Cho Chang Hoon, Yang Zhongxi, Yoo Ki Hyun, Oliveros Alfredo, Jang Mi Hyeon
Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA.
Department of Neurologic Surgery, First Hospital of Jilin University, Changchun, China.
Int Neurourol J. 2018 Oct;22(Suppl 3):S122-130. doi: 10.5213/inj.1836218.109. Epub 2018 Oct 31.
Although aging causes functional declines in cognition, the molecular mechanism underlying these declines remains largely unknown. Recently, the spindle checkpoint kinase budding uninhibited by benzimidazole-related 1 (BubR1) has emerged as a key determinant for age-related pathology in various tissues including brain. However, the neurobehavioral impact of BubR1 has not been explored. In this study, we investigated the role of BubR1 in behavioral function.
To investigate the neurobiological functions of BubR1 in vivo, we utilized transgenic mice harboring BubR1 hypomorphic alleles (BubR1H/H mice), which produce low amounts of BubR1 protein, as well as mice that have specific knockdown of BubR1 in the adult dentate gyrus. To assess anxiety-like behavior, the above groups were subjected to the elevated plus maze and the light-dark test, in addition to utilizing the tail-suspension and forced-swim test to determine depression-like behavior. We used novel object recognition to test for memory-related function.
We found that BubR1H/H mice display several behavioral deficits when compared to wild-type littermates, including increased anxiety in the elevated-plus maze test, depression-like behavior in the tail suspension test, as well as impaired memory function in the novel object recognition test. Similar to BubR1H/H mice, knockdown of BubR1 within the adult dentate gyrus led to increased anxiety-like behavior as well as depression-like behavior, and impaired memory function.
Our study demonstrates a requirement of BubR1 in maintaining proper affective and memory-related behavioral function. These results suggest that a decline in BubR1 levels with advanced age may be a crucial contributor to age-related hippocampal dysfunction.
尽管衰老会导致认知功能下降，但其潜在的分子机制仍 largely 未知。最近，纺锤体检查点激酶苯并咪唑相关 1 未受抑制的芽殖蛋白（BubR1）已成为包括大脑在内的各种组织中与年龄相关病理的关键决定因素。然而，BubR1 的神经行为影响尚未得到探索。在本研究中，我们调查了 BubR1 在行为功能中的作用。
为了在体内研究 BubR1 的神经生物学功能，我们利用了携带 BubR1 低表达等位基因的转基因小鼠（BubR1H/H 小鼠），其产生少量的 BubR1 蛋白，以及在成年齿状回中特异性敲低 BubR1 的小鼠。为了评估焦虑样行为，除了利用尾悬和强迫游泳试验来确定抑郁样行为外，上述组还进行了高架十字迷宫和明暗试验。我们使用新物体识别来测试记忆相关功能。
我们发现，与野生型同窝小鼠相比，BubR1H/H 小鼠表现出几种行为缺陷，包括在高架十字迷宫试验中焦虑增加、在尾悬试验中出现抑郁样行为，以及在新物体识别试验中记忆功能受损。与 BubR1H/H 小鼠相似，成年齿状回中 BubR1 的敲低导致焦虑样行为以及抑郁样行为增加，并且记忆功能受损。
我们的研究表明 BubR1 在维持适当的情感和记忆相关行为功能方面是必需的。这些结果表明，随着年龄增长 BubR1 水平的下降可能是与年龄相关的海马功能障碍的关键因素。
