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Nov 2018

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The Mouse Gambling Task: Assessing Individual Decision-making Strategies in Mice
小鼠博弈任务:个体决策策略评估   

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Abstract

Decision-making is a complex cognitive process which consists of choosing one option among several alternatives. In humans, this process is featured in the Iowa gambling task (IGT), a decision-making task that mimics real life situations by reproducing uncertain conditions based on probabilistic rewards or penalties (see Background). Several authors wanted to adapt the IGT in rodents with subtle differences in protocols that match various aspects of the human task. Here we propose, for the first time in mice, a protocol that contains the most important characteristics of the IGT: 4 different options, choices based on 4 ambiguous outcomes with immediate and long term rewards, a total of 100 trials, no learning of the contingency before the task, and presence of both a certain reward and a probable penalty. During this task, mice have to choose between options more or less advantageous in the short and long term by developing a decision-making strategy that differs between individuals. Therefore, the strength of this protocol is that it is one of the first to enable the study of decision-making in a complex situation, and demonstrates inter-individual differences regarding decision-making strategies in mice.

Keywords: Decision-making (决策), Mouse (小鼠), Inter-individual differences (个体差异), Gambling (博弈), Reward (奖励), Maze (迷宫), Strategies (策略)

Background

Decision-making is a cognitive process which consists of choosing one option among several alternatives. It progresses from the exploration of unknown options to the exploitation of preferred ones (Bechara et al., 1994). During this cognitive process, the decision maker evaluates the value of each option regarding his/her own preferences and the probability to get it. This computation brings him/her to select one strategy among others. Such strategies are featured in the Iowa gambling task (IGT), a decision-making task that mimics real life situations by reproducing uncertain conditions based on probabilistic rewards or penalties (Bechara et al., 1994). During this task, subjects have to implicitly discover (through somatic markers) which option is advantageous in the long term, with the progressive discovery that options are not available under fixed and predictable contingencies. Several authors adapted the IGT in rodents (de Visser et al., 2011a; van den Bos et al., 2014) to study neurobiological substrates of decision-making (non-exhaustive exemples: Homberg et al., 2008; Pais-Vieira et al., 2009; Zeeb et al., 2009; de Visser et al., 2011a, 2011b and 2011c; Young et al., 2011; Zeeb and Winstanley, 2011; Koot et al., 2012; Pittaras et al., 2013; Rivalan et al., 2013; Peña-Oliver et al., 2014; Van Enkhuizen et al., 2014; Fitoussi et al., 2015; Milienne-Petiot et al., 2017), sex differences (G van den Bos et al., 2012; Georgiou et al., 2018), drugs effect on decision-making (Sanchez-Roige et al., 2015; Gueye et al., 2016; de Laat et al., 2018; Ferland et al., 2017 and 2018), and environmental (Van Hasselt et al., 2012; Koot et al., 2013; Loi et al., 2017a and 2017b) or physiological features on decision-making (Pais-Vieira et al., 2009; de Visser et al., 2011b and 2011c; Koot et al., 2012). So far, the existence of inter-individual differences in decision-making has been linked to specific behaviors (Rivalan et al., 2009 and 2013; Ferland and Winstanley, 2017) and differential neuronal (Rivalan et al., 2009; Fitoussi et al., 2015) or regional neurochemical activity (Pittaras et al., 2016a and 2016b). The numerous adaptations were either in an operant chamber (e.g., Rivalan et al., 2009; Zeeb et al., 2009) or in a maze (e.g., van den Bos et al., 2006; Pittaras et al., 2013 and 2016a). Several reviews provide exhaustive details about the differences and the protocols’ procedures (e.g., de Visser et al., 2011a; van den Bos et al., 2006 and 2014). The protocol that we propose here matches, for the first time in mice, the most important characteristics of the IGT: 4 different options, choices based on 4 ambiguous outcomes with immediate and long term rewards, a total of 100 trials, no learning of the contingencies before the task, and presence of both a certain reward and a probable penalty (Pittaras et al., 2013, 2016a, 2016b and 2018).

Our protocol allows for a precise analysis of individual decision-making strategies in ambiguous situations in mice. Therefore, it can be used to characterize decision-making deficits in a large number of pathological mouse models and assess putative treatments. Additionally, it can be used to test alteration/improvement of decision-making strategies in extreme situations (e.g., lack of sleep, stress). Another very interesting point of this protocol is that it targets inter-individual variability. Indeed, outside of pathological conditions, risky or rigid decision-making could lead to behaviors that have unhealthy consequences over life (drug taking, car accident, unsuitable behavior, etc.). Therefore, by using this protocol, it is possible to understand the neurobiological basis of such behaviors, which provides insight of how to prevent these behaviors.

Materials and Reagents

  1. 8 standard water bottle caps
  2. Paper towel 
  3. Plastic Pasteur pipette
  4. Mice (any strains and sex)
  5. Dustless Precision Pellets (BioServ, New Jersey, catalog number: F0163), Grain-based, 20 mg 
  6. Quinine (Quinine hydrochloride dihydrate, Sigma, catalog number : Q1125-10G)
  7. Distilled water
  8. 10% ethanol

Equipment

  1. Balance
  2. Timer
  3. Skinner cages (optional)
    Apparatus: Identical operant chambers (20 cm x 24 cm x 16 cm, Figure 2A) from ImetronicR (Pessac, France, http://www.imetronic.com/devices/polymodal-system/) are used. Each box includes a house light system delivering approximately 20 lux of white diffused light, 5 holes and a food magazine, located on the wall opposite to the holes, that can deliver food pellets (dustless Precision Pellets, Grain-based, 20 mg, BioServ, New Jersey). During habituation only the central hole and the magazine, equipped with infrared beams detecting head entries, are available.
  4. Maze with four transparent arms (20 cm long x 10 cm wide), an opaque start box (20 cm x 20 cm) and a choice area

Procedure

The experiment consists of two weeks of habituation in the operant chamber followed by one week of the Mouse Gambling Task in the maze (Figure 1).


Figure 1. Timeline of the experiments. MGT: Mouse Gambling Task.


  1. Animals
    1. Depending on your scientific question, this protocol can be done with males or females, different strains and ages or environments (e.g., light cycle), provided that they are mice that can undergo controlled food restriction. In our condition, male C57Bl/6J mice that are 3 to 6 months old at the beginning of the experiments (Charles’ River, Orleans, France) are housed by three or four, in a temperature-controlled room (21 ± 2 °C), with a 12 light/12 dark cycle (lights on at 08:00 AM). We always perform experiments between 09:00 AM and 06:30 PM. Animals should be treated according to the ethical standards defined by the “Centre National de la Recherche Scientifique” for animal health and care with strict compliance with the EEC recommendations (n°86/609). To perform inter-individual analysis, we advise using approximately 20 to 30 individuals.
    2. During the MGT, mice need to be food-restricted (individually maintained at 85% of the free-feeding weight). Water is always provided ad libitum. The week before starting food restriction, weigh the animals twice (two different days, free-feeding weight) and then provide them a suitable amount of food at the end of each day to stabilize their weight at 85% of their free-feeding weight. We advise starting with 2 g/mouse/day and adapting the amount of food depending on the weight change of each mouse. Add some food pellets in their home cage to get them used to eating it.

  2. Habituation period
    It is important to note that this habituation can be done in other conditions because this first step consists of getting the mice used to being manipulated, eating food pellets, and stabilizing their weights. Therefore, using paradigms other than operant chambers is also possible (e.g., a two arms maze or Barnes maze with food at the end of each arm or in each hole). As an example, our lab uses operant chambers. In this section, we describe the procedure that we used.


    Figure 2. Apparatus and proceedings of the habituation period. A. Photograph of one operant chamber. B. Sequence of events during habituation in the operant chamber. When a mouse pokes its nose in the central hole, it triggers the food pellet dispenser and the central hole is turned off. As soon as the animal visits the magazine, the central hole is switched on again and the animal can do another nose poke.

      Experimental procedure: Each time the mouse pokes in the central hole, a food pellet is delivered in the magazine (Figure 2B). Mice undergo one 30 min habituation session a day. Between each mouse the operant chamber is cleaned with a solution of 10% alcohol. In 10 days, we usually observe an increase in the amount of pellets eaten (from ~5 to ~60 food pellets), which shows that animals are learning the task and are getting used to eating in the experimental paradigm. As the amount of pellets earned increases across days, the amount of food given in their home cage decreases to maintain food motivation and weight.

  3. The mouse gambling task
    Since the experiment can take 10 to 30 min per mouse, and two sessions are done for each mouse per day, we advise doing the task with a maximum of 9 mice per week once the procedure is mastered.
    1. Prepare quinine pellets: One week before starting the Mouse Gambling Task, prepare the quinine pellets. To do so, put around 20 dustless food pellets in a plastic container (e.g., Weighing Dishes). Add a 180 mM solution of quinine with a plastic Pasteur pipette (0.2 ml) until the liquid covers all of the pellets (Van Den Bos et al., 2006). Mix the liquid with the pellets until they all become darker (wet). Next, quickly remove any excess liquid and separate the pellets from one another to avoid sticking while drying. Let them dry overnight. For one week (maximum 9 mice), prepare around 50 quinine pellets.
      Note: Usually, mice don’t eat pellets previously soaked in the quinine solution because it is too bitter. If a mouse eats quinine pellets, you might have to exclude it from the group as it might not consider quinine as a penalty.
    2. The task takes place in a maze with four transparent arms (20 cm long x 10 cm wide) containing an opaque start box (20 cm x 20 cm) and a choice area (Figure 3A). Use standard food pellets as a reward (dustless Precision Pellets, Grain-based, 20 mg, BioServ, New Jersey) and food pellets previously steeped in a 180-mM solution of quinine as a penalty. The quinine pellets are unpalatable but not inedible. There are four different arms: two represent the long term “advantageous” choices and the other two the long term “disadvantageous” choices. For each arm, an immediate reward is located at the end of the arm just in front of a bottle cap containing the delayed reward. In “advantageous” arms, mice systematically find 1 pellet (“small reward”) placed in front of a bottle cap containing food pellets in 18 trials of the 20 trials and quinine pellets for the two remaining trials (Figures 3A and 3B). In the “disadvantageous” arms, mice find two food pellets (“large reward”) placed in front of a bottle cap containing quinine pellets in 19 trials of the 20 and food pellets for the remaining trial (Figures 3A and 3B). Advantageous choices are at first less attractive than disadvantageous ones because of the small immediate reward (1 pellet vs. 2 pellets). Despite this apparent lower attractiveness, advantageous choices are advantageous in the long term because food pellets have a higher probability of being found than quinine pellets (18 trials out of 20). Conversely, disadvantageous choices are less advantageous in the long term because animals have a higher probability of finding quinine pellets than food pellets (19 trials out of 20). Therefore, mice have to favour the small immediate reward (advantageous choices) to obtain the highest amount of pellets possible at the end of the day. Each animal completes 20 trials a day: 10 trials (= 1 session) in the morning (between 09:00 AM and 01:00 PM) and 10 trials (=1 session) during the afternoon (between 02:00 PM and 06:00 PM, Pittaras et al., 2013, 2016a, 2016b and 2018). Clean the maze with a 10% ethanol solution between each mouse.


      Figure 3. Apparatus and characteristics of the options of the Mouse Gambling Task. A. Photograph of the maze composed of four arms (two disadvantageous and two advantageous), a choice area and a starting box. B. Schematic representation of the MGT experimental design. White circles represent food pellets and black circles quinine pellets. Advantageous choices give access to one food pellet and disadvantageous choices give access to two food pellets. These immediate rewards are located at the end of the arm just in front of a bottle cap containing the delayed reward. Then the mouse can find three or four food pellets (18/20) or quinine pellets (2/20) in the advantageous choices, and can find four or five food pellets (1/20) or quinine pellets (19/20) in the disadvantageous choices. We distinguish advantageous choices from disadvantageous ones because mice earn more food pellets after 20 trials by choosing the advantageous ones. If a mouse only chooses arm 1 during the 20 trials, it will obtain 74 pellets (1 x 20 immediate food pellets reward and 18 x 3 food pellets as late reward). Likewise, if a mouse only chooses arms 2, 3, or 4 it will obtain 92, 45, or 44 food pellets respectively.

      Sequence of events of the Mouse Gambling Task
      1. Place the mouse in individual cage in the experimental room for a few minutes.
      2. During the first morning session of the first day, randomly distribute 10 food pellets in the maze, and then place the mouse in the maze for 2 min. If the mouse doesn’t eat half of the available pellets, repeat this procedure during the afternoon of the first day. If the mouse eats more than half of the food pellets available, and for all the next morning and afternoon sessions of the task, put the mouse in the maze for 2 min before starting the task with no food pellet in it.
      3. Place the mouse in the starting box inside an opaque cylinder during 15 s to avoid imposing direction to the mouse.
      4. Take out the cylinder and start the timer.
      5. Stop the timer when the mouse enters more than ¾ of its body into one arm. If it takes more than 2 min, return to Step c. If it takes more than 2 min a second time, go directly to Step g.
      6. Score which arm is visited, the latency to make the choice, the number of food pellets eaten and the number of food pellets available to eat like the example in Figure 4.
      7. Put the mouse back in the cylinder.
      8. Clean the maze with distilled water to mix odors.
      9. Prepare each arm for the next trial following Figure 4.
      10. Go back to Step c until the mouse completes a total of 10 trials in the morning and 10 trials in the afternoon.
      Notes:
      1. As the amount of pellets eaten increases across days, the amount of food given in their home cage decreases to maintain food motivation and weight.
      2. Each day the quinine pellets for the advantageous arms and the food pellets for the disadvantageous arms need to be changed following a pseudo-random sequence (e.g., Figure 4). For one mouse, the position of the advantageous and disadvantageous arms remains the same during the 5 experimental days. Between mice, the position of the advantageous and disadvantageous arms is random (Figure 3A). The running order is changed every day. In other words, a mouse that starts the experimentation on Day 1 (9:00 AM) will be the second one on Day 2 (9:30 AM) to avoid a time-dependent behavior.


        Figure 4. Picture example of table to fill during the task. This table is to fill for one day for one mouse that will do 10 trials in the morning and 10 trials in the afternoon. The first three trials are filled as an example. During the first trial, the mouse chooses the advantageous arm 1 in 2 s and eats 5 food pellets from the 5 food pellets available: 1 food pellet in front of the bottle cap (immediate reward) and 4 food pellets inside the bottle cap (late reward).

Data analysis

  1. Global analysis
    We score the percentage of advantageous choices by day [(number of advantageous choices/number of total choices) x 100], the food pellet consumption (pellets earned), the number of quinine pellets obtained (but not eaten) and the latency to choose the arm during trials. The percentage of advantageous choices with control mice always increases across sessions from chance level to around 70% of advantageous choices (Figure 5A). We also calculate a rigidity score by measuring how many times the mouse chooses the same arm. For example, a rigidity score of 25% means that the mouse chooses the arm by chance and a rigidity score of 100% means that the mouse always chooses the same arm. Therefore, a rigidity score of 50% reflects that the mouse chooses one arm twice as much as the others, and a rigidity score of 75% that animal chooses one arm three times more often than the others (Pittaras et al., 2013, 2016a, 2016b, 2018).
  2. Inter-individual decision-making strategies analysis
    Another interesting characteristic of this protocol is that it allows the study of inter-individual variability during decision-making processes in mice (Pittaras et al., 2016a, 2016b and 2018). To do so, we first calculate the mean advantageous choices of the last 30 trials for each animal. Then, we use the K-mean clustering analysis (with Statistica software, version 12, Timmerman et al., 2013). This method distributes each animal to a set of animals that had the closest mean to its own preference value at the end of the task. It is possible to choose the number of groups but we advise separating animals into three typically-observed subgroups (Pittaras et al., 2013, 2016a, 2016b and 2018): animals that choose a majority of advantageous options at the end of the experiments, called “safe”; animals that explore options until the end of the experiment, called “risky”; and animals that maintain some exploration of available options but favor advantageous options, called “average” (Figure 5B). Interestingly, we have shown previously that these three subgroups are always present in a large group of mice (n = 54) following a Gaussian distribution (with safe and risky as extreme groups). Also, we have shown that these extreme subgroups might be more vulnerable to sleep debt (Pittaras et al., 2018) and could be more vulnerable to psychiatric disorders as they showed some specific traits of these diseases (Pittaras et al., 2016a and 2016b).


    Figure 5. Example of the results usually obtained while doing the Mouse Gambling Task. A. Schematic representation of the mean of the percentage of advantageous choices usually observed for control mice during 5 days of the MGT with an illustration of the exploration phase, during which mice explore options, and of an exploitation phase during which mice exploit their knowledge of the value of each option. During the exploration phase, mouse preferences are close to chance level while during the exploitation phase mice progressively prefer advantageous options. B. Schematic representation of the mean of the percentage of advantageous choices usually observed for the three control subgroups of mice.

Notes

  1. Getting mice used to being manipulated by the person who will conduct the Mouse Gambling Task is really important. It reduces stress, freezing and impulsive behavior during the Mouse Gambling Task which could hide the real decision-making strategy and hence lead to inappropriate results.
  2. Food restricted animals housed by 3 or 4 could lead to some difficulties because of potential home cage dominancy. Give food to a mouse alone in another cage for 1 h if you observe that this mouse is losing more weight than others in the same cage.
  3. Bringing mice close to the experimental room 30 min before starting reduces stress during the task.
  4. If you observe that a mouse is eating the quinine pellets several times:
    1. Change the quinine pellets, the quinine might not taste as strong anymore,
    2. Be sure that the mouse’s weight is not too low,
    3. If the mouse continues to eat quinine pellets (unusual), you might have to exclude it from the group as it does not consider quinine as a penalty.
  5. Technical tips:
    1. Preparing the eight possible options in 8 different bottle caps (one bottle cap with 3 food pellets, one bottle cap with 3 quinine pellets, two bottle cap with 4 food pellets and two bottle caps with 4 quinine pellets, one bottle caps with 5 food pellets and one bottle cap with 5 quinine pellets) before starting helps to change quickly between two trials instead of changing the pellets inside the bottle caps for each trial.
    2. Don’t always use the same bottle caps for the quinine and food pellets to ensure that there is a mixture of odors in each bottle cap.

Acknowledgments

We thank all the people who help setting up this behavioral task: Arnaud Cressant, Pierre Serreau, Jessica Bruijel, Françoise Dellu-Hagedorn, Betty Poly. We also thank Nathan Fisher for his help during the writing process.

Competing interests

Authors have no conflicts of interest or competing interests to declare.

Ethics

Animals are treated according to the ethical standards defined by the “Centre National de la Recherche Scientifique” for animal health and care with strict compliance with the EEC recommendations (no. 86/609).

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简介

决策是一个复杂的认知过程,包括从多个选择中选择一个选择。在人类中,爱荷华州赌博任务(IGT)具有这一过程,该任务是一项决策任务,它通过根据概率性奖励或惩罚来复制不确定的条件,从而模仿现实生活中的情况(请参阅背景)。几位作者希望在与人类任务各个方面相匹配的协议中存在细微差异的情况下,将IGT应用于啮齿动物。在这里,我们首次在小鼠中提出了一种包含IGT 最重要特征的方案:4种不同的选择,基于4种模棱两可的结果进行选择,并具有近期和长期的奖励,总共100次试验,不学习在执行任务之前发生意外情况,并且存在一定的奖励和可能的惩罚。在此任务中,小鼠必须通过制定个体之间不同的决策策略,在短期和长期内或多或少有利的选项之间进行选择。因此,该协议的优势在于它是第一个能够在复杂情况下进行决策研究的协议,并且证明了关于小鼠决策策略的个体差异。
【背景】决策是一种认知过程,包括从几种选择中选择一种。它从探索未知的选择发展为优先选择的选择(Bechara et al。,1994)。在此认知过程中,决策者会根据自己的偏好和获得该偏好的可能性来评估每个选项的价值。这种计算使他/她可以选择其他策略。此类策略在爱荷华州赌博任务(IGT)中具有特色,该任务是通过根据概率性奖励或惩罚来复制不确定条件来模仿现实生活中的情况(Bechara et al。,1994)。在这项任务中,受试者必须隐式地发现(通过躯体标记)从长远来看哪个选择是有利的,并且逐步发现在固定和可预测的意外情况下没有可用的选择。有几位作者对啮齿类动物的IGT进行了改编(de Visser等,2011a; van den Bos等,2014),以研究决策的神经生物学基础(非详尽的示例:Homberg等,2008; Pais-Vieira等,2009; Zeeb等,2009; de Visser <等人,2011a,2011b和2011c; Young等人,2011; Zeeb和Winstanley,2011; Koot等人,2012; Pittaras et al。,2013; Rivalan et al。,2013;Peña-Oliver et al。,2014; Van Enkhuizen et等人,2014年; Fitoussi等人,2015年; Milienne-Petiot等人,2017年),性别差异(G van den Bos 等人,,2012; eorgiou 等,,2018),药物对决策的影响(Sanchez-Roige等,,2015; Gueye et al。,2016; de Laat et al。,2018; Ferland et al。,2017和2018),以及环境(范·哈瑟尔特(Van Hasselt 等,2012; Koot 等,2013; Loi 等,2017a和 2017b)或决策的生理特征(Pais-Vieira等,2009;de Visser等人,2011b和2011c;Koot等,2012年)。到目前为止,决策中个体间差异的存在已与特定行为(Rivalan et al。,2009和2013; Ferland和Winstanley,2017)和微分神经元(Rivalan et al。,2009; Fitoussi et al。,2015)或区域神经化学活性(Pittaras et al。,2016a和2016b)。大量改编是在手术室( eg ,Rivalan et al。,2009; Zeeb et al。,2009)或在迷宫( eg ,VanDen Bos et al。,2006; Pittaras et al。,2016a或2016b ??)。若干评论提供了有关差异和协议程序的详尽信息(例如,de Visser等人,2011a?2011b?或2011c?; VanDen Bos et等,2006年和2014年)。我们在此提出的方案首次在小鼠中匹配了IGT的最重要特征:4种不同的选择,基于4种含糊的结果进行选择,并具有近期和长期的回报,共有100项试验,没有学习任务前的紧急情况,以及一定的奖励和可能的惩罚(Pittaras等人,2013、2016a,2016b和2018)。

我们的协议允许在模棱两可的情况下对小鼠的个体决策策略进行精确分析。因此,它可用于表征大量病理小鼠模型中的决策缺陷并评估推定的治疗方法。此外,它还可用于测试极端情况(例如例如,睡眠不足,压力)下决策策略的改变/改善。该协议的另一个非常有趣的点是它针对个体间的可变性。实际上,在病理条件之外,冒险或僵化的决策可能导致行为对生命造成不良后果(吸毒,交通事故,不适当的行为等)。因此,通过使用此协议,可以了解此类行为的神经生物学基础,从而为如何预防这些行为提供了见识。

关键字:决策, 小鼠, 个体差异, 博弈, 奖励, 迷宫, 策略

材料和试剂

  1. 8个标准水瓶盖
  2. 纸巾
  3. 巴斯德吸管
  4. 小鼠(任何品系和性别)
  5. 无尘精密颗粒(BioServ,新泽西州,目录号:F0163),颗粒状,20毫克
  6. 奎宁(二水合奎宁盐酸盐,Sigma,目录号:Q1125-10G)
  7. 蒸馏水
  8. 10%乙醇

设备

  1. 平衡
  2. 计时器
  3. 剥皮机笼(可选)
    设备:来自ImetronicR(法国,佩萨克, http://www.imetronic.com/devices/polymodal-system/ )。每个盒子都包括一个室内照明系统,该系统提供约20 lux的白色漫射光,5个孔和位于孔对面壁上的食物杂志,该杂志可以递送食物颗粒(无尘精密颗粒,基于谷物的20毫克,BioServ , 新泽西州)。在适应过程中,只有中心孔和配备有红外光束检测头部入口的弹匣可用。
  4. 带有四个透明臂(20厘米长x 10厘米宽),一个不透明的启动盒(20厘米x 20厘米)和一个选择区域的迷宫

程序

该实验包括在手术室中适应两周,然后在迷宫中进行鼠标赌博任务一周(图1)。


图1.实验时间表。 MGT:鼠标赌博任务。


  1. 动物
    1. 根据您的科学问题,可以对雄性或雌性,不同品系和年龄或环境(例如,光照周期)进行此实验,前提是它们是可以控制食物摄入的小鼠。在我们的条件下,将实验开始时3到6个月大的雄性C57Bl / 6J小鼠(法国奥尔良,查尔斯河)收容在温度可控的房间(21±2°C)中,容纳三到四只),并具有12亮/ 12暗周期(在08:00 AM亮起)。我们总是在09:00 AM和06:30 PM之间进行实验。应严格按照EEC的建议(n ° 86/609),按照“国家科学研究中心”为动物健康和护理所规定的道德标准对待动物。为了进行个体间分析,我们建议使用大约20到30个人。
    2. 在MGT期间,需要限制小鼠的饮食(单独保持自由进食重量的85%)。总是随意提供水。开始限制食物的一周前,对动物进行两次称重(两天不同,自由进食的重量),然后在每天结束时为它们提供适量的食物,以使其体重稳定在其自由进食重量的85%处。我们建议从每天每只小鼠2克开始,并根据每只小鼠的体重变化来调整食物量。在他们的笼子里加一些食物颗粒,让他们习惯于食用。

  2. 居住期
    重要的是要注意,这种习惯化可以在其他条件下完成,因为第一步是让老鼠习惯于被操纵,吃掉食物颗粒并稳定体重。因此,也可以使用除手术室以外的其他范例(例如,两个手臂的迷宫或Barnes迷宫,每个手臂的末端或每个孔中都有食物)。例如,我们的实验室使用手术室。在本节中,我们描述了所使用的过程。


    图2.适应期的设备和程序。 A.一个手术室的照片。B.在手术室适应期间的事件顺序。当鼠标在中央孔中戳鼻子时,它会触发食物颗粒分配器,并且中央孔关闭。动物访问弹匣后,中心孔就会再次打开,动物可以再次戳鼻子。

    实验步骤:每次鼠标在中央孔中戳戳时,都会在弹匣中传送食物颗粒(图2B)。小鼠每天进行一次30分钟的习惯训练。在每只小鼠之间,手术室用10%的酒精溶液清洗。在10天之内,我们通常会观察到颗粒的摄入量增加(从约5个食物颗粒到约60个食物颗粒),这表明动物正在学习这项任务,并已习惯于在实验范式中进食。随着整天所赚取的颗粒物数量增加,在其家笼中提供的食物量会减少,以保持食物的动力和体重。

  3. 鼠标赌博任务
    由于实验每只老鼠可能需要10到30分钟,并且每天每只老鼠要进行两次训练,因此,建议您在精通此过程后每周最多9只老鼠来完成这项任务。
    1. 准备奎宁小丸:开始鼠标赌博任务前一周,准备奎宁小丸。为此,将约20个无尘食品颗粒放入一个塑料容器(例如,称量盘)中。用塑料巴斯德吸管(0.2 ml)加入180 mM奎宁溶液,直到液体覆盖所有沉淀为止(Van Den Bos et al。,2006)。将液体与沉淀混合,直到它们全部变黑(变湿)。接下来,迅速除去多余的液体,并将颗粒彼此分开,以免干燥时粘连。让它们干燥过夜。一周(最多9只小鼠),准备约50个奎宁小丸。
      注意:通常,老鼠不吃先前浸泡在奎宁溶液中的沉淀,因为它太苦了。如果老鼠吃了奎宁颗粒,您可能不得不将其排除在组外,因为它可能不会将奎宁视为惩罚。
    2. 该任务在具有四个透明臂(20厘米长x 10厘米宽)的迷宫中进行,其中包含一个不透明的起始框(20厘米x 20厘米)和一个选择区域(图3A)。使用标准食品颗粒作为奖励(无尘精密颗粒,基于谷物的20 mg,新泽西州BioServ)和先前浸泡在180mM奎宁溶液中的食品颗粒作为惩罚。奎宁小丸难吃但不可食用。有四个不同的分支:两个代表长期的“不利”选择,另外两个代表长期的“不利”选择。对于每个手臂,即时奖励位于手臂的末端,紧挨着包含延迟奖励的瓶盖。在“有利”臂中,小鼠有系统地在20个试验中的18个试验中找到1个颗粒(“小奖励”)放置在装有食品颗粒的瓶盖前,其余两个试验中奎宁颗粒(图3A和3B)。在“不利”臂中,小鼠在20个试验中的19个试验中,在装有奎宁颗粒的瓶盖前发现了两个食物颗粒(“大奖励”),其余的试验则是食物颗粒(图3A和3B)。首先,有利的选择比不利的选择更具吸引力,因为立即获得的奖励很少(1个颗粒对2个颗粒)。尽管吸引力明显降低,但从长远来看,有利的选择还是有优势的,因为与奎宁颗粒相比,发现食品颗粒的可能性更高(20个试验中有18个试验)。相反,从长远来看,不利的选择不利,因为与食物颗粒相比,动物发现奎宁颗粒的可能性更高(20个试验中有19个试验)。因此,小鼠必须倾向于小的即时奖励(有利的选择),以便在一天结束时获得尽可能多的药丸。每只动物每天完成20次试验:上午(09:00 AM至01:00 PM)进行10次试验(= 1节),并在下午(02:00 PM至06:06)进行10次试验(= 1期):下午00点,Pittaras等,2013、2016a,2016b和2018)。在每只老鼠之间用10%的乙醇溶液清洁迷宫。


      图3.鼠标赌博任务选项的设备和特征。 A.迷宫的照片,该迷宫由四个臂(两个不利和两个有利),一个选择区域和一个起始框组成。B. MGT实验设计的示意图。白色圆圈代表食物颗粒,黑色圆圈代表奎宁颗粒。有利的选择允许进入一个食物颗粒,而不利的选择使得可以进入两个食物颗粒。这些即时奖励位于手臂末端,紧接在包含延迟奖励的瓶盖之前。然后,鼠标可以在有利的选择中找到三个或四个食物颗粒(18/20)或奎宁颗粒(2/20),并可以在四个位置找到四个或五个食物颗粒(1/20)或奎宁颗粒(19/20)。不利的选择。我们将有利的选择与不利的选择区分开来,因为通过选择有利的选择,小鼠在20次试验后获得了更多的食物颗粒。如果鼠标在20个试验中仅选择第1手臂,它将获得74个颗粒(1 x 20个速食颗粒奖励和18 x 3个颗粒作为后期奖励)。同样,如果鼠标只选择第2、3或4个手臂,则将分别获得92、45或44个食物颗粒。

      鼠标赌博任务的事件顺序
      1. 将鼠标放在实验室的单个笼子中几分钟。
      2. 在第一天的第一个早上,在迷宫中随机分配10个食物颗粒,然后将鼠标放在迷宫中2分钟。如果鼠标没有吃掉可用颗粒的一半,请在第一天下午重复此过程。如果鼠标吃了一半以上的可用食物颗粒,并且在任务的所有第二天早上和下午,都将鼠标放在迷宫中2分钟,然后再开始执行没有食物颗粒的任务。
      3. 在15秒钟之内,将鼠标放在不透明圆柱体内的启动框中,以避免向鼠标强加方向。
      4. 取出钢瓶并启动计时器。
      5. 当鼠标的一只手臂超过其3/4的身体时,请停止计时器。如果需要2分钟以上,请返回到步骤 c 。如果第二次需要2分钟以上,请直接转到步骤g。
      6. 如图4中的示例所示,对访问哪一臂,做出选择的等待时间,食用的食物颗粒的数量以及可食用的食物颗粒的数量进行评分。
      7. 将鼠标放回圆柱体中。
      8. 用蒸馏水清洁迷宫以混合气味。
      9. 准备每个手臂以进行图4所示的下一次试验。
      10. 返回步骤 c ,直到鼠标在上午完成总共10次试验,在下午完成10次试验。
      注释:
      1. 随着整天所吃的小丸数量的增加,在其笼子中提供的食物数量会减少,以保持食物的动力和体重。
      2. 每天需要按照伪随机顺序更改用于有利臂的奎宁颗粒和用于不利臂的食物颗粒( 例如 ,图4) 。对于一只小鼠,在5个实验日中,有利臂和不利臂的位置保持不变。在小鼠之间,有利臂和不利臂的位置是随机的(图3A)。运行顺序每天都会更改。换句话说,在第1天(9:00 AM)开始实验的鼠标将成为第2天(9:30 AM)的第二只鼠标,以避免时间依赖性行为。


        图4.在任务期间要填写的表格的图片示例。该表格将为一只鼠标填充一天,该鼠标将在上午进行10次试验,在下午进行10次试验。以前三个试验为例。在第一次试验中,鼠标在2 s内选择了有利的手臂,并从5种可用的食物颗粒中吃了5种食物颗粒:瓶盖前面有1个食物颗粒(立即奖励),瓶盖内部有4个食物颗粒(后期)奖励)。

数据分析

  1. 全局分析
    我们按天数对有利选择的百分比进行评分[((有利选择的数量/总选择的数量)x 100),食物颗粒的消耗量(所获得的颗粒),获得的奎宁颗粒的数量(但未被食用)和选择的延迟时间在试验中的手臂。对照小鼠的有利选择百分比始终在整个过程中从机会水平增加到有利选择的70%左右(图5A)。我们还通过测量鼠标选择同一条手臂的次数来计算刚度得分。例如,刚度分数为25%表示鼠标偶然选择了手臂,而刚度分数为100%意味着鼠标始终选择了同一只手臂。因此,刚度得分为50%表示鼠标选择一只手臂的频率是另一只手臂的两倍,而刚度得分为75%的动物选择一只手臂的频率是另一只手臂的三倍(Pittaras等人<,2013、2016a,2016b,2018)。
  2. 个体间决策策略分析
    该协议的另一个有趣特征是,它允许研究小鼠决策过程中的个体间变异性(Pittaras等,2016a,2016b和2018)。为此,我们首先为每只动物计算最近30次试验的平均有利选择。然后,我们使用K均值聚类分析(使用Statistica软件,版本12,Timmerman等,2013年)。此方法将每只动物分配给一组在任务结束时具有最接近其自身偏好值的动物。可以选择组的数量,但我们建议将动物分为三个通常观察到的亚组(Pittaras等,2013、2016a,2016b和2018):选择大多数有利选项的动物在实验结束时,称为“安全”;探索选择直到实验结束的动物,称为“风险”;以及对可用选项进行一些探索但偏爱有利选项的动物,称为“平均”(图5B)。有趣的是,我们先前已经证明,这三个亚组始终按照高斯分布(安全和危险为极端组)出现在一大批小鼠(n = 54)中。此外,我们已经表明,这些极端亚组可能更容易遭受睡眠债务的困扰(Pittaras et al。,2018),并且由于他们表现出这些疾病的某些特定特征(Pittaras,因此可能更容易患精神病) et al。,2016a和2016b)。


    图5。通常在执行鼠标赌博任务时获得的结果示例。 A。用示意图说明在MGT的5天中通常观察到的对照小鼠的有利选择百分比的平均值处于探索阶段(在此期间,小鼠探索各种选择),在一个开发阶段(在此阶段,小鼠利用其对每种选择的价值的了解)。在探索阶段,老鼠的偏好接近机会水平,而在探索阶段,老鼠逐渐喜欢有利的选择。B.通常观察到的三个对照组小鼠的优势选择百分比平均值的示意图。

笔记

  1. 让鼠标习惯要执行鼠标赌博任务的人的操作确实很重要。它可以减少鼠标赌博任务期间的压力,冻结和冲动行为,这可能隐藏真正的决策策略,从而导致不合适的结果。
  2. 受食物限制的3或4只动物可能会因为潜在的笼养优势而导致一些困难。如果您观察到这只老鼠的体重比同一个笼子里的其他老鼠的体重减轻了更多,请给它单独喂食1小时。
  3. 在开始前30分钟将小鼠带到实验室附近,以减轻任务过程中的压力。
  4. 如果您观察到小鼠多次食用奎宁颗粒,请执行以下操作:
    1. 更换奎宁颗粒,奎宁的味道可能不再那么浓烈,
    2. 确保鼠标的重量不要太低,
    3. 如果鼠标继续吃奎宁小丸(不常见),则您可能不得不将其从组中排除,因为它不认为奎宁是一种惩罚。
  5. 技术提示:
    1. 在8个不同的瓶盖中准备八个可能的选项(一个瓶盖3个食物颗粒,一个瓶盖3个奎宁颗粒,两个瓶盖4个食物颗粒和两个瓶盖4个奎宁颗粒,一个瓶盖5个食物颗粒以及在开始之前使用一个带有5个奎宁颗粒的瓶盖)有助于在两次试验之间快速更改,而不是在每次试验中都更改瓶盖内的颗粒。
    2. 奎宁和食物颗粒不要总是使用相同的瓶盖,以确保每个瓶盖中都有混合的气味。

致谢

我们感谢所有帮助设置此行为任务的人:Arnaud Cressant,Pierre Serreau,Jessica Bruijel,FrançoiseDellu-Hagedorn,Betty Poly。我们还要感谢内森·费舍尔(Nathan Fisher)在撰写过程中所提供的帮助。

利益争夺

作者没有利益冲突或利益冲突声明。

伦理

严格按照EEC的建议(第86/609号),按照“国家科学研究中心”规定的动物卫生和护理道德标准对动物进行治疗。

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引用:Pittaras, E., Rabat, A. and Granon, S. (2020). The Mouse Gambling Task: Assessing Individual Decision-making Strategies in Mice. Bio-protocol 10(1): e3479. DOI: 10.21769/BioProtoc.3479.
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