Co2 Reactivity and Orexin Activity as Predictors of Extinction Memory to Fear and Reward Cues: Results from a Large Sample of Rats Across Multiple Studies

Abstract

Pavlovian conditioning can be used to model maladaptive associations seen in anxiety/trauma and substance use disorders. One approach to attenuate conditioned responses is extinction learning (also known as exposure therapy), wherein cues are repeatedly presented without the expected fearful or rewarding outcome. Extinction is not effective for all individuals; therefore, identifying biomarkers that can phenotype non-responders is necessary to optimize treatment. The orexin system is involved in fear and reward extinction as well as responses to CO2 exposure. We previously found that CO2 reactivity predicts fear extinction memory and orexin activity, and orexin activity in turn predicts extinction memory. In a separate study, we replicated the finding that CO2 reactivity predicts fear extinction memory and extended this finding to appetitive extinction memory. Here, we combined behavioral and orexin activity data from these three studies to examine whether we might identify new or common predictors of fear and reward extinction with CO2 reactivity and orexin in a larger combined sample. We found that neither CO2 reactivity nor orexin activity predict extinction memory in the combined fear and appetitive sample. We found common CO2 reactivity predictors in the combined fear sample, including a new predictor associated with orexin activity. In an expanded analysis, we found conditioning and extinction may have affected subsequent CO2 reactivity and prior CO2 exposure may decrease orexin activity. Our findings support the potential of CO2 reactivity to serve as a screening tool for identifying likely responders to exposure-based therapy.

Note:
Funding declaration: The presented work was in part funded by R01MH125949 to MWO and R01MH125951 to MHM, JAJS, and MJT and F31AA030936 to MR.

Conflict of Interests: JAJS has received grants from the National Institutes of Health, the Department of Defense, and the Trauma Research and Combat Casualty Care Collaborative Prevention. He has received personal fees from Big Health, Boston University and Brown University for consulting, and from Elsevier and the American Psychological Association for editorial activities. Dr. Smits also has equity interest in Earkick, and has received royalty payments from various publishers. The terms of these arrangements have been reviewed and approved by the University of Texas at Austin in accordance with its conflicts of interest policies. MWO receives compensation as an advisor to Big Health and receives grant support from National Institute of Mental Health, the National Institute on Drug Abuse, and Big Health, United States, and he receives royalties from book publications from various publishers. All other authors report no conflicts of interest.

Ethical Approval: All procedures were conducted in compliance with the National Institutes of Health Guide for the Care and Use of Experimental Animals and were approved by the Institutional Animal Care and Use Committee of the University of Texas at Austin.

Keywords: extinction, CO2 reactivity, fear, reward, orexin, individual differences