Physical and computational methods of investigating the relationship between stress, cognition, and behavior in the context of the KOR-dynorphin system

Abstract

Motivation: Chronic stress is an aversive experience that can have maladaptive effects on an individual’s cognition and behavior, ultimately leading to increased risk of developing conditions such as anxiety, depression, or amplifying symptoms of drug use disorder. Stress-induced release of dynorphin activates the kappa opioid receptor (KOR), causing short- and long-term disturbances at the behavioral, circuit, and cellular levels. Contents: This thesis discusses experimental and computational methods to probe the KORdynorphin system at the behavioral, circuit, and cellular levels are described. At the behavioral level, the differential reinforcement of low response rate and delayed alternation tasks are used to investigate KOR effects on aspects of motivated behavior. At the circuit level, in vivo fiber photometry is used to illuminate important aspects of reward signaling following stress. Finally, at the circuit level, real-time cellular microscopy is used to investigate the cellular pathways activated via KOR, providing potential therapeutic targets for stress-induced pathophysiologies. Results: The behavioral assays demonstrated that KOR activation causes cognitive disruptions that affect both inhibitory control as well as working memory-dependent decision making. The fiber photometry results demonstrated that stress causes a KOR dependent increase in dopamine neuron activity in a major reward center, following the stress exposure. Finally, the real-time cellular measurements revealed a new branch of G-protein coupled receptor signaling that results in production of reactive oxygen species which leads to permanent KOR inactivation.