This is an application for an NIH K01 Mentored Research Scientist Development Award. The long-term objective of this application is to understand how neurons in the orbitofrontal cortex (OFC) contribute to decision-making behavior. This is a fundamental objective in the study of drug abuse, a condition in which individuals consistently make self-harming decisions, and in which OFC function is known to be altered. The experiments will focus on a common feature of everyday decision-making: when offered a choice between several items (such as products on a supermarket shelf), humans briefly shift the focus of their gaze onto each of the items prior to rendering their decision. Recent studies have shown - somewhat against intuition - that these visual fixations can actively influence whether an item is chosen: specifically, longer fixation on a given item makes it more likely to be chosen than the alternatives. This bias takes hold naturally during free viewing, and when longer fixation is forced experimentally. Given that humans constantly move their eyes, this gaze-based choice bias could weigh into many of the decisions we make on a daily basis. To investigate the neural basis of this gaze-based choice bias, three experiments will be performed. In the first, an animal model of this behavior will be established. The subjects will be presented with two visual targets associated with different reward magnitudes (values), and will fix their gaze on these targets for variable lengths of time prior to choosing one. The key question will be the degree to which longer fixation on a given target increases that target's likelihood of being chosen, as it does in humans. In the second experiment, the subjects will perform the above task while the activity of OFC neurons is monitored. Here, the key question will be the degree to which OFC neural activity signals the value of the currently fixated target, even when other targets of differing value are shown simultaneously. This kind of value signal is thought to be a key signal that drives the gaze-based choice bias in humans. Finally, the subjects will perform the task while the neural activity of the OFC is disrupted. The key question will be whether the tendency to choose longer-fixated targets is attenuated by this disruption, indicating that the neurons of the OFC play a direct causal role in the behavior. Taken together these experiments will provide insight into neural mechanisms that are critical for everyday decisions, and that may be compromised in individuals with addiction-related deficits in OFC function. During the award period, the candidate will undergo rigorous training in the neurophysiological techniques used in the experiments, and in the study of decision-making behavior. In addition to these scientific domains, training efforts will also focus on publishing productivity, and on other professional skills such as grantsmanship. The training will consist of hands-on experience, tutorials from several mentors, and coursework. Completing the proposed research project and associated training will enable the candidate to become a successful independent investigator in the neurobiology of decision-making.
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