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

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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.