Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover
Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover
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DOI：
10.1101/lm.67603
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发表时间：
2003-11-01
影响因子：
2
通讯作者：
Huston, JP
中科院分区：
文献类型：
--
作者：
Dere, E;De Souza-Silva, MA;Huston, JP
大脑的组胺能系统与海马区突触的可塑性、学习和记忆以及大脑的奖励和强化有关。我们过去的药理和损伤研究表明，大脑的组胺系统与中脑边缘多巴胺系统相互作用，对大脑强化的相应奖赏系统产生抑制作用，从而调节学习和记忆能力。鉴于大脑强化和记忆过程之间的密切功能关系，小鼠大脑组胺合成的完全中断是通过其合成酶组氨酸脱羧酶(HDC)的遗传破坏来实现的，这可能会对学习产生不同的影响，这取决于任务固有的强化偶发事件。在这里，我们研究了在非强化的物体探索任务和负强化的水迷宫任务中，HDC基因中断对小鼠的影响，以及对参与大脑奖励和强化的新脑纹状体和腹侧纹状体多巴胺系统的影响。组氨酸脱羧酶基因敲除(HDC-KO)小鼠在新纹状体中有较高的二氢苯乙酸浓度和较高的二氢苯乙酸/多巴胺比率。在腹侧纹状体，HDC-KO小鼠的二氢苯乙酸/多巴胺和3-甲氧基酪胺/多巴胺比值较高。此外，HDC-KO小鼠在隐藏和线索平台任务中的水迷宫表现出改善，但缺乏基于时间关系的对象辨别能力。我们的数据表明，大脑组胺合成的中断可以通过不同和独立的机制同时具有促进记忆和抑制记忆的作用，并进一步表明这些相反的作用与任务固有的强化偶发事件有关。
The brain's histaminergic system has been implicated in hippocampal synaptic plasticity, learning, and memory, as well as brain reward and reinforcement. Our past pharmacological and lesion studies indicated that the brain's histamine system exerts inhibitory effects on the brain's reinforcement respective reward system reciprocal to mesolimbic dopamine systems, thereby modulating learning and memory performance. Given the close functional relationship between brain reinforcement and memory processes, the total disruption of brain histamine synthesis via genetic disruption of its synthesizing enzyme, histidine decarboxylase (HDC), in the mouse might have differential effects on learning dependent on the task-inherent reinforcement contingencies. Here, we investigated the effects of an HDC gene disruption in the mouse in a nonreinforced object exploration task and a negatively reinforced water-maze task as well as on neo- and ventro-striatal dopamine systems known to be involved in brain reward and reinforcement. Histidine decarboxylase knockout (HDC-KO) mice had higher dihydrophenylacetic acid concentrations and a higher dihydrophenylacetic acid/dopamine ratio in the neostriatum. In the ventral striatum, dihydrophenylacetic acid/dopamine and 3-methoxytyramine/dopa mine ratios were higher in HDC-KO mice. Furthermore, the HDC-KO mice showed improved water-maze performance during both hidden and cued platform tasks, but deficient object discrimination based on temporal relationships. Our data imply that disruption of brain histamine synthesis can have both memory promoting and suppressive effects via distinct and independent mechanisms and further indicate that these opposed effects are related to the task-inherent reinforcement contingencies.