**1. Introduction**

Diets high in added sugars, particularly fructose, have adverse metabolic consequences and are associated with oxidative stress, insulin resistance, and cardiometabolic disorders [1–4]. Beyond its known metabolic health risks, high fructose consumption has been linked to impairments in peripheral and central appetite signaling and may promote feeding behavior [5–10]. Emerging data also indicates that high fructose diets have a profound impact on brain function [11,12], particularly within the hippocampus, a brain region involved in memory, learning, and food intake regulation that is particularly vulnerable to dietary and metabolic insults [13–15]. Experimental studies in animal

models have shown that high fructose consumption leads to hippocampal insulin resistance [16,17], neuroinflammation [18,19], and reduced hippocampal neurogenesis [20], and suggests a potential mechanistic basis for fructose induced cognitive deficits [17,18,21].

The findings that hippocampal function is highly sensitive to excess fructose consumption are particularly relevant to the study of obesity and excess weight gain considering the role the hippocampus plays in energy regulation. In rodents, hippocampal lesions [14] or inactivation [15] increase food consumption and body weight. The translation of these findings to humans has been supported by experiments in patients with brain lesions. Patients with lesions to the temporal lobe have been shown to overeat in response to food presentation relative to healthy controls and patients with lesions in other brain regions, even after consuming an energy dense meal [22,23]. Considering these findings together, the hippocampus appears to be highly important in the inhibition of food consumption; therefore, in the case of hippocampal impairment by external insults, such as excessive consumption of fructose, humans and animals may overeat and consequently gain additional weight.

Human hippocampal connectivity has been found to be quite extensive [24], and evidence from animal models suggests that the ability of the hippocampus to inhibit appetitive behaviors may rely on its connections to other brain areas. Prior findings have demonstrated that disconnection lesions (the elimination of all direct and indirect connections) between the ventral hippocampus and the contralateral prefrontal cortex in rodents impairs general behavioral inhibition in a 5-choice reaction time task [25]. More specifically related to obesity, a monosynaptic glutamatergic pathway between the ventral hippocampus and the medial prefrontal cortex has been identified as important in the control of energy regulation. Chemogenic inactivation of this pathway has been shown to increase food consumption, indicating the activation of this pathway may be important in the ability to suppress overeating [26]. The hippocampus is also connected to the lateral septum, and activation of this excitatory pathway inhibits food intake [27]. Other hippocampal-dependent feeding pathways include connections with the amygdala and hypothalamus [18,28]. While diets high in fructose or other added sugars have been found to alter hippocampal physiology [18,20], and metabolic insults, such as obesity, have been shown to decrease hippocampal global brain connectivity [29], the impact of dietary fructose or added sugar intake on the microstructure of pathways that connect the hippocampus to other brain regions has not yet been studied.

Recent studies in rodents have shown that the effects of high fructose diets on hippocampal function are particularly damaging during sensitive periods of neurocognitive development, such as childhood and adolescence [18], but few studies have attempted to translate these findings to humans. To address this gap in knowledge, we used in vivo magnetic resonance imaging (MRI) methods, which provide a non-invasive way to examine the neurodevelopment of the human brain. T1-weighted acquisitions allow quantification of grey matter volume in specific regions of the brain, and diffusion tensor imaging (DTI) is a sensitive imaging method that can characterize the microstructural architecture of white matter tracts that connect distinct brain regions [30]. We used both structural MRI and diffusion MRI to examine the associations between dietary fructose and added sugar intake and hippocampal development in healthy children aged 7 to 11 years. Based on studies in animal models, we hypothesized that higher dietary intake of added sugars, particularly fructose, would be associated with alterations in hippocampal volume and in the microstructure of white matter tracts that connect the hippocampus to other brain regions.
