Chronic nicotine exposure induces molecular and transcriptomic endophenotypes associated with mood and anxiety disorders in a cerebral organoid neurodevelopmental model

Emma K Proud; Mar Rodríguez-Ruiz; Dana M Gummerson; Sebastian Vanin; Daniel B Hardy; Walter J Rushlow; Steven R Laviolette

doi:10.3389/fphar.2024.1473213

Chronic nicotine exposure induces molecular and transcriptomic endophenotypes associated with mood and anxiety disorders in a cerebral organoid neurodevelopmental model

Front Pharmacol. 2024 Dec 23:15:1473213. doi: 10.3389/fphar.2024.1473213. eCollection 2024.

Authors

Emma K Proud^{1

2

3}, Mar Rodríguez-Ruiz^{1

2

3}, Dana M Gummerson^{1

2

3}, Sebastian Vanin⁴, Daniel B Hardy^{4

5

6}, Walter J Rushlow^{1

2

7}, Steven R Laviolette^{1

2

3

7}

Affiliations

¹ Addiction Research Group, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
² Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada.
³ St. Jopsephs Health Care, Lawson Health Research Institute, London, ON, Canada.
⁴ Department of Physiology and Pharmacology, Western University, London, ON, Canada.
⁵ Department of Obstetrics and Gynecology, Western University, London, ON, Canada.
⁶ St. Josephs Healthcare, Children's Health Research Institute, London, ON, Canada.
⁷ Department of Psychiatry, University of Western Ontario, London, ON, Canada.

Abstract

Introduction: Prenatal nicotine exposure (PNE) from maternal smoking disrupts regulatory processes vital to fetal development. These changes result in long-term behavioral impairments, including mood and anxiety disorders, that manifest later in life. However, the relationship underlying PNE, and the underpinnings of mood and anxiety molecular and transcriptomic phenotypes remains elusive.

Methods: To model nicotine exposure during prenatal development, our study used human cerebral organoids that were chronically exposed to nicotine and collected for molecular analyses.

Results: Short-term, nicotine altered molecular markers of neural identity, mood and anxiety disorders and those involved in maintaining the excitatory/inhibitory (E/I) balance in the cortex. RNA sequencing further revealed transcriptomic changes in genes pertaining to embryonic development, neurogenesis, and DNA binding. Long-term, mature organoids demonstrated similar disruptions in E/I balance, decreased expression of neural identity markers, and altered dopamine receptor expression.

Discussion: Collectively, our results demonstrate that nicotine-induced alterations occur acutely and persist at later stages of development. These findings validate an in vitro model of PNE to better comprehend the emergence of neuropsychiatric molecular and transcriptomic endophenotypes resulting from gestational nicotine exposure.

Keywords: anxiety; depression; human cerebral organoids; prenatal development; prenatal nicotine exposure.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Canadian Institutes of Health Research (MOP-189943) and a Natural Science and Engineering Research Council Graduate Fellowship to EP and DG.