Deciding 'if' and 'when' to act: A neuroanatomical and neurochemical investigation

在执行一项自愿行动时，考虑到在特定环境中行动的潜在好处，一个人不仅要决定选择哪种行动，还要决定是否首先发起一项行动。试想一只豹子在权衡是去麻烦地追赶一只鹿，还是继续在树荫下休息，期待更好的猎物最终会出现。只要追求一个选择需要努力和时间，而不是其他追求，行动的动机就需要考虑潜在的回报，环境中其他机会的分布，以及行动的成本。如果鹿是豹子最喜欢的食物，豹子可能会决定采取行动，开始捕猎，但如果其他机会很少，或者如果鹿不需要什么努力就能捕猎，豹子也可能会这样做。然而，如果成本、收益或环境（即上下文信息）与此相反，则不可能启动任何行动，豹子可能保持不活动并继续休息。我的主要目标是了解上下文信息如何影响动物的行动意愿，以及它如何通过大脑回路施加这种影响。为了实现这一目标，我将使用多种方法：我将训练猕猴完成一项简单的基于计算机的任务。他们将有机会为潜在的回报而采取行动，并应决定是采取行动以获得机会的利益并承担其成本，还是不采取行动并等待未来的回报。当动物完成任务时，当前机会的好处及其发生的环境会发生变化。我将使用数学模型来预测动物在当前环境下的行动意愿。当动物执行任务时，我将用功能性磁共振成像（fMRI）记录它们的大脑活动。功能磁共振成像是一种非侵入性成像方法，可以产生大脑的整体图像。使用这种方法，我将确定调节环境信息和动物行动意愿之间关系的大脑区域。然而，fMRI是一种“相关”方法。为了证明这种行为是否由已识别的大脑区域“引起”，我将使用经颅超声（TUS）神经刺激。TUS神经刺激是一种新颖的非侵入性方法，即使在距离表面一定深度的地方也能短暂地局部改变大脑活动。fMRI和TUS显示了大脑中哪些区域跟踪情境信息对行动意愿的影响。然而，为了获得更全面的了解，我们还需要确定传递这些信息的化学信使。在项目的第二部分，我将使用TUS将药理学药物输送到大脑中的特定目标，并研究它们对大脑和行为的影响。通过这样做，我将能够确定在调节情境信息对行动意愿的影响方面发挥重要作用的主要化学信使。理解大脑的行动意愿机制不仅对建立对决策的全面理解至关重要，而且在这样做的过程中，我们还可以寻求理解可能由该回路功能障碍引起的适应不良行为，例如当环境变化时未能采取适当的行动。这种失败的特征是冷漠和冲动，这些症状在许多精神和神经疾病中普遍存在。此外，在我的项目中有很多机会可以改善动物福利。例如，使用每只动物作为自己的对照（重复测量设计）减少了使用的动物数量，非侵入性技术（fMRI， TUS）的应用减少了伤害并促进了将研究结果转化为人类。这项研究将在牛津大学生物医学科学大楼进行，这里是世界领先的非人类灵长类动物研究中心之一，并得到跨学科合作者网络的支持。

When performing a voluntary action, one has to decide not only which action to choose but whether or not to initiate an action in the first place, given the potential benefits of acting in a particular environment. Consider a leopard weighing up whether to go to the trouble of chasing a deer or continue resting under the shadow of a tree in the expectation that better prey will eventually come along. Insofar as pursuing an option requires effort and time away from other pursuits, motivation to act requires considering the potential reward(s), the distribution of other opportunities in the environment, and the cost of action. The leopard may decide to act and start a hunt if the deer is her preferred food, but she may also do so if other opportunities are currently few and far between or if the deer requires little effort to hunt. If the costs, benefits, or environment (i.e., contextual information) are otherwise, however, then no action may be initiated, and the leopard may remain inactive and continue resting.My key goal is to understand how contextual information influences animals' willingness-to-act and how it exerts this influence via brain circuits. To achieve this goal, I will use a combination of methods:I will train macaques on a simple computer-based task. They will be presented with opportunities to act for potential reward and should decide whether to act in order to receive the benefits of the opportunity and incur its costs or refrain from action and wait for future ones. The benefits of a current opportunity and the environment in which it occurs change as animals go through the task. I will use mathematical models to predict animals' willingness-to-act given the current context. While animals are performing the task, I will record their brain activity with functional magnetic resonance imaging (fMRI). fMRI is a non-invasive imaging method that can produce an overall picture of the brain. Using this method, I will identify brain areas that mediate the relationship between contextual information and animals' willingness-to-act. fMRI, however, is a 'correlational' method. To show whether the behaviour is 'caused' by the identified brain areas, I will use transcranial ultrasound (TUS) neurostimulation. TUS neurostimulation is a novel and non-invasive method that can transiently and focally alter brain activity even at some depth from the surface.fMRI and TUS show which areas in the brain track the effect of contextual information on willingness-to-act. However, to get a broader picture one also needs to identify the chemical messengers that transmit this information. In the second part of the project, I will use TUS to deliver pharmacological agents to specific targets in the brain and investigate their effect on the brain and behaviour. By doing so, I will be able to identify major chemical messengers that play important roles in mediating the influence of contextual information on willingness-to-act.Understanding the brain mechanisms of willingness-to-act is not only essential for building a comprehensive understanding of decision making, but in doing so, we can also seek to understand maladaptive behaviours that potentially arise from dysfunction in this circuitry such as failure to act appropriately when environments change. Such failures characterise apathy and impulsivity, symptoms prevalent in a number of psychiatric and neurological disorders. Additionally, there are multiple opportunities within my project to improve animal welfare. For example, using each animal as its own control (repeated-measures design) reduces the number of animals used and the application of non-invasive techniques (fMRI, TUS) reduces harm and facilitates translation of findings to humans. This research will be carried out at the Oxford University Biomedical Sciences Building, home to one of the world-leading centres for non-human primate research, with support from a cross-disciplinary network of collaborators.