High-palatable and caloric foods are widely overconsumed due to hedonic mechanisms that prevail over caloric necessities leading to overeating and overweight. The nucleus accumbens (NAc) is a key brain area modulating the reinforcing effects of palatable foods and is crucially involved in the development of eating disorders. We describe that prolonged exposure to high-caloric chocolate cafeteria diet leads to overeating and overweight in mice. NAc functionality was altered in these mice, presenting structural plasticity modifications in medium spiny neurons, increased expression of neuroinflammatory factors and activated microglia, and abnormal responses after amphetamine-induced hyperlocomotion. Chronic inactivation of microglia normalized these neurobiological and behavioural alterations exclusively in mice exposed to cafeteria diet. Our data suggest that prolonged exposure to cafeteria diet produces neuroplastic and functional changes in the NAc that can modify feeding behaviour. Microglia activation and neuroinflammation play an important role in the development of these neurobiological alterations.

This work was supported by the European Commission, FP7 (#HEALTH‐F2‐2013‐602891) to R.M.; the Spanish Ministerio de Economía y Competitividad‐MINECO (#SAF2014‐59648‐P‐FEDER), the Spanish Instituto de Salud Carlos III, RETICS‐RTA (#RD12/0028/0023‐FEDER) and the Generalitat de Catalunya, AGAUR (#2014‐SGR‐1547) to R.M. The financial support of the Fundació La Marató‐TV3 (#201620‐30) is also acknowledged. We would like to thank the Advance Light Microscopy Unit of the Center for Genomic Regulation for their technical assistance on the acquisition and processing of microscopy images. S. M‐N. was supported by CAPES fellowship of the Brazilian Government (Programa Ciência Sem Fronteiras).