Jonathan D. Wallis - US grants

[unreadable] DESCRIPTION (provided by applicant): While we know much about the neuronal mechanisms that underlie simple reward-directed behaviors, such as conditioning, we know very little about how reward information interacts with executive processes such as working memory. The aim of this grant is to examine how different rewards are held in working memory, compared and then selected, in order to allow efficient, flexible behavior. Monkeys will be trained to choose one of two sequentially presented rewards, separated by a brief delay. Thus, the monkey has to hold the first reward in working memory until the second reward is presented, at which point it compares the two rewards and selects one for its choice. We will record the activity of single neurons in the prefrontal cortex (RFC) while the monkey is performing this task. We will examine whether RFC neurons maintain information about the reward during the delay (indicative of working memory processes), and whether this encoding is relatively abstract and flexible which would facilitate the evaluation of widely disparate rewards and goals. We will investigate the neuronal processes that underlie the comparison and selection of the two rewards, processes which are important components of decision-making. We will also compare how primary and secondary reinforcers are held in working memory. Dysfunction of the RFC, particularly the orbitofrontal region, has been implicated in drug addiction. A failure to use working memory representations of alternate rewards and goals (such as quitting the drug) might exacerbate addiction by preventing the addict from exerting top-down control over addictive behavior. Thus, understanding the neuronal mechanisms that determine how choices and priorities are made between different rewards may provide us with a clearer understanding of the pathology of addiction, and with alternative therapeutic strategies aimed at boosting top-down control and attenuating the likelihood of relapse in the recovering addict [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The neural mechanisms underlying choice behavior are important for understanding addiction, a characteristic of which is a failure to exert control over choices. The frontal lobe is critical to choice behavior since damage to this region produces specific impairments in decision-making. Two areas of the frontal lobe are of particular interest: anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). Tasks that require decision-making and choice behavior consistently activate both areas, and both areas contain neurons that encode various aspects related to the value of choice alternatives. In addition, both ACC and OFC are involved in addiction: addicts show structural and functional changes in the two areas. However, we have little understanding about what each area independently contributes to the process of choice behavior. To determine this, we will use neurophysiological techniques to record simultaneously from both areas while subjects are engaged in tasks designed to involve either ACC or OFC. We will compare and contrast the functional properties of ACC and OFC neurons. Our aim is to dissociate the functions of the two areas based on their neurophysiological properties there by providing a deeper understanding of the role that they play in addiction. Theoretical frameworks of choice behavior highlight two processes that must occur. First, the individual must predict the likely outcome of selecting either alternative. Second, the individual must evaluate the predicted outcomes in order to determine which is more valuable. The anatomy of ACC and OFC suggests the differential contribution that the two areas may make to these processes. ACC and OFC both connect with areas responsible for processing reward-related information. However, ACC strongly connects with motor areas and only weakly with sensory areas, while OFC shows the opposite pattern. Thus, the first hypothesis we will test is that ACC neurons predict outcomes associated with different behavioral responses whereas OFC neurons predict outcomes associated with environmental stimuli. We will test this hypothesis by recording the activity of ACC and OFC neurons during tasks where the subject has to base choices on response- outcome or stimulus-outcome associations. The second hypothesis we will test is that ACC, but not OFC, evaluates the amount of effort necessary to earn a payoff. We will test this hypothesis by contrasting the encoding of ACC and OFC neurons during a task that requires our subject to integrate an outcome's value (which we manipulate by varying the magnitude of a juice reward) with the effort required to obtain the outcome (which we manipulate using a torque adjustable lever that the subject must press to earn the reward). To summarize, our specific aims are as follows: 1. Determine the contribution of ACC and OFC to the process of predicting outcomes associated with responses or stimuli respectively 2. Determine the contribution of ACC and OFC to the evaluation of effort-based choices PUBLIC HEALTH RELEVANCE: This project focuses on the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), two areas of the brain that show structural and functional changes in people addicted to drugs. We will record the electrical activity from neurons in both areas during two tasks designed to tax different aspects of choice behavior. Addiction is characterized by a difficulty in exerting control over choice behavior, and so understanding the physiological underpinnings of this process could allow us to develop novel therapeutic strategies for the treatment of addictive behavior.