Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa-CONICET, Santa Fe, Argentina.
Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa-CONICET, Santa Fe, Argentina; Departamento de Bioquímica Clínica y Cuantitativa, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina.
J Nutr Biochem. 2023 Dec;122:109451. doi: 10.1016/j.jnutbio.2023.109451. Epub 2023 Sep 23.
Mesolimbic dopaminergic circuit is essential for food reward and motivational behaviors and can contribute to weight gain and obesity. Litter reduction is a classical model for studying the effects of neonatal overfeeding and overweight. Litters of Wistar rats were reduced to 4 pups/dam for small litter (SL) and 10 pups/dam for normal litter at postnatal day (PND) 4. Immediately after performing the feeding behavior tests, the animals were sacrificed in PND21 and PND90. The ventral tegmental area (VTA), Nucleus Accumbens Core (NAcC) and Shell (NAcSh) were isolated from frozen brain sections using the Palkovits micropunch technique. RNA and DNA were extracted from these areas, gene expression was measured by RT-qPCR and DNA methylation levels were measured by MSRM-qPCR technique. SL-PND21 animals presented increased expression levels of Tyrosine Hydroxylase and Dopamine Receptor D2 in VTA, decreased expression levels of dopamine active transporter (DAT) in VTA, and higher expression levels of DAT in NAcC. On the other hand, SL-PND90 animals showed decreased expression levels of Dopamine Receptor D1 and higher expression of DAT in NAcSh. These animals also evidenced impaired sensory-specific satiety. In addition, altered promoter methylation was observed at weaning, and remained in adulthood. This work demonstrates that neonatal overfeeding induces disruptions in the mesolimbic dopaminergic circuitry and causes alterations in feeding behavior from weaning to adulthood, suggesting that the neonatal period is critical for the normal development of dopaminergic circuit that impact on feeding behavior.
中脑边缘多巴胺能回路对于食物奖赏和动机行为至关重要，并且可能导致体重增加和肥胖。减少产仔数是研究新生期过度喂养和超重影响的经典模型。在产后第 4 天（PND），Wistar 大鼠的产仔数减少为 4 只/母鼠（小产仔数，SL）和 10 只/母鼠（正常产仔数）。在进行喂养行为测试后，立即在 PND21 和 PND90 处死动物。使用 Palkovits 微穿孔技术从冷冻脑切片中分离腹侧被盖区（VTA）、伏隔核核心（NAcC）和壳（NAcSh）。从这些区域提取 RNA 和 DNA，通过 RT-qPCR 测量基因表达，通过 MSRM-qPCR 技术测量 DNA 甲基化水平。SL-PND21 动物在 VTA 中表现出酪氨酸羟化酶和多巴胺受体 D2 的表达水平增加，VTA 中的多巴胺主动转运体（DAT）表达水平降低，以及 NAcC 中的 DAT 表达水平升高。另一方面，SL-PND90 动物表现出多巴胺受体 D1 的表达水平降低和 NAcSh 中 DAT 的表达水平升高。这些动物还表现出感觉特异性饱食受损。此外，在断奶时观察到启动子甲基化改变，并且在成年期仍然存在。这项工作表明，新生期过度喂养会导致中脑边缘多巴胺能回路紊乱，并导致从断奶到成年期的进食行为改变，这表明新生期对于影响进食行为的多巴胺能回路的正常发育至关重要。
