Elizabeth A. West, Ph.D. - US grants

DESCRIPTION (provided by applicant): The ability of an animal to alter behavior in response to changes in their environment is known as flexible goal-directed behavior. Patients with neuropsychiatric disorders (e.g., addiction, ADHD, and autism) often have difficulty with this type of behavior. In the laboratory one type of task used to measure flexible goal directed behavior is a conditioned reinforcer devaluation task. In this task, animals form associations between stimuli (e.g. objects) and specific reinforcer(s) (e.g. various food rewards). The reinforcer is subsequently "devalued" by selective satiation (feeding one of the foods ad libitum). Following devaluation, normal subjects adjust their responding which reflects the new "value" of the reinforcer. The orbitofrontal cortex (OFC) in conjunction with several other brain structures (e.g., amygdala, striatum) is an important neural substrate involved in the conditioned reinforcer devaluation task. However, it is unknown if OFC is necessary for linking the decreased value of the food to the stimuli that predicts it, or guiding choices during testing. The goal of this proposal is to elucidate the neural circuitry involved in different stages of reinforcer devaluation. Specifically, the proposed experiments plan to determine the role of the OFC in reinforcer devaluation and compare and contrast the roles in rodents and non human primates. I propose to use reversible pharmacological manipulations in macaque monkeys to study the role of OFC during different stages of reinforcer devaluation (forming associations, registering a change in reinforcer value, updating reinforcer value to the stimuli, guiding choices to reflect the change in value). Reversible pharmacological manipulations provide an opportunity to delineate the role of OFC involved in individual phases of the task. In addition I plan to compare the role of the OFC in conditioned reinforcer devaluation across species. To achieve this, I developed a new rodent (rat) reinforcer- devaluation task that further reconciles the differences between the monkey and the rat tasks used to date. I also propose to study the effects of lesion in rats in the new rat reinforcer devaluation task to compare directly with previous work using various forms of reinforcer devaluation tasks in rats. Further understanding of the neural circuitry underlying flexible goal- directed behavior will help elucidate mechanisms for impairments in patients with neuropsychiatric disorders. This will provide new and more selective target systems for therapeutic intervention for individuals with maladaptive reward processing. The following aims will be used to reach my goals: specific aim 1-Determine the role of OFC in different phases of reinforcer devaluation in macaque monkeys. Specific aim 2- Determine the role of OFC in reinforcer devaluation in rats. A direct comparison OFC across species in a specific reinforcer devaluation task will enhance our understanding of the neural circuitry involved in flexible goal directed behavior. PUBLIC HEALTH RELEVANCE: Patients with addiction, autism, or attention deficit hyperactivity disorder are impaired in adjusting responding based on consequences. These types of deficits are studied by measuring the ability of a subject to alter behavior based on changing outcomes. The goal of this proposal is to further understand the role of a specific brain structure (orbitofrontal cortex) using a task which measures changing behavior.

DESCRIPTION (provided by applicant): The ability of an animal to alter behavior in response to changes in their environment is necessary for survival. Patients with neuropsychiatric disorders, especially addictive disorders, often have difficulty with this type of behavioral flexibility. One can measure the ability of an animal to alter goal-directed behavior following a change in outcome value using a reinforcer devaluation task. In this task, animals form associations between stimuli (e.g. cue) and specific reinforcer(s) (e.g. food rewards). The reinforcer is subsequently devalued by selective satiation (providing the food ad libitum). Following devaluation, normal subjects adjust their responding which reflects the new value of the reinforcer in the absence of new associative learning. The nucleus accumbens (NAc), in conconjuction with several other brain structures (e.g., orbitofrontal cortex and basolateral amygdala), is necessary for behavioral flexibly as measured by reinforcer devaluation tasks. However, it is unknown how DA input from the ventral tegmental area (VTA) to the NAc encodes goal-directed behavior following devaluation in real-time, or how manipulations of DA release can modulate this behavior. In order to assess this, two Specific Aims are proposed to address these issues. Aim 1 is designed to use electrochemical methods (fast scan cyclic voltammetry) to measure rapid DA signaling in the NAc core and shell to reward predictive cues and responses following reward devaluation. Aim 2 will use optogenetic manipulations to artificially stimulate DA release in NAc during acquisition or expression of the reinforcer devaluation task. Understanding the neural circuitry underlying flexible goal-directed behavior will help elucidate neural impairments in patients with neuropsychiatric disorders. As such, the proposed studies will provide critical insight into potentially new and more selective target systems for therapeutic intervention for individuals with maladaptive reward seeking, a hallmark of drug addiction.

Project Summary/Abstract Balancing habitual and flexible strategies for navigating the environment is necessary for behavior that is both cognitively efficient and adaptive to change, and perturbations that disrupt this balance can result in significant behavioral impairments. For example, patients with substance abuse disorders often have difficulty altering their behavior to respond to changing outcomes, leading to poor decision-making. In the rat, a history of cocaine impairs the ability to adjust behavior away from reward-predictive cues following reward devaluation, a canonical measure of flexible behavior (i.e., cocaine leads to inflexible behavior). Interestingly, different striatal substrates underlie flexible, goal-directed behaviors (nucleus accumbens, NAc) and inflexible, habitual behaviors (dorsal lateral striatum, DLS), and proper balance between the NAc and DLS and their associated networks is critical for adaptive (flexible) but efficient (habitual) behavior. Thus, the current application will examine how a history of cocaine tips that balance and alters the neural network signaling that drives flexible and inflexible strategies. Balancing these subcortical networks requires cortical input. Specifically, distinct mPFC subregions (prelimbic cortex, PrL; and infralimbic cortex, IL) are differentially involved in flexible and inflexible strategies, respectively. Thus, to more fully characterize how a history of cocaine results in lasting behavioral impairments, I propose 4 specific aims to examine specific effects of a history of cocaine or effects of specific manipulations to networks driving flexibility. In aim 1, I will determine how a history of cocaine alters PrL and NAc cell firing and network dynamics (local field potentials) to reward predictive cues during learning and flexible behavior. In aim 2, I will determine if prelimbic cortical (PrL) inputs to the NAc core are causally linked to both flexible behavior and its neural encoding in the NAc. In aim 3, I will independently determine how a history of cocaine alters IL and DLS cell firing and network dynamics to reward predictive cues during learning and flexible behavior. Finally, in aim 4, I will determine if the IL to substania nigra (the primary input into DLS) pathway is causally linked to flexible behavior and neural encoding in the DLS. Together, these specific aims will characterize the balance between two parallel circuits (one involving PrL and NAc, and one involving IL and DLS) in behavioral flexibility and determine how a history of cocaine shifts this balance towards inflexible (habitual) circuitry and behavior. Understanding the neural circuitry underlying flexible vs habitual behavior and how neural encoding in these regions is altered by drug use will provide critical insight into new and more selective targets for therapeutic intervention for patients with substance abuse disorders.