Human milk oligosaccharides (HMO)s are a key component in human milk and represent an important dietary modulator of infant gut microbiota composition and associated gut-brain axis development and homeostasis. The brain reward system, specifically the mesolimbic dopamine (DA) projections from the ventral tegmental area (VTA) to nucleus accumbens (NAc) is involved in the motivation and preference for food. The objective of the present study was to determine if HMO fortified diets given during the critical period of reward system development (p21) could affect the structure of the reward system. At weaning (p21), Sprague-Dawley rats were randomized to one of four fortified diet groups: Control, 3′sialyllactose (3′FL), 2′-fucosyllactose (2′FL), or a combination of 3′SL and 2′FL (3′SL + 2′FL). Messenger RNA (mRNA) expression was quantified for DA and appetite associated markers in the VTA and NAc and western blots measured the immediate early gene FosB and its isoform ΔFosB. Females fed the 3′SL + 2′FL fortified diet displayed a decrease in DAT expression in the VTA and an increase in leptin expression in the NAc. Females displayed an overall lower expression of NAc D2, VTA ghrelinR, and VTA leptin. In males, VTA DAT and FosB were negatively correlated with body weight and systemic leptin. Sex differences in the expression of DA markers underscore the need to investigate this phenomenon and understand the functional significance in preventing or treating obesity. This study highlights sex differences in response to HMO supplementation and the need for further investigations into the functional significance of nutritional interventions during DA system development.

人乳寡糖（HMO）是人乳中的关键成分，代表婴儿肠道菌群组成以及相关的肠脑轴发育和体内平衡的重要饮食调节剂。大脑的奖励系统，特别是从腹侧被盖区（VTA）到伏隔核（NAc）的中脑边缘多巴胺（DA）投影参与了食物的动机和偏爱。本研究的目的是确定在奖励系统发展的关键时期（p21）给予的HMO强化饮食是否会影响奖励系统的结构。断奶时（p21），将Sprague-Dawley大鼠随机分为四个强化饮食组之一：对照组，3'唾液乳糖（3'FL），2'-岩藻糖乳糖（2'FL）或3'SL和2的组合'FL（3'SL + 2'FL）。信使RNA（mRNA）的表达在VTA和NAc中用于DA和食欲相关标志物的定量分析，而Western印迹法则用于检测早期早期基因FosB及其同工型ΔFosB。饲喂3'SL + 2'FL强化饮食的雌性动物在VTA中的DAT表达降低，而在NAc中的瘦蛋白表达升高。女性显示出NAc D2，VTA ghrelinR和VTA瘦素的总体较低表达。在男性中，VTA DAT和FosB与体重和全身性瘦素呈负相关。DA标记表达的性别差异强调了研究这种现象并了解预防或治疗肥胖症的功能意义的必要性。