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.

Public Health Relevance

Patients suffering from substance abuse disorders are impaired in their ability to alter behavior in response to negative consequences (i.e., behavior becomes inflexible). Thus, it is important to understand how a history of drug use alters neural circuity underlying flexible goal-directed and inflexible habitual behavior. This proposal aims to examine the effects of cocaine and the underlying neural circuits that mediate flexible behavior providing crucial information for potential treatments of drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Transition Award (R00)
Project #
4R00DA042934-03
Application #
10055804
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sorensen, Roger
Project Start
2020-03-01
Project End
2023-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Rowan University School/Osteopathic Med
Department
Anatomy/Cell Biology
Type
Schools of Osteopathic Medicine
DUNS #
078789801
City
Stratford
State
NJ
Country
United States
Zip Code
08084