brain, microbiota, early-life, development, learning and memory 24 mediating the negative effects of early life unhealthy dietary factors on neurocognitive 48 outcomes. 49 50The gut microbiome is increasingly implicated in modulating neurocognitive 53 development and consequent functioning 1,2 . Early life developmental periods represent 54 critical windows for the impact of indigenous gut microbes on the brain, as evidenced by 55 the reversal of behavioral and neurochemical abnormalities in germ free rodents when 56 inoculated with conventional microbiota during early life, but not during adulthood [3][4][5] . 57Dietary factors are a critical determinant of gut microbiota diversity and can alter gut 58 bacterial communities, as evident from the microbial plasticity observed in response to 59 pre-and probiotic treatment, as well as the "dysbiosis" resulting from consuming 60unhealthy, yet palatable foods that are associated with obesity and metabolic disorders 61 (e.g., "Western diet"; foods high in saturated fatty acids and added sugar) 6 . In addition 62 to altering the gut microbiota, consumption of these dietary factors yields long-lasting 63 memory impairments, and these effects are more pronounced when consumed during 64 early life developmental periods vs. during adulthood 7-9 . Whether diet-induced changes 65 in specific bacterial populations are functionally related to altered early life 66 neurocognitive outcomes, however, is poorly understood. 67
68The hippocampus, which is well known for its role in spatial and episodic memory and 69 more recently for regulating learned and social aspects of food intake control 10-15 , is 70 particularly vulnerable to the deleterious effects of Western dietary factors [16][17][18] . During 71 the juvenile and adolescent stages of development, a time when the brain is rapidly 72 developing, consumption of diets high in saturated fat and sugar 19-21 or sugar alone 22-25 73 impairs hippocampal function while in some cases preserving memory processes that do 74 5 not rely on the hippocampus. While several putative underlying mechanisms have been 75investigated, the precise biological pathways linking dietary factors to neurocognitive 76 dysfunction remain largely undetermined 9 . Here we aimed to determine whether sugar-77 induced alterations in gut microbiota during early life are causally related to 78 hippocampal-dependent memory impairments observed during adulthood. 79 80 Early-life sugar consumption impairs hippocampal-dependent memory 81 function without affecting other neurocognitive domains 82 83Results from the Novel Object in Context (NOIC) task, which measures hippocampal-84 dependent episodic contextual memory function 26 , reveal that while there were no 85 differences in total exploration time of the combined objects on days 1 or 3 of the task 86 ( Fig. 1A,B), animals fed sugar solutions in early life beginning at PN 28 had a reduced 87 capacity to discriminate an object that was novel to a specific context when animals 88 were tested during adulthood (PN 6...