Chronic brain histamine depletion in adult mice induced depression-like behaviours and impaired sleep-wake cycle
Chronic brain histamine depletion in adult mice induced depression-like behaviours and impaired sleep-wake cycle
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DOI：
10.1016/j.neuropharm.2020.108179
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发表时间：
2020-06
影响因子：
4.7
通讯作者：
Y. Yamada;T. Yoshikawa;Fumito Naganuma;Takako Kikkawa;N. Osumi;K. Yanai
中科院分区：
文献类型：
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作者：
Y. Yamada;T. Yoshikawa;Fumito Naganuma;Takako Kikkawa;N. Osumi;K. Yanai
组胺作为一种神经递质调节各种生理过程。脑组胺是由一种必需的氨基酸组氨酸在组氨酸脱羧酶(HDC)的催化下合成的。HDC阳性神经元主要存在于下丘脑后部的结节乳头核(TMN)，并向整个大脑投射轴突。最近的研究报道，在几种神经疾病中观察到成人大脑中组胺水平的慢性下降。然而，人们对较低的组胺水平是否在这些疾病中起到致病作用还知之甚少。在目前的研究中，我们在成年小鼠的大脑中诱导了慢性组胺缺乏，以便直接解释组胺能神经系统受损与由此产生的表型之间的关系。将表达Cre重组酶的腺相关病毒显微注射到8周龄HDC Flox小鼠(CKO小鼠)的TMN中，以诱导8周龄的慢性脑组胺缺乏。免疫组织化学显示Cre重组酶在CKO小鼠TMN中有表达。CKO脑组织HDC表达减少，组胺含量减少。行为学研究表明，CKO小鼠的慢性组胺耗竭导致了类似抑郁的行为，减少了在家中的活动，并损害了厌恶记忆。睡眠分析显示，CKO小鼠全天的清醒时间减少，非快速眼动睡眠时间增加。综上所述，这项研究清楚地表明，成年小鼠大脑中的慢性组胺耗竭在脑功能障碍中起到了致病作用。
Histamine acts as a neurotransmitter to regulate various physiological processes. Brain histamine is synthesized from an essential amino acid histidine in a reaction catalysed by histidine decarboxylase (Hdc). Hdc-positive neurons exist mainly in the tuberomammillary nucleus (TMN) of the posterior hypothalamus and project their axons to the entire brain. Recent studies have reported that a chronic decrease in histamine levels in the adult human brain was observed in several neurological disorders. However, it is poorly understood whether lower histamine levels play a causative role in those disorders. In the present study, we induced chronic histamine deficiency in the brains of adult mice to allow direct interpretation of the relationship between an impaired histaminergic nervous system and the resultant phenotype. To induce chronic brain histamine deficiency starting in adulthood, adeno-associated virus expressing Cre recombinase was microinjected into the TMN of Hdc flox mice (cKO mice) at the age of 8 weeks. Immunohistochemical analysis showed expression of Cre recombinase in the TMN of cKO mice. The reduction of histamine contents with the decreased Hdc expression in cKO brain was also confirmed. Behavioural studies revealed that chronic histamine depletion in cKO mice induced depression-like behaviour, decreased locomotor activity in the home cage, and impaired aversive memory. Sleep analysis showed that cKO mice exhibited a decrease in wakefulness and increase in non-rapid eye movement sleep throughout the day. Taken together, this study clearly demonstrates that chronic histamine depletion in the adult mouse brain plays a causative role in brain dysfunction.