Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntingtons disease
Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntingtons disease
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DOI：
10.1093/hmg/ddt203
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发表时间：
2013-09-01
影响因子：
3.5
通讯作者：
Petersen, Asa
中科院分区：
文献类型：
--
作者：
Lundh, Sofia Hult;Nilsson, Nathalie;Petersen, Asa
抑郁、焦虑等精神症状是亨廷顿病的重要临床特征。然而，精神病学特征的潜在神经生物学基础尚未完全了解。为了探索抑郁症和焦虑症在HD的生物学起源，我们使用了一个小鼠模型，表达人类全长突变亨廷顿蛋白，BACHD小鼠。我们发现BACHD小鼠早在2月龄时就表现出抑郁和焦虑样特征，如使用Porsolt强迫游泳试验（FST），蔗糖偏好试验和高架十字迷宫（ESTA）评估的。接受抗阿托舍曲林长期治疗的BACHD小鼠与溶媒治疗的BACHD小鼠在FST和THR方面无差异。行为表现发生在海马细胞增殖/神经发生减少或下丘脑垂体肾上腺轴上调的情况下。然而，焦虑和抑郁调节基因的改变存在于BACHD小鼠的下丘脑，包括神经肽Y，速激肽受体3和囊泡单胺转运体2型的mRNA表达减少，以及可卡因和安非他明调节的转录本的表达增加。有趣的是，在老年BACHD小鼠中，下丘脑中的食欲素神经元群体增加并显示细胞萎缩。此外，失活的突变亨廷顿蛋白在一个子集的下丘脑神经元阻止抑郁症的发展。总之，我们的数据表明，BACHD小鼠重演临床HD与早期精神方面，并指出下丘脑功能障碍的作用，在抑郁症和焦虑症的发展。
Psychiatric symptoms such as depression and anxiety are important clinical features of Huntingtons disease (HD). However, the underlying neurobiological substrate for the psychiatric features is not fully understood. In order to explore the biological origin of depression and anxiety in HD, we used a mouse model that expresses the human full-length mutant huntingtin, the BACHD mouse. We found that the BACHD mice displayed depressive- and anxiety-like features as early as at 2 months of age as assessed using the Porsolt forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM). BACHD mice subjected to chronic treatment with the anti-depressant sertraline were not different to vehicle-treated BACHD mice in the FST and EPM. The behavioral manifestations occurred in the absence of reduced hippocampal cell proliferation/neurogenesis or upregulation of the hypothalamicpituitaryadrenal axis. However, alterations in anxiety- and depression-regulating genes were present in the hypothalamus of BACHD mice including reduced mRNA expression of neuropeptide Y, tachykinin receptor 3 and vesicular monoamine transporter type 2 as well as increased expression of cocaine and amphetamine regulated transcript. Interestingly, the orexin neuronal population in the hypothalamus was increased and showed cellular atrophy in old BACHD mice. Furthermore, inactivation of mutant huntingtin in a subset of the hypothalamic neurons prevented the development of the depressive features. Taken together, our data demonstrate that the BACHD mouse recapitulates clinical HD with early psychiatric aspects and point to the role of hypothalamic dysfunction in the development of depression and anxiety in the disease.