Developing and Validating Novel Genetically Encoded Sensors in Animal Behavioral Models to Investigate KOR-Dynorphin Interactions

Abstract

Deaths from the opioid epidemic have been increasing steadily in recent years and have prompted many studies investigating various neural circuits related to addiction. Previous work has shown that both κ-opioid receptor (KOR) agonists and antagonists have potential as therapeutic treatments for individuals suffering from addiction and as alternative analgesics to substitute for addictive substances such as morphine. However, various aspects of KOR-dynorphin actions in different brain regions remain unclear and require further investigation to understand how stress can contribute to substance use disorders. Therefore, we have performed methods for testing, validating, and developing the use of novel genetically encoded sensors to probe KOR-mediated signaling pathways in animal models. We tested these sensors at single cell resolution, bulk neuronal activity, and in behavioral assays. Additionally, we leverage information gained from these sensors to investigate spatial KOR distribution in the PFC and its effect on cognitive disruptions. We found that HyPerRed, kLight, and GCaMP provide useful and unique information regarding circuit dynamics. Ultimately, these findings will allow for more effective investigation into the neural circuits that govern stress and addiction.