Value-based decision-making is the process of evaluating options in the environment to inform the best course of action. Abundant behavioral evidence demonstrates that value-based decision-making is impaired in addiction. An improved understanding of how value-based decisions are computed and executed by defined cell types is critical to identifying and ultimately treating the circuit disturbances that underlie maladaptive decision-making in addiction. To date, the vast majority of studies examining the neural correlates of value- based decision-making have been conducted in behaving primates. While primates are capable of performing complex cognitive tasks, we currently lack primate-compatible tools for recording and manipulating the activity of precisely defined populations of neurons. This has placed limitations on how much primate studies can tell us about the role of anatomically and genetically defined cell types in value-based decision-making. This proposal overcomes this obstacle by developing a new task to study value-based decision-making in rats. Rats are capable of performing complex cognitive tasks, but they are also amenable to modern techniques for recording and manipulating the activity of defined cell types. Preliminary data demonstrate that rats are capable of making appropriate value-based decisions, and demonstrate that value-based decision-making is critically dependent on activity in the orbitofrontal cortex. The goal of this proposal is to characterize how neurons in the orbitofrontal cortex interact with downstream neural circuits to mediate value-based decision-making. In the K99 mentored phase, the candidate will optogenetically inhibit orbitofrontal axon terminals in distinct brain areas in animals making value-based decisions to identify the critical output pathway through which choices computed in the orbitofrontal cortex are implemented. Preliminary efforts reveal that the projection from the orbitofrontal cortex to the dorsal striatum is likely the key output pathway through which value-based decisions are mediated. The candidate will then ask how information is transformed as it is transmitted from the orbitofrontal cortex to the dorsal striatum by combining optogenetic inhibition of axon terminals with in vivo extracellular electrophysiological recordings in rats performing the value-based decision- making task. The proposed K99 research will not only determine how neurons in the orbitofrontal cortex interact with downstream neural circuits to mediate choice, but will also provide the candidate with critical training in in vivo electrophysiology and dimensionality reduction techniques for analysing big data in world- class labs at Stanford University. In the R00 independent phase, the applicant will apply this training to ask how different decision-related parameters map onto distinct cell types in the dorsal striatum. Collectively, the proposed research will provide some of the first insights into how value-based decisions are mediated by anatomically and genetically defined cell types. This promises to illuminate new therapeutic strategies for addiction, while also generating many new lines of enquiry for the applicant as an independent investigator.
Addiction is characterized by impaired value-based decision-making; addicts consistently choose to engage in drug seeking behavior at the expense of other rewarding activities. The goal of this proposal is to determine how neurons in the orbitofrontal cortex interact with downstream neural circuits to compute and execute value- based decisions. The proposed research will reveal how anatomically and genetically defined cell types mediate value-based decision-making in the healthy brain, which is a critical prerequisite to isolating the circuit disruptions that underlie maladaptive decision-making in addiction.
