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

动机机制：皮质-基底神经节-多巴胺回路在奖励追求和冷漠中的作用

• 批准号: MR/X022080/1
• 负责人: Mark Walton
• 金额: $ 119.85万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX022080%2F1
• 关键词: Mechanisms; Motivation; Role; Cortical; Basal

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.

缺乏追求目标的动力--被称为“冷漠”--是许多大脑疾病中一个非常常见和致残的问题，包括精神分裂症、帕金森病和阿尔茨海默病。冷漠会对生活质量产生毁灭性的影响。它与患者的不良结局和护理人员的更大痛苦有关。目前，它在很大程度上也是耐药的。因此，临床上需要开发新的有效疗法。提高动机有可能改善幸福感，并减轻几种致残疾病的医疗负担。由于冷漠是许多不同大脑疾病的症状，一种有希望的方法是在大脑通常如何权衡选择的成本和收益的背景下考虑冷漠：基于努力的奖励决策。例如，大脑中的化学物质多巴胺和相关的大脑区域，如基底神经节和额叶皮层，在基于努力的决策中发挥着关键作用，对动物模型和人类患者的研究表明，这些回路在冷漠中功能失调。然而，虽然这项研究揭示了这些作为治疗的潜在目标，但我们还不了解这些大脑区域如何与多巴胺相互作用，以激励决定努力追求奖励。为了研究这个问题，我们设计了一个新颖的、自然主义的成本效益决策任务，要求大鼠根据所付出的努力和获得的奖励大小来选择是否追求奖励。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些决定奠定了基础，这些决定是关于是否，何时以及如何积极地追求提供的奖励。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通过额叶皮层和基底神经节中的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，它可以作为一个支架来研究当我们破坏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，在一个实验中，我们将在大鼠执行这项任务时同时记录这些不同大脑区域的许多神经元。这将使我们不仅能够简单地比较每个区域的大脑活动如何反映不同的任务变量，并最终确定是否追求提供的奖励，而且，至关重要的是，确定这些信息是否实际上更强烈地反映在不同大脑区域的神经元活动模式中。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的释放，这种传感器使我们能够监测自由行为动物大脑化学物质在数周内的真实的时间波动，我们的第二个目标是确定多巴胺释放、额叶和基底神经节回路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，我们将管理一种药物，诱导人类和动物模型的冷漠，同时我们记录大鼠的神经活动，因为他们执行我们的决策任务。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，多巴胺的短暂中断如何影响大鼠克服奖励努力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，帮助我们了解神经活动模式和追求奖励的动机如何受到正常或中断的多巴胺的影响，这是通往新的基于神经调节的方法治疗冷漠症状的关键一步。