Nutritional Ketosis Attenuates Sucrose Bingeing-Induced Behavioral Deficits by Improving Synaptic Plasticity and Anti-Inflammatory Signalling in the Prefrontal Cortex of Male and Female Mice

Binge eating, one of the defining characteristics of binge eating disorder, has been linked to poor health span. Animals, like humans, selectively binge on highly palatable foods, implying that the binge-like behavior is motivated by hedonic rather than metabolic signals. Given the association between reward processing and food intake, this study explored sex-specific underlying biological mechanisms, including synaptic, neuroimmune and neurometabolic correlates of binge-like sucrose drinking, compulsivity and anxiety-like behaviors, utilizing a preclinical model of hedonic sucrose drinking. Throughout the experiment, male and female mice binged on a sweet solution when given food ad libitum with free access and a choice between water and a 10% (w/v) sucrose solution, with females consuming more sucrose. The sucrose intake was positively correlated with transcription of genes for dopamine receptors (Drd1, Drd2) in the PFC of male and female mice. Sucrose-bingeing increased PFC neuroinflammation, concomitantly increasing region-specific blood-brain barrier permeability in males. Sucrose bingeing elevated the transcription of glucose metabolism genes (Slc2a3, Glo1) while inhibiting ketone oxidation pathway genes (Slc16a1, Oxct1, Acat1) in the PFC of males and females. Nutritional ketosis attenuated sucrose bingeing, compulsivity and anxiety-like behaviors in sucrose-dependent male and female mice by suppressing the transcription of reward-related genes (Drd1, Drd2) while promoting an anti-inflammatory neuroimmune microenvironment in the PFC of male and female mice in a sex-dependent manner. Overall, this study identified synaptic, neuroimmune and neurometabolic mechanisms as novel druggable targets and nutritional ketosis as a potential therapy for diseases where binge-like eating, compulsivity and anxiety-like behaviors are the main symptoms, such as binge eating disorder. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/651641v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@f4f91dorg.highwire.dtl.DTLVardef@10f0f9forg.highwire.dtl.DTLVardef@1caa2baorg.highwire.dtl.DTLVardef@81a2e1_HPS_FORMAT_FIGEXP M_FIG C_FIG