Mechanisms of Motivation: The Role of Cortical-Basal Ganglia-Dopamine Circuits in Reward Pursuit and Apathy

缺乏追求目标的动力--也就是众所周知的“冷漠”--在许多大脑疾病中是一个非常常见的、使人丧失能力的问题，包括精神分裂症、帕金森氏症和阿尔茨海默氏症。冷漠可能会对生活质量产生毁灭性的影响。它与患者较差的结局和他们的照顾者更大的痛苦有关。目前，它在很大程度上也是治疗耐药的。因此，临床上有必要开发新的有效治疗方法。提高动力有可能改善幸福感，并在几种致残情况下减轻医疗负担。由于冷漠是许多不同大脑疾病的症状，一个有希望的方法是在大脑通常如何权衡选择的成本和好处的背景下考虑冷漠：基于努力的决策以获得回报。例如，大脑化学物质多巴胺和连接的大脑区域，如基底节和额叶皮质，在基于努力的决策中发挥着关键作用，在动物模型和人类患者中的研究表明，这些回路在冷漠中功能障碍。然而，尽管这项研究揭示了这些是潜在的治疗目标，但我们还没有理解这些大脑区域如何与多巴胺相互作用，以激励做出努力追求回报的决定。这个项目旨在解决我们知识中的这一关键差距。为了研究这个问题，我们为老鼠设计了一个新颖的、自然主义的成本收益决策任务，要求它们根据需要付出的努力和获得的回报的大小来选择是否追求回报。这项任务现在为我们探索神经活动和大脑化学的变化如何支持这样的决定奠定了基础，这些决定涉及是否、何时以及如何积极地追求悬赏。我们的第一个目标是揭示与这类决策相关的信息通常是如何由额叶皮质和基底节神经细胞或神经元的特定活动模式以及多巴胺释放来表示的。然后，这可以作为一个脚手架来研究当我们干扰多巴胺来模拟与冷漠相关的功能障碍时会发生什么。为了做到这一点，在一项实验中，我们将在大鼠执行这项任务时，同时记录这些不同脑区的许多神经元。这将使我们不仅可以简单地比较每个区域内的大脑活动如何反映不同的任务变量，并最终是否追求提供的奖励，而且关键是，还可以确定这种信息是否实际上由不同大脑区域的神经元活动模式更强地代表。在第二个实验中，我们将使用新开发的荧光传感器来监测多巴胺何时释放，这些传感器允许我们监测自由行为动物在数周内大脑化学物质的实时波动。我们的第二个目标是确定多巴胺释放、额叶和基底节回路中的神经活动以及动机缺陷之间的直接关系。为了做到这一点，在一个实验中，我们将在人类和动物模型中使用一种诱导冷漠的药物，同时记录老鼠在执行决策任务时的神经活动。在第二个实验中，我们将研究当我们的记录显示多巴胺正常释放时，多巴胺的非常短暂的中断如何影响大鼠克服努力获得奖励的意愿及其神经活动。总之，这些实验将为我们提供新的基础性见解，帮助我们理解神经活动和追求奖励的动机模式如何受到正常或中断的多巴胺的影响，这是迈向基于神经调节的新方法治疗冷漠症状的关键一步。

A lack of motivation to pursue a goal - known as "apathy" - is a very common and disabling problem in many brain disorders, including schizophrenia, Parkinson's disease and Alzheimer's disease. Apathy can have a devastating impact on quality of life. It is associated both with poorer outcomes for patients and greater distress in their caregivers. It is currently also largely treatment resistant. There is therefore a substantial clinical need to develop new effective therapies. Improving motivation has the potential to improve well-being and reduce the healthcare burden across several disabling conditions.As apathy is a symptom in so many different brain disorders, one promising approach has been to consider apathy in the context of how the brain normally weighs up the costs and benefits of a choice: effort-based decision making for reward. For example, the brain chemical dopamine and connected brain regions such as the basal ganglia and frontal cortex play key roles in effort-based decision making, and studies in animal models and human patients suggest that these circuits are dysfunctional in apathy. However, while this research has revealed these as potential targets for treatments, we are held back by not yet understanding how these brain regions interact with dopamine to motivate decisions to put in effort pursuing reward. This project is designed to address this key gap in our knowledge.To investigate this question, we have designed a novel, naturalistic cost-benefit decision making task for rats which requires them to choose whether or not to pursue a reward based on the amount of effort it will take to do this and the size of the reward they would gain. This task now sets the stage for us to explore how changes neural activity and brain chemistry underpin such decisions about if, when and how vigorously to pursue an offered reward. Our first objective is to uncover how information relevant to this type of decision is normally represented by particular patterns of activity in nerve cells, or neurons, in the frontal cortex and basal ganglia, and by dopamine release. This can then act as a scaffold to investigate what happens when we disrupt dopamine to simulate the dysfunction associated with apathy. To do this, in one experiment we will record many neurons simultaneously across these different brain areas as rats perform this task. This will allow us not simply to compare how brain activity within each region reflects the different task variables and ultimately whether to pursue the offered reward, but also, crucially, to determine whether this information is in fact more strongly represented by the activity patterns of neurons across different brain regions. In a second experiment, we will monitor when dopamine is released using newly developed fluorescent sensors that permit us to monitor real time fluctuations in brain chemicals across many weeks in freely behaving animals.Our second objective is to determine the direct relationship between dopamine release, neural activity in frontal and basal ganglia circuits, and deficits in motivation. To do this, in one experiment, we will administer a drug that induces apathy in humans and animal models while we record neural activity in rats as they perform our decision making task. In a second experiment, we will then examine how very brief disruptions of dopamine at times when our recordings showed that dopamine is normally released affect rats' willingness to overcome effort for reward and their neural activity. Together, these experiments will provide us with new foundational insights to help us understand how patterns of neural activity and motivation to pursue reward is influenced by normal or disrupted dopamine, which is a crucial step on the path towards new neuromodulation-based approaches to the treatment of symptoms of apathy.