Laboratory of Neuroendocrinology, Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 862, Edifício de Ciências Biomédicas, 7° andar, Vila Clementino, São Paulo, CEP 04023-062, Brasil.
Departament of Physiology, Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, Córdoba, Argentina.
Mol Neurobiol. 2021 Mar;58(3):1036-1051. doi: 10.1007/s12035-020-02181-0. Epub 2020 Oct 20.
The serotoninergic system plays an important role in the ontogeny of the mammalian central nervous system, and changes in serotonin production during development may lead to permanent changes in brain cytoarchitecture and function. The present study investigated the programming effects of neonatal serotonin depletion on behavior and molecular components of the serotoninergic system in adult male and female rats. Subcutaneous para-chlorophenylalanine (pCPA) administration (100 mg kg) was performed daily on postnatal days 8-16 to deplete brain serotonin content. During adulthood, elevated plus-maze, open field, social interaction, forced swimming, and food, saline, and sucrose intake tests were performed. Relative expression of serotonin neurotransmission components in several brain areas was determined by qPCR. Additionally, serotonin immunofluorescence and neuropeptide mRNA expression were assessed in dorsal raphe (DRN) and paraventricular (PVN) nuclei, respectively. Rat performance in behavioral tests demonstrated a general increase in locomotor activity and active escape behavior as well as decreased anxiety-like behavior after neonatal brain serotonin depletion. The behavioral programming effects due to neonatal serotonin depletion were more pronounced in females than males. At the gene expression level, the mRNA of Tph1 and Tph2 were lower in DRN while Htr2c was higher in the amygdala of pCPA-treated males, while Htr1a, Htr2c, Oxt, Avp, Crh, and Trh were not different in any treatments or sex in PVN. The results indicate that neonatal serotonin depletion has long-term consequences on locomotion and anxiety-like behavior associated with long-lasting molecular changes in the brain serotoninergic system in adult rats.
血清素能系统在哺乳动物中枢神经系统的发育中起着重要作用，发育过程中血清素产生的变化可能导致大脑细胞结构和功能的永久性改变。本研究探讨了新生鼠脑内血清素耗竭对成年雄性和雌性大鼠行为和血清素能系统分子成分的编程效应。在生后第 8-16 天，每天给予皮下对氯苯丙氨酸（pCPA）（100mg/kg）以耗竭脑内血清素含量。成年后，进行高架十字迷宫、旷场、社交互动、强迫游泳和食物、盐水和蔗糖摄入测试。通过 qPCR 测定几个脑区的血清素神经传递成分的相对表达。此外，分别在中缝背核（DRN）和室旁核（PVN）评估血清素免疫荧光和神经肽 mRNA 表达。大鼠在行为测试中的表现表明，新生鼠脑内血清素耗竭后，一般的运动活性和主动逃避行为增加，焦虑样行为减少。由于新生鼠脑内血清素耗竭导致的行为编程效应在雌性中比雄性更明显。在基因表达水平上，DRN 中 Tph1 和 Tph2 的 mRNA 水平降低，而杏仁核中 Htr2c 的 mRNA 水平升高，而 pCPA 处理的雄性 PVN 中 Htr1a、Htr2c、Oxt、Avp、Crh 和 Trh 的 mRNA 水平在任何处理或性别中均无差异。结果表明，新生鼠脑内血清素耗竭对成年大鼠的运动和焦虑样行为有长期影响，并与大脑血清素能系统的持久分子变化有关。
