The modern obesogenic environment contains an abundance of food cues (e.g., sight, smell of food) as well cues that are associated with food through learning and memory processes. Food cue exposure can lead to food seeking and excessive consumption in otherwise food-sated individuals, and a high level of food cue responsivity is a risk factor for overweight and obesity. Similar food cue responses are observed in experimental rodent models, and these models are therefore useful for mechanistically identifying the neural circuits mediating food cue responsivity. This review draws from both experimental rodent models and human data to characterize the behavioral and biological processes through which food-associated stimuli contribute to overeating and weight gain. Two rodent models are emphasized - cue-potentiated feeding and Pavlovian-instrumental transfer - that provide insight in the neural circuits and peptide systems underlying food cue responsivity. Data from humans are highlighted that reveal physiological, psychological, and neural mechanisms that connect food cue responsivity with overeating and weight gain. The collective literature identifies connections between heightened food cue responsivity and obesity in both rodents and humans, and identifies underlying brain regions (nucleus accumbens, amygdala, orbitofrontal cortex, hippocampus) and endocrine systems (ghrelin) that regulate food cue responsivity in both species. These species similarities are encouraging for the possibility of mechanistic rodent model research and further human research leading to novel treatments for excessive food cue responsivity in humans.

Emerging evidence highlights a critical relationship between gut microbiota and neurocognitive development. Excessive consumption of sugar and other unhealthy dietary factors during early life developmental periods yields changes in the gut microbiome as well as neurocognitive impairments. However, it is unclear whether these two outcomes are functionally connected. Here we explore whether excessive early life consumption of added sugars negatively impacts memory function via the gut microbiome. Rats were given free access to a sugar-sweetened beverage (SSB) during the adolescent stage of development. Memory function and anxiety-like behavior were assessed during adulthood and gut bacterial and brain transcriptome analyses were conducted. Taxa-specific microbial enrichment experiments examined the functional relationship between sugar-induced microbiome changes and neurocognitive and brain transcriptome outcomes. Chronic early life sugar consumption impaired adult hippocampal-dependent memory function without affecting body weight or anxiety-like behavior. Adolescent SSB consumption during adolescence also altered the gut microbiome, including elevated abundance of two species in the genus Parabacteroides (P. distasonis and P. johnsonii) that were negatively correlated with hippocampal function. Transferred enrichment of these specific bacterial taxa in adolescent rats impaired hippocampal-dependent memory during adulthood. Hippocampus transcriptome analyses revealed that early life sugar consumption altered gene expression in intracellular kinase and synaptic neurotransmitter signaling pathways, whereas Parabacteroides microbial enrichment altered gene expression in pathways associated with metabolic function, neurodegenerative disease, and dopaminergic signaling. Collectively these results identify a role for microbiota "dysbiosis" in mediating the detrimental effects of early life unhealthy dietary factors on hippocampal-dependent memory function.

Low-calorie sweetener (LCS) consumption in children has increased dramatically due to its widespread presence in the food environment and efforts to mitigate obesity through sugar replacement. However, mechanistic studies on the long-term impact of early-life LCS consumption on cognitive function and physiological processes are lacking. Here, we developed a rodent model to evaluate the effects of daily LCS consumption (acesulfame potassium, saccharin, or stevia) during adolescence on adult metabolic, behavioral, gut microbiome, and brain transcriptomic outcomes. Results reveal that habitual early-life LCS consumption impacts normal postoral glucose handling and impairs hippocampal-dependent memory in the absence of weight gain. Furthermore, adolescent LCS consumption yielded long-term reductions in lingual sweet taste receptor expression and brought about alterations in sugar-motivated appetitive and consummatory responses. While early-life LCS consumption did not produce robust changes in the gut microbiome, brain region-specific RNA-Seq analyses reveal LCS-induced changes in collagen- and synaptic signaling-related gene pathways in the hippocampus and nucleus accumbens, respectively, in a sex-dependent manner. Collectively, these results reveal that habitual early-life LCS consumption has long-lasting implications for glucoregulation, sugar-motivated behavior, and hippocampal-dependent memory in rats, which may be based in part on changes in nutrient transporter, sweet taste receptor, and central gene pathway expression.