Deciding 'if' and 'when' to act: A neuroanatomical and neurochemical investigation

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When performing a voluntary action, one has to decide not only which action to choose but whether or not to initiate an action in the first place, given the potential benefits of acting in a particular environment. Consider a leopard weighing up whether to go to the trouble of chasing a deer or continue resting under the shadow of a tree in the expectation that better prey will eventually come along. Insofar as pursuing an option requires effort and time away from other pursuits, motivation to act requires considering the potential reward(s), the distribution of other opportunities in the environment, and the cost of action. The leopard may decide to act and start a hunt if the deer is her preferred food, but she may also do so if other opportunities are currently few and far between or if the deer requires little effort to hunt. If the costs, benefits, or environment (i.e., contextual information) are otherwise, however, then no action may be initiated, and the leopard may remain inactive and continue resting.My key goal is to understand how contextual information influences animals' willingness-to-act and how it exerts this influence via brain circuits. To achieve this goal, I will use a combination of methods:I will train macaques on a simple computer-based task. They will be presented with opportunities to act for potential reward and should decide whether to act in order to receive the benefits of the opportunity and incur its costs or refrain from action and wait for future ones. The benefits of a current opportunity and the environment in which it occurs change as animals go through the task. I will use mathematical models to predict animals' willingness-to-act given the current context. While animals are performing the task, I will record their brain activity with functional magnetic resonance imaging (fMRI). fMRI is a non-invasive imaging method that can produce an overall picture of the brain. Using this method, I will identify brain areas that mediate the relationship between contextual information and animals' willingness-to-act. fMRI, however, is a 'correlational' method. To show whether the behaviour is 'caused' by the identified brain areas, I will use transcranial ultrasound (TUS) neurostimulation. TUS neurostimulation is a novel and non-invasive method that can transiently and focally alter brain activity even at some depth from the surface.fMRI and TUS show which areas in the brain track the effect of contextual information on willingness-to-act. However, to get a broader picture one also needs to identify the chemical messengers that transmit this information. In the second part of the project, I will use TUS to deliver pharmacological agents to specific targets in the brain and investigate their effect on the brain and behaviour. By doing so, I will be able to identify major chemical messengers that play important roles in mediating the influence of contextual information on willingness-to-act.Understanding the brain mechanisms of willingness-to-act is not only essential for building a comprehensive understanding of decision making, but in doing so, we can also seek to understand maladaptive behaviours that potentially arise from dysfunction in this circuitry such as failure to act appropriately when environments change. Such failures characterise apathy and impulsivity, symptoms prevalent in a number of psychiatric and neurological disorders. Additionally, there are multiple opportunities within my project to improve animal welfare. For example, using each animal as its own control (repeated-measures design) reduces the number of animals used and the application of non-invasive techniques (fMRI, TUS) reduces harm and facilitates translation of findings to humans. This research will be carried out at the Oxford University Biomedical Sciences Building, home to one of the world-leading centres for non-human primate research, with support from a cross-disciplinary network of collaborators.