Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Córdoba, Argentina; Instituto de Farmacología Experimental Córdoba (IFEC - CONICET), Córdoba, Argentina.
Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Córdoba, Argentina.
Neuropharmacology. 2024 Nov 1;258:110099. doi: 10.1016/j.neuropharm.2024.110099. Epub 2024 Aug 5.
Clinical evidence suggests that early malnutrition promotes symptoms related to psychiatric disorders later in life. Nevertheless, the molecular mechanisms underpinning nutritional injury induce depression remains unknown. The purpose of the present study was to evaluate whether perinatal protein restriction increases vulnerability to developing depressive-like behavior in adulthood by focusing on anhedonia, a core symptom of depression. To this, male adult Wistar rats submitted to a protein restriction schedule at perinatal age (PR-rats), were subjected to the sucrose preference test (SPT), the novel object recognition test (NORT), the forced swim test (FST), and the elevated plus maze (EPM), and compared to animals fed with a normoprotein diet. To investigate neurobiological substrates linked to early protein undernutrition-facilitated depressive-like behavior, we assessed the levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the nucleus accumbens (NAc), and evaluated the reversal of anhedonic-like behavior by infusing ANA-12. We found that early malnutrition decreased sucrose preference, impaired performance in the NORT and increased immobility time in the FST. Furthermore, perinatal protein-restriction-induced anhedonia correlated with increased BDNF and p-TrkB protein levels in the NAc, a core structure in the reward circuit linked with anhedonia. Finally, bilateral infusion of the TrkB antagonist ANA-12 into the NAc shell ameliorated a reduced sucrose preference in the PR-rats. Altogether, these findings revealed that protein restriction during pregnancy and lactation facilitates depressive-like behavior later in life and may increase the risk of developing anhedonia by altering BDNF-TrkB in the NAc shell.
临床证据表明，早期营养不良会促进以后生活中与精神障碍相关的症状。然而，支持营养损伤诱导抑郁的分子机制尚不清楚。本研究旨在评估围产期蛋白质限制是否会通过关注快感缺失（抑郁的核心症状）增加成年后发展为抑郁样行为的易感性。为此，对围产期（PR-大鼠）接受蛋白质限制方案的雄性成年 Wistar 大鼠进行蔗糖偏好测试（SPT）、新物体识别测试（NORT）、强迫游泳测试（FST）和高架十字迷宫（EPM）测试，并与喂食正常蛋白饮食的动物进行比较。为了研究与早期蛋白质缺乏促进抑郁样行为相关的神经生物学基础，我们评估了伏隔核（NAc）中脑源性神经营养因子（BDNF）及其受体 TrkB 的水平，并评估了 ANA-12 输注对快感缺失样行为的逆转作用。我们发现，早期营养不良会降低蔗糖偏好，损害 NORT 中的表现，并增加 FST 中的不动时间。此外，围产期蛋白质限制引起的快感缺失与 NAc 中 BDNF 和 p-TrkB 蛋白水平升高相关，NAc 是与快感缺失相关的奖励回路的核心结构。最后，将 TrkB 拮抗剂 ANA-12 双侧输注到 NAc 壳中改善了 PR-大鼠的蔗糖偏好降低。总之，这些发现表明，妊娠和哺乳期的蛋白质限制会促进以后生活中的抑郁样行为，并可能通过改变 NAc 壳中的 BDNF-TrkB 增加快感缺失的风险。
