Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit

doi:10.1038/s41380-025-03113-x

. 2025 Jul 28.

doi: 10.1038/s41380-025-03113-x. Online ahead of print.

Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit

Mohammed H Sarikahya^{1

2

3}, Samantha L Cousineau⁴, Marta De Felice^{1

2

3}, Hanna J Szkudlarek^{1

2

3}, Kendrick Lee^{2

3

5

6}, Aleksandra Doktor⁴, Amanda Alcaide¹, Marieka V DeVuono^{1

2

3}, Anubha Dembla¹, Karen Wong^{1

2}, Mathanke Balarajah^{1

4}, Sebastian Vanin^{2

3

5

6}, Miray Youssef^{1

2

3}, Kuralay Zhaksylyk^{1

2

3}, Madeline Machado^{1

2

3}, Haseeb Mahmood^{1

2

3}, Susanne Schmid^{2

7}, Ken K-C Yeung⁴, Daniel B Hardy^{2

3

5

6}, Walter Rushlow^{1

2

8}, Steven R Laviolette^{9

10

11

12

13}

Affiliations

¹ Addiction Research Group, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.
² Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.
³ Lawson Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada.
⁴ Departments of Chemistry and Biochemistry, Western University, London, ON, N6A 3K7, Canada.
⁵ Departments of Physiology and Pharmacology, and Obstetrics and Gynecology, Western University, London, ON, N6A 5C1, Canada.
⁶ Children's Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada.
⁷ Department of Psychology, Western University, London, ON, N6A 3K7, Canada.
⁸ Department of Psychiatry, Western University, London, ON, N6A 3K7, Canada.
⁹ Addiction Research Group, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada. steven.laviolette@schulich.uwo.ca.
¹⁰ Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada. steven.laviolette@schulich.uwo.ca.
¹¹ Lawson Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada. steven.laviolette@schulich.uwo.ca.
¹² Department of Psychiatry, Western University, London, ON, N6A 3K7, Canada. steven.laviolette@schulich.uwo.ca.
¹³ Division of Maternal, Fetal and Newborn Health, Children's Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada. steven.laviolette@schulich.uwo.ca.

PMID: 40721894
DOI: 10.1038/s41380-025-03113-x

Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit

Mohammed H Sarikahya et al. Mol Psychiatry. 2025.

. 2025 Jul 28.

doi: 10.1038/s41380-025-03113-x. Online ahead of print.

Authors

Affiliations

¹ Addiction Research Group, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.
² Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.
³ Lawson Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada.
⁴ Departments of Chemistry and Biochemistry, Western University, London, ON, N6A 3K7, Canada.
⁵ Departments of Physiology and Pharmacology, and Obstetrics and Gynecology, Western University, London, ON, N6A 5C1, Canada.
⁶ Children's Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada.
⁷ Department of Psychology, Western University, London, ON, N6A 3K7, Canada.
⁸ Department of Psychiatry, Western University, London, ON, N6A 3K7, Canada.
⁹ Addiction Research Group, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada. steven.laviolette@schulich.uwo.ca.
¹⁰ Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada. steven.laviolette@schulich.uwo.ca.
¹¹ Lawson Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada. steven.laviolette@schulich.uwo.ca.
¹² Department of Psychiatry, Western University, London, ON, N6A 3K7, Canada. steven.laviolette@schulich.uwo.ca.
¹³ Division of Maternal, Fetal and Newborn Health, Children's Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada. steven.laviolette@schulich.uwo.ca.

PMID: 40721894
DOI: 10.1038/s41380-025-03113-x

Abstract

Prenatal Δ9-tetrahydrocannabinol exposure (PTE) poses long-lasting neuropsychiatric risks, as evidenced by clinical and preclinical studies, yet the neurobiological mechanisms remain poorly defined. Emerging evidence implicates the neurolipidome, a critical mediator of neurodevelopment and endocannabinoid signaling, as a potential contributor. Here, we demonstrate that dietary omega-3 fatty acid supplementation sex-selectively ameliorates neurodevelopmental deficits induced by PTE in a Wistar rat model. Omega-3 supplementation reduced cognitive and emotional disturbances in male offspring and normalized many neuronal and neurochemical abnormalities in the prefrontal cortex, nucleus accumbens, and ventral hippocampus. However, lipidomic analyses, regardless of omega-3 supplementation, uncovered pronounced, sex-specific PTE-induced disruptions in pathways critical for synaptic integrity and neurodevelopment, including those related to the endocannabinoid system. These findings provide new insights into the interplay between lipid metabolism and the endocannabinoid system in the context of PTE.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

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[1] Swenson K. Cannabis for morning sickness: areas for intervention to decrease Cannabis consumption during pregnancy. J Cannabis Res. 2023;5:22. - PubMed - PMC

[2] Swenson K. Cannabis for morning sickness: areas for intervention to decrease Cannabis consumption during pregnancy. J Cannabis Res. 2023;5:22. - PubMed - PMC

[3] 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. - PubMed - PMC

[4] 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. - PubMed - PMC

[5] Rava A, Trezza V. Emerging roles of endocannabinoids as key lipid mediators for a successful pregnancy. Int J Mol Sci. 2023;24:5220. - PubMed - PMC

[6] Rava A, Trezza V. Emerging roles of endocannabinoids as key lipid mediators for a successful pregnancy. Int J Mol Sci. 2023;24:5220. - PubMed - PMC

[7] Richardson KA, Hester AK, McLemore GL. Prenatal Cannabis exposure - the “first hit” to the endocannabinoid system. Neurotoxicol Teratol. 2016;58:5–14. - PubMed

[8] Richardson KA, Hester AK, McLemore GL. Prenatal Cannabis exposure - the “first hit” to the endocannabinoid system. Neurotoxicol Teratol. 2016;58:5–14. - PubMed

[9] Sarikahya MH, Cousineau SL, De Felice M, Szkudlarek HJ, Wong KKW, DeVuono MV, et al. Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network. Mol Psychiatry. 2023;28:4234–50. - PubMed

[10] Sarikahya MH, Cousineau SL, De Felice M, Szkudlarek HJ, Wong KKW, DeVuono MV, et al. Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network. Mol Psychiatry. 2023;28:4234–50. - PubMed

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Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit

Affiliations

Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit

Authors

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Abstract

Conflict of interest statement

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