Myra Bower^1,2, Andrew Lombardi¹, Cate Hensley ², Curtis Borski^1,2, Kora Kastengren^1,2, Erika Mehrhoff^1,2, Charles Hoeffer^1,2 Marissa Ehringer^1,2, Jerry Stitzel^1,2

Tobacco use remains the world’s leading cause of preventable death and disease. Nicotine use disorder is characterized by immediate neuronal adaptations that may promote use. While studies of neurons are informative, a critical perspective is missing for other cell types. Astrocytes are dynamic regulators of brain homeostasis and active participants of neurocircuitry underlying substance use disorders. Clusterin (CLU), a gene identified by large scale human genome wide association studies (GWAS) of smoking, is a gene also primarily expressed by astrocytes. Using a mouse model, we investigated the role of Clusterin in nicotine induced astrocyte morphology and reward behavior. Immunohistochemical staining for area and Sholl analysis of tissue collected 24 hours after nicotine or saline control identified differences due to Clusterin knockout. Mouse astrocytes were assessed in both primary cell culture exposed to nicotine (100 um) and in adult hippocampus after subcutaneous nicotine injection (0.35 mg/kg). Clusterin loss reduced the morphological response of astrocytes to nicotine in vitro and in vivo. Clusterin knock-out and wild-type mice were also tested for nicotine reward by conditioned place preference at the same dose. Additionally, we also see a trend (p = 0.07) for Clusterin knock-out towards a place aversion to nicotine, suggesting loss of the gene induces a more unpleasant experience at this dose. These data support Clusterin as a genetic modulator of nicotine-conditioned responses and glial plasticity that may prevent nicotine use in mice.

¹Department of Integrative Physiology, University of Colorado at Boulder;

²Institute for Behavioral Genetics, University of Colorado at Boulder.