Investigating CNR1+ Corticostriatal Activity in Co-Exposure Models of FASD

Texas A&M University Health Science Ctr, College Station TX

Investigators

Abstract

PROJECT SUMMARY Fetal Alcohol Spectrum Disorders (FASDs) are the most common neurodevelopmental disorders worldwide. Numerous studies have documented the causal role of gestational alcohol exposure in offspring anatomical and neurobehavioral FASD phenotypes. However, in human populations, FASD outcomes are frequently complicated by additional co-occurring but poorly understood risk factors, including paternal preconception alcohol consumption and maternal co-use of other psychoactive substances (polysubstance use). Recent studies indicate that both of these co-occurring variables can increase the risk of FASD symptoms in offspring. Therefore, the objective of this proposal is to investigate, in rodent models, translationally relevant forms of PAE, i.e., 1) paternal preconception alcohol use, and 2) maternal co-use of alcohol with a common psychoactive drug class, cannabinoids. My central hypothesis is that these two variables will exacerbate behavioral deficits and interfere with cannabinoid receptor 1 (CNR1)-regulated corticostriatal activity, a neural circuit associated with FASD- characteristic behavioral disorders. The K99 phase will include investigations of dual-parental alcohol exposure. Specific Aim 1 will test my hypothesis that dual-parent alcohol exposure impairs affect and increases alcohol-seeking behaviors in adult offspring compared to single-parent exposures. Specific Aim 2 will use ribosome labeling/capture to investigate transcriptomic changes in corticostriatal synapses in adult offspring, and test my hypothesis that offspring with dual-parental alcohol exposure will exhibit greater reductions in synaptic CNR1 transcript networks than single-parent exposures. The R00 phase extends from my research findings that offspring with prenatal simultaneous alcohol and cannabinoid exposure (SAC) consume more alcohol than single-drug exposed offspring. In Specific Aim 3, I will perform in vivo and ex vivo assessments of corticostriatal CNR1+ activity using circuit- specific chemogenetic interventions. I will synthesize behavioral, genetic, and physiological measures to test my hypothesis that SAC-associated motor impairments and ethanol self-administration are attributable to hyperactive glutamate transmission from CNR1+ corticostriatal neurons. This project will advance our understanding of the impact of common risk factors on PAE-induced neurodevelopmental outcomes, improve strategies to mitigate PAE-associated risks, and provide foundational support for my future transition to an independent investigator. This research addresses specific priorities listed in NIAAA’s latest Strategic Plan by 1) investigating paternal alcohol exposure contributions, and 2) identifying neurobiological mechanisms underlying health consequences that persist into adulthood. Finally, this work will enhance the translational relevance of animal models to human FASD, and inform public health recommendations surrounding gestational substance exposure.