Wednesday, April 24, 2024
4/24/2024
PROJECT SUMMARY The high rate of prenatal alcohol use combined with an increase in marijuana prevalence and acceptance in society today, has led to an increase in comorbid maternal alcohol and cannabinoid exposure with little understanding of the potential lasting effects on offspring. Prenatal cannabinoid and alcohol exposure are known to alter neurodevelopment and induce lasting behavioral changes including higher rates of alcohol and drug abuse later in life. ¿9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, binds cannabinoid receptors and activates the endocannabinoid (EC) system. The EC system is critically involved in brain development and modulates synaptic transmission processes, including those in the central nucleus of the amygdala (CeA; a hub of stress/anxiety processing critical to the development of addiction). Disruption of the EC system through prenatal drug use is thought to underlie a predisposition for those individuals to addictive behaviors. Using a model of prenatal THC, alcohol, or both vapor exposure (PTE, PAE, and PTAE, respectively), my K99/R00 Pathway to Independence proposal aims to identify if PTE and/or PAE perturb or impact development to cause long lasting alterations in 1) anxiety-like behaviors, 2) motivation to seek and consume alcohol, 3) CeA neurotransmission, and 4) underlying CeA EC signaling in a sex-specific manner. My preliminary results indicate lasting, sex-specific changes in anxiety-related behaviors, as well as changes in EC signaling in the CeA, a region unexplored with PTE and comorbid PAE. My goal is to develop an independent research project utilizing a multitude of techniques to approach the issue of maternal alcohol and cannabinoid use at all levels. This holistic approach includes combining behavior, electrophysiology, targeted pharmacology, molecular, optical, and omics techniques to elaborate on the developmental outcomes induced by THC and alcohol parental insult. During the K99 phase I will identify the consequences of PAE and/or PTE (via vapor inhalation) on the predisposition of offspring to consume alcohol and anxiety-like behaviors later in life (under the mentorship of Drs. Thomas and Roberts); on the lasting mechanistic alterations in CeA neuronal functions and EC signaling (under the mentorship of Dr. Roberto); and on in vivo activity of a key EC regulating enzyme Fatty Acid Amide Hydrolase (FAAH) using novel optical tools with bioluminescence imaging technology (under the mentorship of Dr. Roberts). The training I will receive during this award will equip me with the multidisciplinary techniques needed to continue this research independently to investigate the mechanisms underlying these PTE and PAE-induced alterations in the CeA during the R00 phase (with guidance from my advisory team: Drs. Lovinger, Valenzuela, Cravatt, Christie, Mayfield, and Miller). Overall, this project will provide mechanistic insight into the effects of PTE, PAE and comorbid PTAE on later in life addictive behaviors and physiological function in the CeA that may implicate candidate pathways for further investigation and/or treatment strategies.
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