Behavioral, Hormonal, and Neurochemical Outcomes of Neonatal Repeated Shaking Brain Injury in Male Adult Rats
Behavioral, Hormonal, and Neurochemical Outcomes of Neonatal Repeated Shaking Brain Injury in Male Adult Rats
复制标题
雄性成年大鼠新生儿反复震颤脑损伤的行为、激素和神经化学结果
DOI：
10.1016/j.physbeh.2018.11.025
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发表时间：
2019
期刊：
影响因子：
2.9
通讯作者：
Ueda S.
中科院分区：
文献类型：
--
作者：
Tanaka H;Ehara A;Nakadate K;Yoshimoto K;Shimoda K;Ueda S.
众所周知，童年期的虐待环境与成年期的个体焦虑行为有关。虽然已经提出了肾上腺皮质类固醇受体的失衡和单胺能神经元系统的功能障碍，但其潜在机制尚未完全了解。为了解决这些问题，我们最近开发了一种新的新生大鼠摇晃性脑损伤（SBI）模型。这些模型大鼠在大脑皮层和海马的灰质中显示出短暂的微血管化。使用这个模型，我们评估了新生儿反复轻度SBI对随后的行为和应激反应的影响，我们进一步研究了海马和中枢单胺能神经元系统中肾上腺皮质类固醇受体介导这种异常的可能贡献。采用旷场实验进行的行为学筛查显示，出生后3-7天（P）摇晃的大鼠的自主活动和探索行为明显低于出生后8 -14天（P <0.05）摇晃的大鼠，提示新生儿SBI的关键期。在高架十字迷宫（elevated plus maze，EFL）和亮/暗转换（light/dark transition，L/D）实验中，模型组大鼠在EFL开放臂和L/D实验灯箱中的时间较少，表现出成年后的焦虑样行为。在成人中，新的EPM诱导的促肾上腺皮质激素（ACTH）和皮质酮（CORT）的反应显着增加新生儿SBI。进一步的实验表明，该模型大鼠海马中盐皮质激素受体（MR）的表达显著下调，而糖皮质激素受体（GR）的表达无明显变化。这些结果表明，新生儿SBI诱导的海马MR的下调减弱了下丘脑-垂体-肾上腺（HPA）轴的负反馈，从而导致ACTH和CORT的分泌异常。此外，神经化学分析表明，摇晃大鼠的多巴胺（DA），5-羟色胺（5-HT），5-羟吲哚乙酸（5-HIAA），和去甲肾上腺素（NA）的内侧前额叶皮质（dmPFC）的背侧部分的水平较高。在杏仁核中，观察到较高的5-HIAA和较低的NA水平。这两个区域都与焦虑和压力有关。总之，新生儿SBI对单胺能系统的影响也可能参与了该模型中行为和激素反应的变化。
It is well known that an abusive environment in childhood is related to individual anxiety behavior in adulthood. Though an imbalance of adrenocorticosteroid receptors and a dysfunction of monoaminergic neuron systems have been proposed, the underlying mechanisms are not fully understood. To address these problems, we recently developed a new model of shaking brain injury (SBI) in neonatal rats. These model rats showed transient microhemorrhages in the gray matter of the cerebral cortex and hippocampus. Using this model, we assessed the effects of neonatal repeated mild SBI on subsequent behavior and the stress response, and we further examined the possible contribution of adrenocorticosteroid receptors in the hippocampus and central monoaminergic neuron systems mediating such abnormalities. Behavioral screening examination with a novel open-field test showed that the rats with postnatal day (P) 3–7 shaking had significantly reduced locomotor activity and exploration behaviors than those with late (P8–14) shaking periods, indicating a critical period for neonatal SBI. In the elevated plus maze (EPM) and the light/dark transition (L/D) tests, the model rats spent less time in the open arm of the EPM and the light box of the L/D test, indicating anxiety-like behavior as adults. In adults, the novel EPM-induced adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) responses were significantly increased by neonatal SBI. Further experiments showed that the expression of mineralocorticoid receptor (MR), but not glucocorticoid receptor (GR), was significantly downregulated in the hippocampus of this model rat. These results suggest that neonatal SBI-induced downregulation of MRs in the hippocampus attenuates negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which results in abnormal secretion of ACTH and CORT. Furthermore, the neurochemical analysis showed that shaken rats had higher dopamine (DA), serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), and noradrenaline (NA) levels in the dorsal part of the medial prefrontal cortex (dmPFC). In the amygdala, higher 5-HIAA and lower NA levels were observed. Both areas are known to be anxiety and stress-related. Taken together, the effects of neonatal SBI on the monoaminergic systems may also be involved in the changes of behavioral and hormonal responses in this model.