Substance use disorder is a chronic, intractable disease characterized by pathological risk-taking behavior, which engenders ongoing drug seeking despite the risk of consequences. This proposal harnesses a rat model to understand the neuronal activity that contributes to risky decision-making. The Risky Decision-Making Task (RDT) offers choice between a small, safe reward and a large reward accompanied by an escalating risk of mild foot shock. While risk-taking on average decreases with increasing risk of punishment, the RDT reveals wide variability in risk preference, including a subpopulation of rats that consistently prefer the large reward despite high risk of punishment. Understanding the neuronal mechanisms of this natural variability in risky decision-making may contribute to development of treatments that target aberrant decision-making processes in substance abusers. A likely locus of the functional activity driving risky decision-making is the orbitofrontal cortex (OFC), an area implicated in several modalities of risk-based decision-making as well as vulnerability to substance use. Experiments in this proposal will assess how differences in OFC processing drive individual differences in risk-taking by measuring and manipulating OFC activity during risky decision-making.
Aim one will utilize in vivo single-unit electrophysiology to measure functional neuronal activity in OFC during risky decision-making. Activity will be measured during a specially designed version of RDT that parses apart distinct epochs within the decision-making process: pre-decision deliberation, and post-decision outcome anticipation. To determine how OFC predicts individual biases in risk-taking, event-evoked OFC activity will be compared between rats with different levels of risk preference.
Aim two will utilize optogenetic inhibition to suppress OFC activity during different epochs within risky decision-making. This will identify the causal role of OFC in driving risk-taking, and determine if OFC modulation of risk-taking diverges as a function of risk- preference. The experiments outlined above will both measure and manipulate OFC activity during an understudied form of addiction-relevant risky decision-making, which may lead to novel biomarkers and/or precise treatments for the chronic insensitivity to risk of punishment observed in addiction. In addition, this proposal will offer a strong training component including critical technical skills, complex data analysis and signal processing, the opportunity for multiple high impact publications, and strong mentorship from a team of investigators at various career stages.
Risky decision-making is a hallmark behavior in the formation of addictions. Understanding the biological basis of risky decision-making is critical for the identification of biomarkers and development of novel preventative and therapeutic treatments of addiction. This project seeks to identify the role the orbitofrontal cortex plays in risky decision making using real-time recording and manipulation of neuronal activity.
