed Central Article Google Scholar
Yuan S, Shi Y, Guo K, Tang S-J. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice. J. Neuroimmune Pharmacol. 2018;13:230–6.
Zhuang Z-Y, Wen Y-R, Zhang D-R, Borsello T, Bonny C, Strichartz GR, et al. A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance. J Neurosci. 2006;26:3551–60.
CAS PubMed PubMed Central Article Google Scholar
Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J, et al. A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci: Off J Soc Neurosci. 2004;24:7353–65.
Hilla AM, Diekmann H, Fischer D. Microglia Are Irrelevant for Neuronal Degeneration and Axon Regeneration after Acute Injury. J Neurosci. 2017;37:6113–24.
CAS PubMed PubMed Central Article Google Scholar
Janova H, Arinrad S, Balmuth E, Mitjans M, Hertel J, Habes M, et al. Microglia ablation alleviates myelin-associated catatonic signs in mice. J Clin Inv. 2017;128:734–45.
Reshef R, Kudryavitskaya E, Shani-Narkiss H, Isaacson B, Rimmerman N, Mizrahi A, et al. The role of microglia and their CX3CR1 signaling in adult neurogenesis in the olfactory bulb. eLife. 2017;6:e30809.
PubMed PubMed Central Article Google Scholar
Oliva AA, Jiang M, Lam T, Smith KL, Swann JW. Novel Hippocampal Interneuronal Subtypes Identified Using Transgenic Mice That Express Green Fluorescent Protein in GABAergic Interneurons. J Neurosci. 2000;20:3354–68.
CAS PubMed PubMed Central Article Google Scholar
Schroder K, Tschopp J. The Inflammasomes. Cell 2010;140:821–32.
CAS PubMed Article Google Scholar
Hutchinson MR, Coats BD, Lewis SS, Zhang Y, Sprunger DB, Rezvani N, et al. Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia. Brain Behav Immun. 2008;22:1178–89.
CAS PubMed PubMed Central Article Google Scholar
Grace PM, Strand KA, Galer EL, Urban DJ, Wang X, Baratta MV, et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci. 2016;113:E3441–E3450.
CAS PubMed PubMed Central Article Google Scholar
Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, et al. The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells. 2003;8:645–54.
CAS PubMed Article Google Scholar
Song N, Li T. Regulation of NLRP3 Inflammasome by Phosphorylation. Front Immunol. 2018;9:2305.
PubMed PubMed Central Article Google Scholar
Servick K. Primed for pain. Science 2016;354:569–71.
CAS PubMed Article Google Scholar
Araldi D, Khomula EV, Ferrari LF, Levine JD. Fentanyl Induces Rapid Onset Hyperalgesic Priming: Type I at Peripheral and Type II at Central Nociceptor Terminals. J Neurosci. 2018;38:2226–45.
CAS PubMed PubMed Central Article Google Scholar
Chen Y, Moutal A, Navratilova E, Kopruszinski C, Yue X, Ikegami M, et al. The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females. Sci Transl Med. 2020;12:eaay7550.
CAS PubMed PubMed Central Article Google Scholar
Liu X, Bae C, Gelman B, Chung JM, Tang S-J Mechanism and role of astrogliosis in the pathogenesis of HIV-associated pain. bioRxiv 2021: 2021.2004.2028.441838.
Prescott SA, Sejnowski TJ, De, Koninck Y. Reduction of anion reversal potential subverts the inhibitory control of firing rate in spinal lamina I neurons: towards a biophysical basis for neuropathic pain. Mol Pain. 2006;2:32.
PubMed PubMed Central Article Google Scholar
Ahmadi S, Lippross S, Neuhuber WL, Zeilhofer HU. PGE(2) selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. Nat Neurosci. 2002;5:34–40.
CAS PubMed Article Google Scholar
Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, Woolf CJ. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci: Off J Soc Neurosci. 2002;22:6724–31.
Tsuda M, Kohro Y, Yano T, Tsujikawa T, Kitano J, Tozaki-Saitoh H, et al. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain. 2011;134:1127–39.
Ohmichi M, Ohmichi Y, Ohishi H, Yoshimoto T, Morimoto A, Li Y, et al. Activated spinal astrocytes are involved in the maintenance of chronic widespread mechanical hyperalgesia after cast immobilization. Mol. Pain. 2014;10:6.
Sasaki M, Kamiya Y, Bamba K, Onishi T, Matsuda K, Kohno T, et al. Serotonin Plays a Key Role in the Development of Opioid-Induced Hyperalgesia in Mice. J Pain. 2021;22:715–29.
Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35.
Kao S-C, Zhao X, Lee C-Y, Atianjoh FE, Gauda EB, Yaster M, et al. Absence of μ opioid receptor mRNA expression in astrocytes and microglia of rat spinal cord. Neuro Report. 2012;23:378–84. https://doi.org/10.1097/WNR.1090b1013e3283522e3283521b
Stiene-Martin A, Zhou R, Hauser KF. Regional, developmental, and cell cycle-dependent differences in mu, delta, and kappa-opioid receptor expression among cultured mouse astrocytes. Glia 1998;22:249–59.
CAS PubMed PubMed Central Article Google Scholar
Stiene-Martin A, Gurwell JA, Hauser KF. Morphine alters astrocyte growth in primary cultures of mouse glial cells: evidence for a direct effect of opiates on neural maturation. Brain Res Dev Brain Res. 1991;60:1–7.
CAS PubMed PubMed Central Article Google Scholar
Ikeda H, Miyatake M, Koshikawa N, Ochiai K, Yamada K, Kiss A, et al. Morphine modulation of thrombospondin levels in astrocytes and its implications for neurite outgrowth and synapse formation. J Biol Chem. 2010;285:38415–27.
CAS PubMed PubMed Central Article Google Scholar
Gong G, Hu L, Qin F, Yin L, Yi X, Yuan L, et al. Spinal WNT pathway contributes to remifentanil induced hyperalgesia through regulating fractalkine and CX3CR1 in rats. Neurosci Lett. 2016;633:21–27.
CAS PubMed Article Google Scholar
Nomachi A, Nishita M, Inaba D, Enomoto M, Hamasaki M, Minami Y. Receptor Tyrosine Kinase Ror2 Mediates Wnt5a-induced Polarized Cell Migration by Activating c-Jun N-terminal Kinase via Actin-binding Protein Filamin A. J Biol Chem. 2008;283:27973–81.
CAS PubMed Article Google Scholar
We are grateful for the productive discussion and insights from Dr. Ye Zhang. This work was supported by NIH grants R01NS079166 (SJT), R01DA036165 (SJT), R01NS095747 (SJT), 1R01DA050530 (SJT, JMC) and 1R01NS122571 (SJT). Subo Yuan participated in a part of behavioral testing experiments.
Stony Brook University Pain and Anesthesia Research Center (SPARC), Stony Brook University, Stony Brook, 11794, NY, USA
Xin Liu, Adriana DiBua, Livia Schutz, Martin Kaczocha, Michelino Puopolo & Shao-Jun Tang
Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, 11794, NY, USA
Xin Liu, Adriana DiBua, Livia Schutz, Martin Kaczocha, Michelino Puopolo & Shao-Jun Tang
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, 77555, TX, USA
Chilman Bae, Bolong Liu, Yong-Mei Zhang, Jin Mo Chung & Shao-Jun Tang
School of Electrical, Computer, and Biomedical Engineering, Southern Illinois University, Carbondale, 62901, IL, USA
Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 W Tianhe Rd, Guangzhou, 510630, China
Bolong Liu & Xiangfu Zhou
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu Province, China
Laboratory of Anesthesia & Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
Donghang Zhang & Cheng Zhou
Center for Cancer Research, Cancer and Developmental Biology Laboratory, Cell Signaling in Vertebrate Development Section, NCI-Frederick, NIH, Frederick, 21702, MD, USA
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
Experimental design: SJT. Data collection and analysis: XL, CB, BL, DZ, CZ, YZ, AD, LS, MK, MP. Providing critical reagents: TPY. Manuscript preparation: XL, SJT, XZ, JMC, TPY.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Springer Nature or its licensor 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.
Liu, X., Bae, C., Liu, B. et al. Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01815-0
DOI: https://doi.org/10.1038/s41380-022-01815-0
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
Molecular Psychiatry (Mol Psychiatry) ISSN 1476-5578 (online) ISSN 1359-4184 (print)