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Abstract
Background: Glycogen synthase kinase 3 beta (Gsk3b) is central in a gene network regulated by ethanol in mouse medial prefrontal cortex (mPFC). GSK3B abundance/activity modulations regulate ethanol consumption, suggesting GSK3B could be a target in treating alcohol use disorder. However, the critical cell type in this ethanol response is not yet known, nor have sex differences in GSK3B modulations been fully investigated. Here we report results of GSK3B overexpression selectively in CamKIIa+ mPFC cells on multiple behaviors.
Methods: Mice underwent stereotaxic injections to overexpress GSK3B in mPFC CamKIIa+ cells or control virus (n=4-6/sex/virus). We assayed working memory using a 5min delay novel-object recognition test (NOR), basal anxiety-like behavior via light/dark box (LDB), 5-weeks 2-bottle choice, intermittent ethanol access to measure ethanol consumption and preference, withdrawal-induced anxiety-like behavior 24hrs after last ethanol access, and taste-preference for saccharin (1.2mM) and quinine (200uM). Location of injections and deletion/overexpression was validated via immunofluorescence.
Results: In initial results, GSK3B overexpression produced a significant sex*genotype interaction in NOR (p=0.018), percent distance traveled in the light during LDB (p=0.025), 24hr ethanol consumption (p=0.040), and 2hr and 24hr ethanol preference (p=0.019; p=0.007 respectively). There was no effect on taste-preference Extension to fully statistically powered studies (n=15/sex/virus) are currently underway.
Conclusions: GSK3B is a promising target for treatment of alcohol use disorder as inhibition decreases ethanol self-administration. However, sufficient preclinical analysis requires full evaluation of GSK3B-modulated behaviors in both sexes. These experiments showed CaMKIIa+ cells are critical in the GSK3B-ethanol pathway, as well as revealed sex-specific responses to overexpression.
Publication Date
2023
Keywords
AUD, alcohol, ethanol, GSK3B, glycogen synthase kinase 3 beta, two bottle choice, anxiety, working memory
Disciplines
Behavioral Neurobiology | Molecular and Cellular Neuroscience | Molecular Genetics | Neuroscience and Neurobiology | Pharmacology
Faculty Advisor/Mentor
Michael Miles
Is Part Of
VCU Graduate Research Posters
Included in
Behavioral Neurobiology Commons, Molecular and Cellular Neuroscience Commons, Molecular Genetics Commons, Pharmacology Commons