Dopamine receptor 1 neurons in the dorsal striatum regulate food anticipatory circadian activity rhythms in mice.
Dopamine receptor 1 neurons in the dorsal striatum regulate food anticipatory circadian activity rhythms in mice.
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DOI：
10.7554/elife.03781
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发表时间：
2014-09-12
期刊：
影响因子：
7.7
通讯作者：
Steele AD
中科院分区：
文献类型：
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作者：
Gallardo CM;Darvas M;Oviatt M;Chang CH;Michalik M;Huddy TF;Meyer EE;Shuster SA;Aguayo A;Hill EM;Kiani K;Ikpeazu J;Martinez JS;Purpura M;Smit AN;Patton DF;Mistlberger RE;Palmiter RD;Steele AD
食物预期活动（FAA）的日常节律是独立于视交叉上核调节的，视交叉上核介导对光的节律，但建立FAA的神经回路仍然是难以捉摸的。在这项研究中，我们发现缺乏多巴胺D1受体的小鼠（D1R KO小鼠）的FAA明显减少，而缺乏多巴胺D2受体的小鼠FAA正常。为了确定多巴胺在哪里发挥作用，我们限制了多巴胺缺乏小鼠背纹状体的多巴胺信号表达；这些小鼠出现了FAA。在背纹状体中，D1R - KO小鼠生物钟基因period2的日常表达节律被明显抑制。每天同一时间的D1R药理激活足以在野生型小鼠中建立预期活性。这些结果表明，多巴胺信号传递给背纹状体中表达d1r的神经元在FAA的表现中起重要作用，可能通过同步调节动机过程和行为输出的昼夜节律振荡器来实现。如果你曾经坐过长途飞机，你可能对时差很熟悉。这种迷失方向的感觉之所以发生，是因为我们的大脑有“内部时钟”，它记录着昼夜循环，并控制着我们什么时候感到最累，什么时候最清醒。快速地从一个时区飞到另一个时区会导致这个时钟与当地时间不同步。然后，大脑的生物钟需要时间来慢慢调整，以适应新环境中的明暗程度。人类——以及其他动物、植物、甚至藻类——都有类似的生物钟，用来控制行为和预测事件，比如吃饭的时间。这些时钟可以根据以前的食物供应经验来设定，并且可以独立于那些遵循昼夜循环的时钟。例如，老鼠体内有生物钟，使它们在晚上更活跃，白天睡觉。然而，如果食物只在白天提供，比如在下午2点，饥饿的老鼠会在醒来时迅速调整，以便在提供食物时立即获得食物。此外，在新的喂食时间之前的几个小时里，老鼠会倾向于跳来跳去，四处走动；这被称为“食物预期活动”。研究人员已经研究这种活动大约40年了，但是大脑的特定区域和支持这些进食行为节奏的过程仍然未知。现在，Gallardo等人已经证明，老鼠需要多巴胺——一种通常被称为大脑“感觉良好的化学物质”的神经递质——来维持支持食物预期活动的内部时钟。神经递质是在神经元之间传递信号的化学物质；一个神经元释放这种化学物质，另一个神经元利用神经元表面被称为受体的蛋白质来检测它。两种主要的受体——D1受体和D2受体——检测多巴胺。Gallardo等人发现D1受体对于维持进食相关的日常节律很重要，而D2受体则不然。此外，多巴胺只需要在大脑的背纹状体中产生，就会发生食物预期活动。这表明只有这个区域的D1受体影响这种活动，尽管大脑的许多其他区域也含有这些受体。下一个挑战是解开控制食物预期行为的神经回路。例如，是什么“告诉”背纹状体中的神经元动物饿了？哪些D1受体表达神经元传递食物预期行为的时间信息，传递到哪里？此外，如果人类也有类似的生物钟，那么通过测试来观察饮食失调患者的生物钟是否失调，可以帮助我们更好地了解这些情况。DOI: http://dx.doi.org/10.7554/eLife.03781.002
Daily rhythms of food anticipatory activity (FAA) are regulated independently of the suprachiasmatic nucleus, which mediates entrainment of rhythms to light, but the neural circuits that establish FAA remain elusive. In this study, we show that mice lacking the dopamine D1 receptor (D1R KO mice) manifest greatly reduced FAA, whereas mice lacking the dopamine D2 receptor have normal FAA. To determine where dopamine exerts its effect, we limited expression of dopamine signaling to the dorsal striatum of dopamine-deficient mice; these mice developed FAA. Within the dorsal striatum, the daily rhythm of clock gene period2 expression was markedly suppressed in D1R KO mice. Pharmacological activation of D1R at the same time daily was sufficient to establish anticipatory activity in wild-type mice. These results demonstrate that dopamine signaling to D1R-expressing neurons in the dorsal striatum plays an important role in manifestation of FAA, possibly by synchronizing circadian oscillators that modulate motivational processes and behavioral output. DOI: http://dx.doi.org/10.7554/eLife.03781.001 If you have ever traveled a long distance by plane, you will likely be familiar with jet lag. This disorientating sensation occurs because our brains have ‘internal clocks’ that keep track of the day–night cycle and control when we feel most tired or most alert. Flying rapidly from one time zone to another causes this clock to fall out of sync with the local time. It then takes time for the brain's clock to slowly adjust by responding to the levels of light and dark in the new environment. Humans—and other animals, plants, and even algae—have similar internal clocks, which are used to control behavior and predict events, such as the timing of a meal. These clocks can be set based on previous experiences of when food has been available and can be independent of those that follow the daily cycle of light and dark. Mice, for example, have internal clocks that make them more active at night and sleep during the day. However, if food is only provided during the day—say, at 2 o'clock in the afternoon—hungry mice will quickly adjust when they are awake in order to get the food as soon it is provided. Also, for a few hours before their new feeding time the mice will tend to jump and move around more; this is known as ‘food anticipatory activity’. Researchers have been studying this activity for around 40 years, but the specific regions of the brain and the processes that support these rhythms of feeding behavior remained unknown. Now, Gallardo et al. have shown that mice need dopamine—a neurotransmitter that is often called the brain's ‘feel-good chemical’—to maintain the internal clock that supports food anticipatory activity. Neurotransmitters are chemicals that carry signals between neurons; one neuron releases the chemical, and another detects it using proteins on the neuron's surface called receptors. Two main types of receptors—called D1 receptors and D2 receptors—detect dopamine. Gallardo et al. found that D1 receptors are important for maintaining feeding-related daily rhythms, but that D2 receptors are not. Additionally, dopamine only needs to be produced in a region of the brain called the dorsal striatum for food anticipatory activity to occur. This suggests that only D1 receptors in this region influence this activity, though there are many other regions of the brain that contain these receptors. The next challenge is to unravel the neural circuits that control food anticipation behavior. For example, what ‘tells’ the neurons in the dorsal striatum that an animal is hungry? Which of the D1 receptor expressing neurons relay the information about the timing of food anticipatory behavior and to where? Also, if a similar clock operates in humans, testing to see if it is misregulated in people with eating disorders could help us to better understand these conditions. DOI: http://dx.doi.org/10.7554/eLife.03781.002