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影响。它与患者的较差结果和其护理人员的更大痛苦有关。目前它在很大程度上也具有治疗耐药性。因此，临床迫切需要开发新的有效疗法。提高动机有可能改善健康状况并减轻多种残疾情况下的医疗负担。由于冷漠是许多不同大脑疾病的症状，因此一种有希望的方法是在大脑正常情况下考虑冷漠选择的成本和收益：基于努力的奖励决策。例如，大脑化学物质多巴胺和基底神经节和额叶皮层等相连的大脑区域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，这些回路在冷漠时会出现功能障碍。然而，虽然这项研究揭示了这些是潜在的治疗目标，但我们仍因尚未了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奖励的决定而受到阻碍。该项目旨在解决我们知识中的这一关键空白。为了研究这个问题，我们为老鼠设计了一种新颖的、自然主义的成本效益决策任务，要求它们根据奖励的数量选择是否追求奖励。做到这一点需要付出的努力以及他们将获得的回报的大小。这项任务现在为我们探索神经活动和大脑化学变化如何支持有关是否、何时以及如何积极地追求所提供的奖励的决策奠定了基础。我们的第一个目标是揭示与此类决策相关的信息通常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。然后，这可以充当支架来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，在一项实验中，当老鼠执行这项任务时，我们将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比较每个区域内的大脑活动如何反映不同的任务变量以及最终是否追求所提供的奖励，而且至关重要的是，还可以确定这些信息实际上是否更强烈地由神经元的活动模式代表跨越不同的大脑区域。在第二个实验中，我们将使用新开发的荧光传感器监测多巴胺何时释放，这些传感器使我们能够监测自由行为动物的大脑化学物质在数周内的实时波动。我们的第二个目标是确定多巴胺释放与神经元之间的直接关系。额叶和基底神经节回路的活动以及动机缺陷。为此，在一项实验中，我们将施用一种药物，在人类和动物模型中诱导冷漠，同时记录大鼠执行决策任务时的神经活动。在第二个实验中，我们将检查当我们的记录显示多巴胺正常释放时，多巴胺的短暂干扰如何影响老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见解，帮助我们了解正常或紊乱的多巴胺如何影响神经活动模式和追求奖励的动机，这是迈向基于神经调节的新治疗方法的关键一步冷漠的症状。