A genetic contribution of the cerebellum in alcohol consumption: differences between C57BL/6J and C57BL/6N substrains

Chloe Michelle Erikson

doi:10.7273/000005081

The creation and consumption of fermented beverages such as ales and wines date back to the Neolithic period where alcohol was most often used for ritualistic and spiritualistic purposes. Now in the modern age, alcohol is the most widely used recreational drug in the world – consumed for its neural depressant effects, which at low doses cause euphoria, reduced anxiety, increased sociability, and motor deficits. While at low doses somewhat harmless, excessive alcohol consumption can lead to binge drinking and alcohol dependence which pose significant threats to the dependent individual, their associated friends and family, and society more broadly. Continued excessive alcohol consumption across the lifetime of an individual can develop from a myriad of social, biological, and/or psychological reasons. From a biological perspective, alcohol dependence has a strong genetic component as illustrated by human twin and familial studies. While such genetic influences are complex as no single genetic mutation accounts for the development of alcohol dependence, the focus of this thesis is how a genetic contribution of the cerebellum alters neural responses to alcohol which influence the psychological experience of alcohol and thus may contribute to an increased predilection of abusive consumption. Specifically, it is established that genetically driven, low sensitivity of cerebellar-mediated aversive alcohol responses can facilitate or enable a transition to harmful patterns of high alcohol consumption, and ultimately perpetuate the development of dependence. Therefore, a better understanding of how this genetic influence of the cerebellum contributes to the development of alcohol use disorders should be further elucidated. Chapters in this thesis describe a genetically determined neurological difference and underlying mechanism within the cerebellum that might explain differences in initial sensitivity to alcohol and thus alcohol consumption behavior between mouse species that exhibit high and low alcohol preference. Based on those findings, further studies presented in this thesis support that manipulating cerebellar granule cell signaling, using both pharmacological and chemogenetic techniques, can alter alcohol consumption behavior. Collectively, the findings in this dissertation suggest that differences in cerebellar neurological responses to alcohol likely influence alcohol consumption behavior, and, therefore, that screening for, or pharmacological interventions to alter those responses would be an exciting area of research for preventing the development of and treating existing alcohol use disorders.

A genetic contribution of the cerebellum in alcohol consumption: differences between C57BL/6J and C57BL/6N substrains

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