Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

Laviolette, Steven R.

Abstract

Prenatal nicotine exposure (PNE) from maternal smoking disrupts regulatory processes vital to fetal development. These changes result in long-term behavioural impairments, including mood and anxiety disorders, that manifest later in life. However the relationship underlying PNE, and the underpinnings of mood/anxiety molecular phenotypes remains elusive. To model nicotine exposure during prenatal development, our study used human cerebral organoids that were chronically exposed to nicotine and collected for molecular analyses. Short-term, nicotine altered molecular markers of neural identity, mood/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. Collectively, our results demonstrated that nicotine altered E/I balance, dopamine receptor expression and changes in neural identity markers that persist into later stages of development. These findings validate an in vitro model of PNE to better comprehend the emergence of neuropsychiatric molecular phenotypes resulting from gestational nicotine exposure.

Summary for Lay Audience

In recent years, there has been a rise in nicotine vaping among women of reproductive age due to the misconception that vaping is safer than smoking traditional cigarettes. Yet, vapes contain higher doses of nicotine that pass through the placental barrier and affect the brain of the developing fetus. Previous research suggests that prenatal nicotine exposure (PNE) can negatively impact many important processes vital to fetal development and can cause long-lasting changes in brain regions associated with mood and anxiety control. Clinical studies indicate that the children of mothers who smoke nicotine during pregnancy have a much higher likelihood of developing anxiety and depression later in life. However, the mechanism underlying PNE, and the emergence of these neuropsychiatric disorders is not well understood. To overcome the limitations of other human and animal-based models, our project uses human cerebral organoids to further investigate this relationship. Cerebral organoids are tiny, lab-grown, brains created from reprogrammed human skin cells. They contain similar structures and cell types found in the prenatal human brain and are a great model to study the effect of gestational drug exposure, such as PNE, on the developing brain. Cerebral organoids were treated with one of three doses of nicotine or no nicotine, for 14 days, and collected immediately following nicotine exposure and at 6 months. The collected organoids underwent various molecular experiments to examine nicotine-induced changes in cortical development, markers linked to mood and anxiety disorders and changes in gene expression. We found that immediately following nicotine exposure, there are changes in markers of neural identity, mood/anxiety disorders (nicotinic acetylcholine and dopamine receptors) and markers associated with maintaining the excitatory/inhibitory (E/I) balance in the cortex. RNA sequencing also revealed transcriptomic changes in genes pertaining to embryonic development, neurogenesis, and DNA binding. Mature organoids show similar disruptions in E/I balance, decreased neural identity markers and altered dopamine receptor expression. Altogether, these findings validate an in vitro model of PNE to better comprehend the emergence of neuropsychiatric molecular phenotypes later in development resulting from chronic nicotine exposure.

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