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Impact of prenatal delta-9-tetrahydrocannabinol exposure on mouse brain development: a fetal-to-adulthood magnetic resonance imaging study

Molecular Psychiatry volume 31, pages 256–269 (2026)Cite this article

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Abstract

While cannabis use during pregnancy is often perceived as harmless, little is known about its consequences on offspring neurodevelopment. There is an urgent need to map the effects of prenatal cannabis exposure on the brain through the course of the lifespan. We used magnetic resonance imaging spanning nine timepoints, behavioral assays, and electron microscopy to build a trajectory from gestation to adulthood in mice exposed prenatally to delta-9-tetrahydrocannabinol (THC). Our results demonstrate a spatio-temporal patterning, with ventriculomegaly in THC-exposed embryos followed by a deceleration of brain growth in neonates that is sustained until adulthood, especially in females. We observed consistently impacted regions in both the cortex and subcortex, aligned with sex-dependent changes to social behavior in neonates and increased anxiety-like behavior in adolescents. Our results suggest prenatal THC exposure has a sustained sex-dependent impact on neurodevelopment that may persist into early adulthood.

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Fig. 1: Experimental timelines.
Fig. 2: Sample size and offspring growth.
Fig. 3: Brain results from MRI.
Fig. 4: Behavioral results in embryos and adolescents.
Fig. 5: Electron microscopy in embryo and neonate hippocampi.

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Data availability

Data are available at Zenodo: https://doi.org/10.5281/zenodo.13820977.

Code availability

Code is available on GitHub: https://github.com/lani1/pte_paper.

References

  1. LaSalle JM. Placenta keeps the score of maternal cannabis use and child anxiety. Proc Natl Acad Sci USA. 2021;118:e2118394118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chang JC, Tarr JA, Holland CL, De Genna NM, Richardson GA, Rodriguez KL, et al. Beliefs and attitudes regarding prenatal marijuana use: perspectives of pregnant women who report use. Drug Alcohol Depend. 2019;196:14–20.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Young-Wolff KC, Tucker L-Y, Alexeeff S, Armstrong MA, Conway A, Weisner C, et al. Trends in self-reported and biochemically tested marijuana use among pregnant females in California from 2009-2016. JAMA. 2017;318:2490–1.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Young-Wolff KC, Sarovar V, Tucker L-Y, Conway A, Alexeeff S, Weisner C, et al. Self-reported daily, weekly, and monthly cannabis use among women before and during pregnancy. JAMA Netw Open. 2019;2:e196471.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Young-Wolff KC, Sarovar V, Tucker L-Y, Ansley D, Goler N, Conway A, et al. Trends in cannabis polysubstance use during early pregnancy among patients in a large health care system in Northern California. JAMA Netw Open. 2022;5:e2215418.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Westfall RE, Janssen PA, Lucas P, Capler R. Survey of medicinal cannabis use among childbearing women: patterns of its use in pregnancy and retroactive self-assessment of its efficacy against ‘morning sickness’. Complement Ther Clin Pract. 2006;12:27–33.

    Article  PubMed  Google Scholar 

  7. Daniels S, St Pierre M, Sanchez T, Walsh Z. Physician communication and perceived stigma in prenatal cannabis use. J Psychoactive Drugs. 2023;55:290–8.

    Article  PubMed  Google Scholar 

  8. Latuskie KA, Andrews NCZ, Motz M, Leibson T, Austin Z, Ito S, et al. Reasons for substance use continuation and discontinuation during pregnancy: a qualitative study. Women Birth. 2019;32:e57–e64.

    Article  PubMed  Google Scholar 

  9. ElSohly MA, Chandra S, Radwan M, Majumdar CG, Church JC. A comprehensive review of cannabis potency in the United States in the last decade. Biol Psychiatry Cogn Neurosci Neuroimaging. 2021;6:603–6.

    PubMed  Google Scholar 

  10. ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in cannabis potency over the last 2 decades (1995-2014): analysis of current data in the United States. Biol Psychiatry. 2016;79:613–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Luzi S, Morrison PD, Powell J, di Forti M, Murray RM. What is the mechanism whereby cannabis use increases risk of psychosis? Neurotox Res. 2008;14:105–12.

    Article  PubMed  Google Scholar 

  12. Dellazizzo L, Potvin S, Giguère S, Dumais A. Evidence on the acute and residual neurocognitive effects of cannabis use in adolescents and adults: a systematic meta-review of meta-analyses. Addiction. 2022;117:1857–70.

    Article  PubMed  Google Scholar 

  13. Harkany T, Guzmán M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K. The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci. 2007;28:83–92.

    Article  CAS  PubMed  Google Scholar 

  14. Rock EM, Parker LA. Constituents of cannabis sativa. In: Murillo-Rodriguez E, Pandi-Perumal SR, Monti JM, editors. Cannabinoids and neuropsychiatric disorders. Cham: Springer International Publishing; 2021. p. 1–13.

    Google Scholar 

  15. Miranda CC, Barata T, Vaz SH, Ferreira C, Quintas A, Bekman EP. hiPSC-based model of prenatal exposure to cannabinoids: effect on neuronal differentiation. Front Mol Neurosci. 2020;13:119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Verdikt R, Armstrong AA, Cheng J, Hwang YS, Clark AT, Yang X, et al. Metabolic memory of Δ9-tetrahydrocannabinol exposure in pluripotent stem cells and primordial germ cells-like cells. eLife. 2023;12:RP88795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pham AL, Marquardt AE, Montgomery KR, Sobota KN, McCarthy MM, VanRyzin JW. Timing matters: modeling the effects of gestational cannabis exposure on social behavior and microglia in the developing amygdala. bioRxivorg. 2025.

  18. Tortoriello G, Morris CV, Alpar A, Fuzik J, Shirran SL, Calvigioni D, et al. Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J. 2014;33:668–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rompala G, Nomura Y, Hurd YL. Maternal cannabis use is associated with suppression of immune gene networks in placenta and increased anxiety phenotypes in offspring. Proc Natl Acad Sci USA. 2021;118:e2106115118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Paul SE, Hatoum AS, Fine JD, Johnson EC, Hansen I, Karcher NR, et al. Associations between prenatal cannabis exposure and childhood outcomes: results from the ABCD study. JAMA Psychiatry. 2021;78:64–76.

    Article  PubMed  Google Scholar 

  21. Goldschmidt L, Richardson GA, Cornelius MD, Day NL. Prenatal marijuana and alcohol exposure and academic achievement at age 10. Neurotoxicol Teratol. 2004;26:521–32.

    Article  CAS  PubMed  Google Scholar 

  22. Goldschmidt L, Richardson GA, Larkby C, Day NL. Early marijuana initiation: the link between prenatal marijuana exposure, early childhood behavior, and negative adult roles. Neurotoxicol Teratol. 2016;58:40–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Qiu LR, Fernandes DJ, Szulc-Lerch KU, Dazai J, Nieman BJ, Turnbull DH, et al. Mouse MRI shows brain areas relatively larger in males emerge before those larger in females. Nat Commun. 2018;9:2615.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bethlehem RAI, Seidlitz J, White SR, Vogel JW, Anderson KM, Adamson C, et al. Brain charts for the human lifespan. Nature. 2022;604:525–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ge R, Yu Y, Qi YX, Fan Y-N, Chen S, Gao C, Haas SS, New F, Boomsma DI, Brodaty H, et al. Normative modelling of brain morphometry across the lifespan with CentileBrain: algorithm benchmarking and model optimisation. The Lancet. Digital health. 2024;6:e211–21.

  26. Guma E, Cupo L, Ma W, Gallino D, Moquin L, Gratton A, et al. Investigating the ‘two-hit hypothesis’: effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2023;120:110642.

    Article  CAS  PubMed  Google Scholar 

  27. Guma E, do Bordignon PC, Devenyi GA, Gallino D, Anastassiadis C, Cvetkovska V, et al. Early or late gestational exposure to maternal immune activation alters neurodevelopmental trajectories in mice: an integrated neuroimaging, behavioural, and transcriptional study. Biol Psychiatry. 2021;90:328–41. https://doi.org/10.1016/j.biopsych.2021.03.017

    Article  CAS  PubMed  Google Scholar 

  28. Valiquette V, Guma E, Cupo L, Gallino D, Anastassiadis C, Snook E, et al. Examining litter specific variability in mice and its impact on neurodevelopmental studies. Neuroimage. 2023;269:119888.

    Article  PubMed  Google Scholar 

  29. Bara A, Manduca A, Bernabeu A, Borsoi M, Serviado M, Lassalle O, et al. Sex-dependent effects of in utero cannabinoid exposure on cortical function. eLife. 2018;7:e36234.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bisht K, Sharma KP, Lecours C, Sánchez MG, El Hajj H, Milior G, et al. Dark microglia: a new phenotype predominantly associated with pathological states. Glia. 2016;64:826–39.

    Article  PubMed  PubMed Central  Google Scholar 

  31. El Marroun H, Tiemeier H, Steegers EAP, Jaddoe VWV, Hofman A, Verhulst FC, et al. Intrauterine cannabis exposure affects fetal growth trajectories: the generation R study. J Am Acad Child Adolesc Psychiatry. 2009;48:1173–81.

    Article  PubMed  Google Scholar 

  32. Longo S, Bollani L, Decembrino L, Di Comite A, Angelini M, Stronati M. Short-term and long-term sequelae in intrauterine growth retardation (IUGR). J Matern Fetal Neonatal Med. 2013;26:222–5.

    Article  CAS  PubMed  Google Scholar 

  33. Guma E, Bordeleau M, González Ibáñez F, Picard K, Snook E, Desrosiers-Grégoire G, et al. Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment. Proc Natl Acad Sci USA. 2022;119:e2114545119. https://doi.org/10.1073/pnas.2114545119. Accessed 12 April 2022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lerch JP, Gazdzinski L, Germann J, Sled JG, Henkelman RM, Nieman BJ. Wanted dead or alive? The tradeoff between in-vivo versus ex-vivo MR brain imaging in the mouse. Front Neuroinform. 2012;6:6.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Tirado-Muñoz J, Lopez-Rodriguez AB, Fonseca F, Farré M, Torrens M, Viveros M-P. Effects of cannabis exposure in the prenatal and adolescent periods: preclinical and clinical studies in both sexes. Front Neuroendocrinol. 2020;57:100841.

    Article  PubMed  Google Scholar 

  36. Zhou X, Wodtke GT. A regression-with-residuals method for estimating controlled direct effects. Polit Anal. 2019;27:360–9.

    Article  Google Scholar 

  37. Kong V, Devenyi GA, Gallino D, Ayranci G, Germann J, Rollins C, et al. Early-in-life neuroanatomical and behavioural trajectories in a triple transgenic model of Alzheimer’s disease. Brain Struct Funct. 2018;223:3365–82.

    Article  PubMed  Google Scholar 

  38. Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, et al. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA. 2004;101:8174–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shaw P, Malek M, Watson B, Greenstein D, de Rossi P, Sharp W. Trajectories of cerebral cortical development in childhood and adolescence and adult attention-deficit/hyperactivity disorder. Biol Psychiatry. 2013;74:599–606.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Raznahan A, Lerch JP, Lee N, Greenstein D, Wallace GL, Stockman M, et al. Patterns of coordinated anatomical change in human cortical development: a longitudinal neuroimaging study of maturational coupling. Neuron. 2011;72:873–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Trezza V, Campolongo P, Cassano T, Macheda T, Dipasquale P, Carratù MR, et al. Effects of perinatal exposure to delta-9-tetrahydrocannabinol on the emotional reactivity of the offspring: a longitudinal behavioral study in Wistar rats. Psychopharmacology (Berl). 2008;198:529–37.

    Article  CAS  PubMed  Google Scholar 

  42. Lallai V, Manca L, Sherafat Y, Fowler CD. Effects of prenatal nicotine, THC, or Co-exposure on cognitive behaviors in adolescent male and female rats. Nicotine Tob Res. 2022;24:1150–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rubio P, de Fonseca FR, Muñoz RM, Ariznavarreta C, Martin-Calderón JL, Navarro M. Long-term behavioral effects of perinatal exposure to Δ9-tetrahydrocannabinol in rats: possible role of pituitaryadrenal axis. Life Sci. 1995;56:2169–76.

    Article  CAS  PubMed  Google Scholar 

  44. Navarro M, Rubio P, Rodríguez de Fonseca F. Sex-dimorphic psychomotor activation after perinatal exposure to (-)-delta 9-tetrahydrocannabinol. An ontogenic study in Wistar rats. Psychopharmacology (Berl). 1994;116:414–22.

    Article  CAS  PubMed  Google Scholar 

  45. Fine JD, Moreau AL, Karcher NR, Agrawal A, Rogers CE, Barch DM, et al. Association of prenatal cannabis exposure with psychosis proneness among children in the adolescent brain cognitive development (ABCD) study. JAMA Psychiatry. 2019;76:762–4.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Geyer MA. The family of sensorimotor gating disorders: comorbidities or diagnostic overlaps? Neurotox Res. 2006;10:211–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Swerdlow NR, Braff DL, Geyer MA. Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next. J Psychopharmacol. 2016;30:1072–81.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Swerdlow NR, Braff DL, Taaid N, Geyer MA. Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry. 1994;51:139–54.

    Article  CAS  PubMed  Google Scholar 

  49. Sagheddu C, Traccis F, Serra V, Congiu M, Frau R, Cheer JF, et al. Mesolimbic dopamine dysregulation as a signature of information processing deficits imposed by prenatal THC exposure. Prog Neuropsychopharmacol Biol Psychiatry. 2021;105:110128.

    Article  CAS  PubMed  Google Scholar 

  50. Bortolato M, Frau R, Orrù M, Casti A, Aru GN, Fà M, et al. Prenatal exposure to a cannabinoid receptor agonist does not affect sensorimotor gating in rats. Eur J Pharmacol. 2006;531:166–70.

    Article  CAS  PubMed  Google Scholar 

  51. Scattoni ML, Crawley J, Ricceri L. Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders. Neurosci Biobehav Rev. 2009;33:508–15.

    Article  PubMed  Google Scholar 

  52. Rousselet GA, Pernet CR, Wilcox RR. Beyond differences in means: robust graphical methods to compare two groups in neuroscience. Eur J Neurosci. 2017;46:1738–48.

    Article  PubMed  Google Scholar 

  53. Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol. 2003;463:3–33.

    Article  CAS  PubMed  Google Scholar 

  54. Berghuis P, Rajnicek AM, Morozov YM, Ross RA, Mulder J, Urbán GM, et al. Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science. 2007;316:1212–6.

    Article  CAS  PubMed  Google Scholar 

  55. Puighermanal E, Marsicano G, Busquets-Garcia A, Lutz B, Maldonado R, Ozaita A. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nat Neurosci. 2009;12:1152–8.

    Article  CAS  PubMed  Google Scholar 

  56. Tanimura A, Yamazaki M, Hashimotodani Y, Uchigashima M, Kawata S, Abe M, et al. The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission. Neuron. 2010;65:320–7.

    Article  CAS  PubMed  Google Scholar 

  57. Gunn JKL, Rosales CB, Center KE, Nuñez A, Gibson SJ, Christ C, et al. Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open. 2016;6:e009986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gray TR, Eiden RD, Leonard KE, Connors GJ, Shisler S, Huestis MA. Identifying prenatal cannabis exposure and effects of concurrent tobacco exposure on neonatal growth. Clin Chem. 2010;56:1442–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Benevenuto SG, Domenico MD, Martins MAG, Costa NS, de Souza ARL, Costa JL, et al. Recreational use of marijuana during pregnancy and negative gestational and fetal outcomes: an experimental study in mice. Toxicology. 2017;376:94–101.

    Article  CAS  PubMed  Google Scholar 

  60. Gillies R, Lee K, Vanin S, Laviolette SR, Holloway AC, Arany E, et al. Maternal exposure to Δ9-tetrahydrocannabinol impairs female offspring glucose homeostasis and endocrine pancreatic development in the rat. Reprod Toxicol. 2020;94:84–91.

    Article  CAS  PubMed  Google Scholar 

  61. Natale BV, Gustin KN, Lee K, Holloway AC, Laviolette SR, Natale DRC, et al. Δ9-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta. Sci Rep. 2020;10:544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Roeder NM, Penman SL, Richardson BJ, Wang J, Freeman-Striegel L, Khan A, et al. Vaporized Δ-9THC in utero results in reduced birthweight, increased locomotion, and altered wake-cycle activity dependent on dose, sex, and diet in the offspring. Life Sci. 2024;340:122447.

    Article  CAS  PubMed  Google Scholar 

  63. Hume C, Baglot SL, Javorcikova L, Lightfoot SHM, Scheufen J, Hill MN. Effects of prenatal THC vapor exposure on body weight, glucose metabolism, and feeding behaviors in chow and high-fat diet fed rats. Int J Obes. 2024:48:981–92.

  64. Oke SL, Lee K, Papp R, Laviolette SR, Hardy DB. In utero exposure to Δ9-tetrahydrocannabinol leads to postnatal catch-up growth and dysmetabolism in the adult rat liver. Int J Mol Sci. 2021;22:7502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. van Wyk L, Boers KE, van Wassenaer-Leemhuis AG. Post-natal catch-up growth after suspected IUGR at term. American journal of obstetrics and gynecology. 208. New York, NY USA: MOSBY-Elsevier 360 Park Avenue South; 2013. p. 10010–1710. OthersS69–S69

    Google Scholar 

  66. Moore BF, Sauder KA, Shapiro ALB, Crume T, Kinney GL, Dabelea D. Fetal exposure to cannabis and childhood metabolic outcomes: the healthy start study. J Clin Endocrinol Metab. 2022;107:e2862–e2869.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Lee K, Hardy DB. Metabolic consequences of gestational cannabinoid exposure. Int J Mol Sci. 2021;22:9528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ong WY, Mackie K. A light and electron microscopic study of the CB1 cannabinoid receptor in primate brain. Neuroscience. 1999;92:1177–91.

    Article  CAS  PubMed  Google Scholar 

  69. Miederer I, Wiegand V, Bausbacher N, Leukel P, Maus S, Hoffmann MA, et al. Quantification of the cannabinoid type 1 receptor availability in the mouse brain. Front Neuroanat. 2020;14:593793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wu C-S, Zhu J, Wager-Miller J, Wang S, O’Leary D, Monory K, et al. Requirement of cannabinoid CB(1) receptors in cortical pyramidal neurons for appropriate development of corticothalamic and thalamocortical projections: CB1R in the development of sensory networks. Eur J Neurosci. 2010;32:693–706.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Cardinal P, Bellocchio L, Clark S, Cannich A, Klugmann M, Lutz B, et al. Hypothalamic CB1 cannabinoid receptors regulate energy balance in mice. Endocrinology. 2012;153:4136–43.

    Article  CAS  PubMed  Google Scholar 

  72. Tang J, Chen Q, Guo J, Yang L, Tao Y, Li L, et al. Minocycline attenuates neonatal germinal-matrix-hemorrhage-induced neuroinflammation and brain edema by activating cannabinoid receptor 2. Mol Neurobiol. 2016;53:1935–48.

    Article  CAS  PubMed  Google Scholar 

  73. Morales P, Guerrero-Alba R, Marichal-Cancino BA Linking the G-protein-coupled receptor 55 (GPR55) to the cannabinoid receptors (CB1 and CB2): a new narrative. Cannabis Use, Neurobiology, Psychology, and Treatment. United Kingdom: Elsevier; 2023. p. 395–406.

  74. Muller C, Morales P, Reggio PH. Cannabinoid ligands targeting TRP channels. Front Mol Neurosci. 2018;11:487.

    Article  CAS  PubMed  Google Scholar 

  75. O’Sullivan SE. An update on PPAR activation by cannabinoids: cannabinoids and PPARs. Br J Pharmacol. 2016;173:1899–910.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Rodrigues RJ, Marques JM, Köfalvi A. Cannabis, endocannabinoids and brain development: from embryogenesis to adolescence. Cells. 2024;13:1875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Alpár A, Tortoriello G, Calvigioni D, Niphakis MJ, Milenkovic I, Bakker J, et al. Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. Nat Commun. 2014;5:4421.

    Article  PubMed  Google Scholar 

  78. Díaz-Alonso J, Guzmán M, Galve-Roperh I. Endocannabinoids via CB1 receptors act as neurogenic niche cues during cortical development. Philos Trans R Soc Lond B Biol Sci. 2012;367:3229–41.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Portfors CV. Types and functions of ultrasonic vocalizations in laboratory rats and mice. J Am Assoc Lab Anim Sci. 2007;46:28–34.

    CAS  PubMed  Google Scholar 

  80. Caruso A, Ricceri L, Scattoni ML. Ultrasonic vocalizations as a fundamental tool for early and adult behavioral phenotyping of autism spectrum disorder rodent models. Neurosci Biobehav Rev. 2020;116:31–43.

    Article  PubMed  Google Scholar 

  81. Iezzi D, Caceres-Rodriguez A, Chavis P, Manzoni OJJ. In utero exposure to cannabidiol disrupts select early-life behaviors in a sex-specific manner. Transl Psychiatry. 2022;12:501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Weimar HV, Wright HR, Warrick CR, Brown AM, Lugo JM, Freels TG, et al. Long-term effects of maternal cannabis vapor exposure on emotional reactivity, social behavior, and behavioral flexibility in offspring. Neuropharmacology. 2020;179:108288.

    Article  CAS  PubMed  Google Scholar 

  83. Moreno M, Escuredo L, Muñoz R, Rodriguez de Fonseca F, Navarro M. Long-term behavioural and neuroendocrine effects of perinatal activation or blockade of CB1 cannabinoid receptors. Behav Pharmacol. 2005;16:423–30.

    Article  CAS  PubMed  Google Scholar 

  84. Hussain S, Breit KR, Thomas JD. The effects of prenatal nicotine and THC E-cigarette exposure on motor development in rats. Psychopharmacology (Berl). 2022;239:1579–91.

    Article  CAS  PubMed  Google Scholar 

  85. Frau R, Miczán V, Traccis F, Aroni S, Pongor CI. Prenatal THC produces a hyperdopaminergic phenotype accompanied by maladaptive behavioral susceptibility. Nat Neurosci. 2019;22:1975–85.

  86. Persson A, Sim SC, Virding S, Onishchenko N, Schulte G, Ingelman-Sundberg M. Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Mol Psychiatry. 2014;19:733–41.

    Article  CAS  PubMed  Google Scholar 

  87. Marek S, Tervo-Clemmens B, Calabro FJ, Montez DF, Kay BP, Hatoum AS, et al. Reproducible brain-wide association studies require thousands of individuals. Nature. 2022;603:654–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wu C-S, Jew CP, Lu H-C. Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain. Future Neurol. 2011;6:459–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Calvigioni D, Hurd YL, Harkany T, Keimpema E. Neuronal substrates and functional consequences of prenatal cannabis exposure. Eur Child Adolesc Psychiatry. 2014;23:931–41.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Cohen-Bendahan CCC, van de Beek C, Berenbaum SA. Prenatal sex hormone effects on child and adult sex-typed behavior: methods and findings. Neurosci Biobehav Rev. 2005;29:353–84.

    Article  CAS  PubMed  Google Scholar 

  91. Spindle TR, Bonn-Miller MO, Vandrey R. Changing landscape of cannabis: novel products, formulations, and methods of administration. Curr Opin Psychol. 2019;30:98–102.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Baglot SL, Hume C, Petrie GN, Aukema RJ, Lightfoot SHM, Grace LM, et al. Pharmacokinetics and central accumulation of delta-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats. Sci Rep. 2021;11:23990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Baglot SL, VanRyzin JW, Marquardt AE, Aukema RJ, Petrie GN, Hume C, et al. Maternal-fetal transmission of delta-9-tetrahydrocannabinol (THC) and its metabolites following inhalation and injection exposure during pregnancy in rats. J Neurosci Res. 2022;100:713–30.

    Article  CAS  PubMed  Google Scholar 

  94. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4:1770–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sommano SR, Chittasupho C, Ruksiriwanich W, Jantrawut P. The cannabis terpenes. Molecules. 2020;25:5792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cash MC, Cunnane K, Fan C, Romero-Sandoval EA. Mapping cannabis potency in medical and recreational programs in the United States. PLoS ONE. 2020;15:e0230167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Sturman O, Germain P-L, Bohacek J. Exploratory rearing: a context- and stress-sensitive behavior recorded in the open-field test. Stress. 2018;21:443–52.

    Article  PubMed  Google Scholar 

  98. Branchi I, Santucci D, Vitale A, Alleva E. Ultrasonic vocalizations by infant laboratory mice: a preliminary spectrographic characterization under different conditions. Dev Psychobiol. 1998;33:249–56.

    Article  CAS  PubMed  Google Scholar 

  99. Helmer M, Warrington S, Mohammadi-Nejad A-R, Ji JL, Howell A, Rosand B, et al. On the stability of canonical correlation analysis and partial least squares with application to brain-behavior associations. Commun Biol. 2024;7:217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Dinieri JA, Hurd YL. Rat models of prenatal and adolescent cannabis exposure. Methods Mol Biol. 2012;829:231–42.

    Article  CAS  PubMed  Google Scholar 

  101. Drazanova E, Ruda-Kucerova J, Kratka L, Stark T, Kuchar M, Maryska M, et al. Different effects of prenatal MAM vs. perinatal THC exposure on regional cerebral blood perfusion detected by arterial spin labelling MRI in rats. Sci Rep. 2019;9:6062.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Huang S, Liu C, Dai G, Kim YR, Rosen BR. Manipulation of tissue contrast using contrast agents for enhanced MR microscopy in ex vivo mouse brain. Neuroimage. 2009;46:589.

    Article  PubMed  Google Scholar 

  103. Nieman BJ, Bock NA, Bishop J, Chen XJ, Sled JG, Rossant J, et al. Magnetic resonance imaging for detection and analysis of mouse phenotypes. NMR Biomed. 2005;18:447–68.

    Article  PubMed  Google Scholar 

  104. Wadghiri YZ, Blind JA, Duan X, Moreno C, Yu X, Joyner AL, et al. Manganese-enhanced magnetic resonance imaging (MEMRI) of mouse brain development. NMR Biomed. 2004;17:613–9.

    Article  CAS  PubMed  Google Scholar 

  105. Szulc A, Galińska B, Tarasów E, Kubas B, Czernikiewicz A, Dzienis W, et al. Glutamatergic system dysfunction in schizophrenia. A proton magnetic resonance spectroscopy (1H MRS) study. Ann Transplant. 2004;69:33–36.

    Google Scholar 

  106. Rollins CPE, Gallino D, Kong V, Ayranci G, Devenyi GA, Germann J, et al. Contributions of a high-fat diet to Alzheimer’s disease-related decline: a longitudinal behavioural and structural neuroimaging study in mouse models. Neuroimage Clin. 2019;21:101606.

    Article  PubMed  Google Scholar 

  107. Szulc KU, Lerch JP, Nieman BJ, Bartelle BB, Friedel M, Suero-Abreu GA, et al. 4D MEMRI atlas of neonatal FVB/N mouse brain development. Neuroimage. 2015;118:49–62.

    Article  PubMed  Google Scholar 

  108. Sarkar A, Balogun K, Guzman Lenis MS, Acosta S, Mount HT, Serghides L. In utero exposure to protease inhibitor-based antiretroviral regimens delays growth and developmental milestones in mice. PLoS ONE. 2020;15:e0242513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tamashiro KL, Wakayama T, Blanchard RJ, Blanchard DC, Yanagimachi R. Postnatal growth and behavioral development of mice cloned from adult cumulus cells. Biol Reprod. 2000;63:328–34.

    Article  CAS  PubMed  Google Scholar 

  110. Anthwal N, Thompson H. The development of the mammalian outer and middle ear. J Anat. 2016;228:217–32.

    Article  PubMed  Google Scholar 

  111. Demaestri C, Pan T, Critz M, Ofray D, Gallo M, Bath KG. Type of early life adversity confers differential, sex-dependent effects on early maturational milestones in mice. Horm Behav. 2020;124:104763.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Deacon RMJ. Assessing nest building in mice. Nat Protoc. 2006;1:1117–9.

    Article  PubMed  Google Scholar 

  113. Spencer Noakes TL, Henkelman RM, Nieman BJ Partitioning k-space for cylindrical three-dimensional rapid acquisition with relaxation enhancement imaging in the mouse brain. NMR Biomed. 2017;30:e3802.

  114. Germann J, Gouveia FV, Chakravarty MM, Devenyi GA. Longitudinal deformation-based morphometry pipeline to study neuroanatomical differences in structural MRI based on SyN unbiased templates. Aperture Neuro. 2025 [accessed 2025 Aug 25];5. https://doi.org/10.52294/001c.133510.

  115. Avants BB, Tustison NJ, Song G, Cook PA, Klein A, Gee JC. A reproducible evaluation of ANTs similarity metric performance in brain image registration. Neuroimage. 2011;54:2033–44.

    Article  PubMed  Google Scholar 

  116. Chung MK, Worsley KJ, Paus T, Cherif C, Collins DL, Giedd JN, et al. A unified statistical approach to deformation-based morphometry. Neuroimage. 2001;14:595–606.

    Article  CAS  PubMed  Google Scholar 

  117. Friedel M, van Eede MC, Pipitone J, Chakravarty MM, Lerch JP. Pydpiper: a flexible toolkit for constructing novel registration pipelines. Front Neuroinform. 2014;8:67.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Leow AD, Yanovsky I, Chiang M-C, Lee AD, Klunder AD, Lu A, et al. Statistical properties of Jacobian maps and the realization of unbiased large-deformation nonlinear image registration. IEEE Trans Med Imaging. 2007;26:822–32.

    Article  PubMed  Google Scholar 

  119. Schambra U. Prenatal mouse brain atlas: color images and annotated diagrams of: gestational days 12, 14, 16 and 18 sagittal, coronal and horizontal section. London: Springer Science & Business Media; 2008.

  120. Guma E, Snook E, Spring S, Lerch JP, Nieman BJ, Devenyi GA, et al. Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation in mice. Neuroimage Clin. 2021;32:102868.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Baharnoori M, Bhardwaj SK, Srivastava LK. Neonatal behavioral changes in rats with gestational exposure to lipopolysaccharide: a prenatal infection model for developmental neuropsychiatric disorders. Schizophr Bull. 2012;38:444–56.

    Article  PubMed  Google Scholar 

  122. Fernández de Cossío L, Guzmán A, van der Veldt S, Luheshi GN. Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring. Brain Behav Immun. 2017;63:88–98.

    Article  PubMed  Google Scholar 

  123. St-Pierre M-K, Bordeleau M, Tremblay M-È. Visualizing dark microglia. Methods Mol Biol. 2019;2034:97–110.

    Article  CAS  PubMed  Google Scholar 

  124. Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7:16878.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Toné S, Sugimoto K, Tanda K, Suda T, Uehira K, Kanouchi H, et al. Three distinct stages of apoptotic nuclear condensation revealed by time-lapse imaging, biochemical and electron microscopy analysis of cell-free apoptosis. Exp Cell Res. 2007;313:3635–44.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Barnicot NA, Huxley HE. Electron microscope observations on mitotic chromosomes. J Cell Sci. 1965;s3-106:197–214.

    Article  Google Scholar 

  127. Rieder CL, Khodjakov A. Mitosis through the microscope: advances in seeing inside live dividing cells. Science. 2003;300:91–96.

    Article  CAS  PubMed  Google Scholar 

  128. The fine structure of the nervous system: the neurons and supporting cells. CABI databases. https://www.cabidigitallibrary.org/doi/full/10.5555/19772293042. Accessed 18 October 2024.

  129. St-Pierre M-K, Šimončičová E, Bögi E, Tremblay M-È. Shedding light on the dark side of the microglia. ASN Neuro. 2020;12:1759091420925335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Vecchiarelli HA, Bisht K, Sharma KP, Novak SW, Traetta ME, Garcia-Segura ME, et al. Dark microglia are abundant in normal postnatal development, where they remodel synapses via phagocytosis and trogocytosis, and are dependent on TREM2. bioRxiv. 2024:2024.

  131. Harrison XA, Donaldson L, Correa-Cano ME, Evans J, Fisher DN, Goodwin CED, et al. A brief introduction to mixed effects modelling and multi-model inference in ecology. PeerJ. 2018;6:e4794.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Businelli C, de Wit C, Visser GHA, Pistorius LR. Ultrasound evaluation of cortical brain development in fetuses with intrauterine growth restriction. J Matern Fetal Neonatal Med. 2015;28:1302–7.

    Article  PubMed  Google Scholar 

  133. Harrell FE, Davis CE. A new distribution-free quantile estimator. Biometrika. 1982;69:635.

    Article  Google Scholar 

  134. Hochberg Y. A sharper bonferroni procedure for multiple tests of significance. Biometrika. 1988;75:800–2.

    Article  Google Scholar 

  135. Dorr AE, Lerch JP, Spring S, Kabani N, Henkelman RM. High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice. Neuroimage. 2008;42:60–69.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. McGill University, Department of Psychiatry, Montréal, QC, Canada

    Lani Cupo, Annie Phan, Gabriel A. Devenyi & M. Mallar Chakravarty

  2. Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Centre, Douglas Research Centre, Verdun, QC, Canada

    Lani Cupo, Daniel Gallino, Katerina Bradshaw, Annie Phan, Gabriel A. Devenyi & M. Mallar Chakravarty

  3. School of Medical Sciences, Faculty of Health, University of Victoria, Victoria, BC, Canada

    Haley A. Vecchiarelli, Jared VanderZwaag, Mohammadparsa Khakpour, Benneth Ben-Azu & Marie-Eve Tremblay

  4. Cerebral Imaging Centre, Douglas Research Centre, Verdun, QC, Canada

    Daniel Gallino, Jérémie P. Fouquet, Gabriel A. Devenyi & M. Mallar Chakravarty

  5. DELSU Joint Canada-Israel Neuroscience and Biopsychiatry Laboratory, Department of Pharmacology, Faculty of Basic Medical Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria

    Benneth Ben-Azu

  6. Department of Pediatrics, Lurie Center for Autism, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA

    Elisa Guma

  7. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Elisa Guma

  8. Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada

    Shoshana Spring & Brian J. Nieman

  9. Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada

    Shoshana Spring & Brian J. Nieman

  10. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Brian J. Nieman

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  1. Lani Cupo
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  2. Haley A. Vecchiarelli
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Contributions

LC, HAV, DG, JVZ, KB, AP, MK, BB-A, and SS were involved in acquisition, analysis, and interpretation of the study data; LC, EG, JPF, M-ET, GAD, and MMC were involved in the conception and design of the study and analysis and interpretation of the study data; BJN, M-ET, and MMC supervised the research; LC wrote the initial manuscript draft; all authors contributed to reviewing and editing of the manuscript.

Corresponding author

Correspondence to Lani Cupo.

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All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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All methods were performed in accordance with the relevant guidelines and regulations. Approval was obtained from the Douglas Facility Animal Care Committee under the Animal Use Protocol 8181.

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Cupo, L., Vecchiarelli, H.A., Gallino, D. et al. Impact of prenatal delta-9-tetrahydrocannabinol exposure on mouse brain development: a fetal-to-adulthood magnetic resonance imaging study. Mol Psychiatry 31, 256–269 (2026). https://doi.org/10.1038/s41380-025-03189-5

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