Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Neuroscience
Supervisor
Laviolette, Steven R.
Affiliation
Anatomy and Cell Biology
Abstract
Prenatal exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, poses significant neurodevelopmental risks. Extensive research, encompassing preclinical models and epidemiological analyses, consistently demonstrates the adverse outcomes associated with prenatal cannabinoid exposure (PCE). The endocannabinoid system (ECS), particularly within the mesocorticolimbic circuit, is critical for cognitive and emotional regulation. PCE-induced disruptions in ECS signaling can dysregulate neurotransmitter activity, notably within GABAergic, glutamatergic, and dopaminergic systems, heightening the risk of psychiatric disorders. Moreover, PCE is linked to symmetrical fetal growth restriction (FGR) due to compromised placental function, leading to reduced nutrient and oxygen delivery to the fetus, thereby impairing brain development. The resulting insufficiency in placental transfer of essential polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and arachidonic acid (AA), both critical for ECS function, exacerbates these neurodevelopmental disturbances. We hypothesized that PCE leads to disturbances in gestational brain development, resulting in abnormal neurocognition and altered neural fatty acid profiles in later life. We employed a comprehensive set of tools, including behavioral assays to assess cognition/memory and emotional regulation, in vivo extracellular electrophysiology, molecular protein assessments, and matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS). MALDI IMS enabled the assessment of the neural lipidome, and metabolomic changes, focusing on GABA, glutamate, and dopamine. Our research, utilizing a rodent model of prenatal THC exposure, identifies sex-specific alterations in neurotransmitter activity within the nucleus accumbens (NAc), basolateral amygdala (BLA), ventral tegmental area (VTA), prefrontal cortex (PFC), and ventral hippocampus (vHIPP). Our findings revealed a disturbed neuronal phenotype in male progeny in all regions assessed, while female progeny exhibited deficits primarily in the PFC-vHIPP circuit. Interventions with omega-3 supplementation during the perinatal period, and the antioxidant L-Theanine during adolescence, targeting lipidomic and excitotoxic hyperglutamatergic abnormalities respectively, demonstrated promising preventive effects on PCE-induced behavioral and electrophysiological disturbances. These findings highlight the complex impact of PCE on neurodevelopment, emphasizing the potential for targeted interventions to mitigate its adverse effects. Together, these studies provide critical new insights into the role of the ECS and its interactions with fatty acids in regulating mammalian neurodevelopmental processes and associated phenomena in the mesocorticolimbic system.
Summary for Lay Audience
Fetal brain development is highly susceptible to drug-related damage, including cannabis exposure, which its use increasingly common among pregnant women, particularly in younger age groups. Misconceptions about the safety of cannabis during pregnancy, coupled with insufficient guidance from healthcare providers, contribute to this rising trend. Pregnant women use cannabis to manage anxiety, depression, or morning sickness, but this can result in significant risks to fetal health, including preterm birth, stillbirth, low birth weight, or Sudden Infant Death. Even moderate prenatal cannabinoid exposure (PCE) can disrupt fetal brain development, leading to issues with anxiety, mood, and cognition later in life.
If a new mother discovers that she inadvertently exposed her fetus to cannabis and wants to minimize any potential harm, is there anything she can do? Similarly, can adolescents who were exposed to prenatal cannabis against their will reduce any negative effects? With increasing numbers of children with prenatal cannabinoid exposure, the need arises to develop treatments for its consequences.
This study examines the impact of prenatal exposure to Tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, on fetal brain development and long-term neurocognitive outcomes. THC is known to disrupt the endocannabinoid system (ECS), which plays a vital role in brain development, cognition, and emotional regulation. The ECS relies on dietary fatty acids, which are also critical for fetal brain development. We hypothesized that PCE leads to disturbances in gestational brain development, resulting in abnormal neurocognition and altered neural fatty acid profiles in later life. Our findings reveal that prenatal THC exposure disrupts both omega-3 and omega-6 fatty acids, contributing to severe neurocognitive pathology. While omega-3 supplementation during pregnancy can partially mitigate these effects, it does not fully prevent them. Additionally, an adolescent intervention with antioxidants targeting prenatal brain hypoxia shows promise in reducing some of the long-term brain pathology associated with PCE.
Despite the potential for these interventions, cessation of cannabis use during pregnancy remains the most effective strategy for preventing the adverse effects of PCE. This study provides new insights into how prenatal cannabinoid exposure can lead to long-term disruptions in behavior and highlights critical windows for interventions to mitigate these effects.
Recommended Citation
Sarikahya, Mohammed, "The Neurodevelopmental Consequences of Prenatal Cannabinoid Exposure: Pathological Impacts in the Mesocorticolimbic System and Exploratory Therapeutic Interventions" (2024). Electronic Thesis and Dissertation Repository. 10477.
https://ir.lib.uwo.ca/etd/10477
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