Department of Psychology and Neuroscience Program, University of Guelph, Guelph, Ontario, N1G 2W1 Canada.
Department of Neuroscience "Rita Levi Montalcini", University of Turin, 10126 Turin, Italy; NICO - Neuroscience Institute Cavalieri Ottolenghi, Orbassano, 10043 Turin, Italy.
Psychoneuroendocrinology. 2021 Nov;133:105393. doi: 10.1016/j.psyneuen.2021.105393. Epub 2021 Aug 23.
Maternal separation (MS) is a known chronic stressor in the postnatal period and when associated with another paradigm like the activity-based anorexia (ABA) rat model, causes different effects in the two sexes. In ABA females, the separation leads to increased hyperactivity and anxiety reduction, whereas, in males, the separation induces decreased locomotor activity without similar reduction of anxiety-like behaviors as observed in females. To understand the mechanisms altered by MS in synergy with the induction of the anorexic-like phenotype, we considered the reward system, which involves neurons synthesizing dopamine (DA) in the ventral tegmental area (VTA), substantia nigra pars compacta, and serotoninergic neurons in the dorsal raphe nucleus. Moreover, we analyzed the orexin circuit in the lateral hypothalamic area (LHA), which affects DA synthesis in the VTA and is also known to regulate food consumption and locomotor activity. Rats of both sexes were exposed to the two paradigms (MS and ABA), leading to four experimental groups for each sex: non-separated control (CON), non-separated ABA groups (ABA), MS control (MSCON), and MS plus ABA groups (MSABA). Immunohistochemistry analysis was performed to determine quantitative differences in the number of cells expressing DA, orexin, and serotonin (5-HT) among the experimental groups. The results showed that, in the DA system, the effect of MS was more evident in females than in males, with a substantial increase in DA cells in the VTA of MSABA. However, the analysis of the orexin system revealed a similar cellular increment in the LHA in the non-separated ABA groups of both sexes. Regarding 5-HT, there was an opposite effect in males and females of the MSABA groups, with only females showing a greater density of 5-HT cells. The changes in the reward system could partially explain the behavioral data: the hyperactivity, weight loss, and decreased anxiety levels of the MSABA females could be linked to an increase in DA and 5-HT cells, whereas in males, MS could mitigate the behavioral effects of the ABA protocol affecting the anxiety levels and locomotor activity through a lack of increased activation of the reward system.
母体分离（MS）是产后时期已知的慢性应激源，当与另一种范式（如活动性厌食症（ABA）大鼠模型）相关联时，会对两性产生不同的影响。在 ABA 雌性大鼠中，分离会导致过度活跃和焦虑减轻，而在雄性大鼠中，分离会导致运动活性降低，但不会像雌性大鼠那样观察到类似的焦虑样行为减少。为了了解 MS 与诱导厌食样表型协同作用改变的机制，我们考虑了奖励系统，该系统涉及腹侧被盖区（VTA）、黑质致密部合成多巴胺（DA）的神经元和中缝核背侧的 5-羟色胺能神经元。此外，我们分析了外侧下丘脑区（LHA）的食欲素回路，该回路影响 VTA 中的 DA 合成，并且已知调节食物消耗和运动活性。两种性别的大鼠都暴露于两种范式（MS 和 ABA）中，导致每个性别有四个实验组：未分离对照组（CON）、未分离 ABA 组（ABA）、MS 对照组（MSCON）和 MS 加 ABA 组（MSABA）。免疫组织化学分析用于确定实验各组中表达 DA、食欲素和 5-羟色胺（5-HT）的细胞数量的定量差异。结果表明，在 DA 系统中，MS 的影响在雌性大鼠中比在雄性大鼠中更为明显，MSABA 组 VTA 中的 DA 细胞数量显著增加。然而，食欲素系统的分析显示，两性未分离 ABA 组的 LHA 中也出现了类似的细胞增量。关于 5-HT，MSABA 组的雄性和雌性大鼠表现出相反的效应，只有雌性大鼠显示出更高密度的 5-HT 细胞。奖励系统的变化可以部分解释行为数据：MSABA 雌性大鼠的过度活跃、体重减轻和焦虑水平降低可能与 DA 和 5-HT 细胞的增加有关，而在雄性大鼠中，MS 可能通过缺乏奖励系统的激活来减轻 ABA 方案的行为影响，从而影响焦虑水平和运动活性。
