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.

在许多脑部疾病中，缺乏追求目标的动力 - 被称为“冷漠”是一个非常普遍且残疾的问题，包括精神分裂症，帕金森氏病和阿尔茨海默氏病。冷漠会对生活质量产生破坏性的影响。它既与患者的结果较差，也与护理人员的困扰更大有关。目前，它也很大程度上耐药。因此，开发新有效疗法有很大的临床需求。改善动机有可能改善幸福感并减轻几种残疾状况的医疗保健负担。由于冷漠是如此多种不同的脑部疾病的症状，一种有前途的方法是考虑在大脑通常如何权衡选择的成本和福利的背景下进行冷漠：基于努力的决策获得奖励。例如，大脑化学多巴胺和连接的大脑区域（例如基底神经节和额叶皮层）在基于努力的决策中起着关键作用，并且对动物模型和人类患者的研究表明，这些电路在冷漠中功能障碍。但是，尽管这项研究揭示了这些作为治疗的潜在目标，但我们尚未理解这些大脑区域如何与多巴胺相互作用，以激发决定努力追求奖励。该项目旨在解决我们的知识中的这一关键差距。为了调查这个问题，我们为老鼠设计了一个新颖的，自然的成本效益决策任务，要求他们选择是否基于为此所需的努力和所获得的奖励所花费的努力寻求奖励。现在，这项任务为我们探讨了如何改变神经活动和大脑化学的决定，这是关于是否，何时以及如何积极寻求提供的奖励的决定。我们的第一个目标是发现与这种类型的决策相关的信息通常由神经细胞或神经元，额叶皮层和基底神经节的特定活动模式以及多巴胺释放表示。然后，这可以充当脚手架，以研究当我们破坏多巴胺以模拟与冷漠相关的功能障碍时会发生什么。为此，在一个实验中，我们将在大鼠执行此任务时同时记录许多神经元。这将使我们不仅可以比较每个区域内的大脑活动如何反映不同的任务变量，并最终是否寻求所提供的奖励，而且至关重要的是，确定这些信息实际上是否更强烈地由不同大脑区域的神经元的活动模式来表示。在第二个实验中，我们将使用新开发的荧光传感器释放多巴胺何时释放多巴胺，这使我们能够在自由行为的动物中监测多个星期的大脑化学物质中的实时波动。我们的第二个目标是确定多巴胺释放，额叶和基底神经节电路的神经活动之间的直接关系，以及动机中的缺陷。为此，在一个实验中，我们将管理一种吸引人类和动物模型中冷漠的药物，而我们在大鼠执行决策任务时记录了他们的神经活动。在第二个实验中，我们将研究多巴胺的录音表明通常释放多巴胺的多巴胺的短暂破坏如何影响大鼠克服奖励和神经活动的努力的意愿。这些实验将共同为我们提供新的基础见解，以帮助我们了解神经活动的模式和追求奖励的模式如何受到正常或破坏的多巴胺的影响，这是迈向迈向基于神经调节的方法来治疗症状症状的新方法的关键步骤。