The demyelinating agent cuprizone induces a male-specific reduction in binge eating in the binge-prone C57BL/6NJ strain

Richard K. Babbs; Jacob A. Beierle; Julia C. Kelliher; Rose Medeiros; Jeya Anandakumar; Anyaa Shah; Emily J. Yao; Melanie M. Chen; Camron D. Bryant

Here, we examined differences in the myelin proteins MAG and MBP in B6NJ versus B6J mice 293 and the effect of cuprizone on these protein levels. There were no effect of cuprizone treatment 294 or substrain on MAG levels ( Fig.5A ,B). However, for MBP, cuprizone treatment induced a 295 significant decrease in total MBP and in each of the MBP isoforms compared to control mice 296 The demyelinating agent cuprizone induced comparable weight loss in females and males 303 of both the BE-resistant B6J substrain and the BE-prone B6NJ substrain (Figs.1,2 ), yet it induced 304 robust substrain-and sex-dependent effects on PF intake. In contrast to our hypothesis that 305 administration of the demyelinating agent cuprizone would enhance BE, we observed the 306 opposite result -a robust reduction in BE in male but not female mice of the BE-prone B6NJ strain 307 (Fig.3) . The male-selective decrease in BE in cuprizone-treated B6NJ males could not be 308 explained by confounding effects on locomotor activity (Fig.4) contributes to the high mortality rates in cuprizone doses exceeding 0.3% (Hiremath et al., 1998; 314 Stidworthy et al., 2003) . The mechanism behind cuprizone-induced weight loss is unclear, but 315 could involve copper chelation, given that copper deficiency in both rats (C. G. Taylor, Bettger, & 316 Bray, 1988) and mice (Prohaska, 1983 ) results in reduced body weight. In the present study, we 317 report a similar degree of weight loss in both female and male cuprizone-treated mice of both 318 substrains (Fig. 2) . Thus, it is unlikely that weight loss alone is responsible for the male-specific 319 reduction in BE and compulsive-like eating in the BE-prone B6NJ substrain. Also, food restriction-320 induced weight loss promotes rather than reduces BE in rodents (Consoli, Contarino, Tabarin The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/865600 doi: bioRxiv preprint 14 the cuprizone-treated B6NJ males showed a sharp escalation in PF intake from the first to the 339 second training day, after which they plateaued rather than continuing to escalate like their control 340 B6NJ male counterparts (Fig.3G,H) . It is also possible that cuprizone induced an anhedonic-like 341 state selectively in B6NJ males that caused a reduction in PF intake (Sen et al., 2019) or, e.g., 342