CO2 reactivity and orexin activation as predictors of extinction phenotype to fear and reward cues

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PROJECT SUMMARY Maladaptive associative learning underlies the persistent conditioned responses to previously neutral stimuli seen in PTSD and addiction: cues present during the traumatic event result in fear responses in PTSD, and cues that precede rewarding stimuli (such as alcohol or food) lead to reward seeking behavior in addiction. These responses can be attenuated through extinction learning, where cues are repeatedly presented without the previously learned fearful or rewarding outcome. Extinction memories are thought to compete for expression with the original associative memory of the cue and subsequent fearful or rewarding outcome, meaning conditioned responses may return with the passage of time, stress, or change in context (Bouton, 2004). Individual differences in return of conditioned behavior after extinction have been observed in both the laboratory and the clinic (Bush et al., 2007; Clapp et al., 2016), and a number of predictors of fear extinction phenotype have been identified (Galatzer-Levy et al., 2013; Monfils et al., 2019; Shumake et al., 2014, 2018). However, the ability to predict individual differences in reward extinction remains a knowledge gap. Extinction of fear and reward memories are subject to the same return of behavior phenomena and have overlap in neural circuitry that includes the medial prefrontal cortex, amygdala, and hippocampus (Goode & Maren, 2019; Peters et al., 2009). In addition, orexin neurons, which originate in the lateral hypothalamus (LH), have been implicated in the extinction of conditioned responses to fear, food, and alcohol cues. Activation of orexin receptors in the lateral hypothalamus (LH) is positively correlated with the return of conditioned responses to reward and fear cues after extinction (Hamlin et al., 2007; Monfils et al., 2019; Moorman et al., 2016; Sharko et al., 2017) and antagonism of orexin receptors prevents the return of these behaviors (Cason & Aston-Jones, 2013; Flores et al., 2014; Lawrence et al., 2006). Orexin neurons in the LH are also activated by carbon dioxide (CO2) challenge (Johnson et al., 2012; Monfils et al., 2019). It was recently found that behavioral CO2 reactivity has a negative correlation with both fear memory after extinction and orexin activation in the LH and that there is a positive correlation between fear memory after extinction and orexin activation in the LH (Monfils et al., 2019). The central hypothesis of the proposed work is that behavioral reactivity and orexin activation to a CO2 challenge can be used to predict extinction phenotype to both reward and fear cues. This will be tested by determining whether CO2 reactivity predicts long-term extinction memory in food- and alcohol-conditioned rats and whether CO2 reactivity and orexin activation in the LH can identify common predictors of long-term extinction memory to food, alcohol, and fear cues. CO2 reactivity data and brain tissue will be collected from two sets rats that have undergone food or alcohol conditioning, extinction, and a long-term memory test. This will be combined with previously collected data on CO2 reactivity and orexin activation in fear conditioned rats. Statistical modeling will be used to determine which subcomponents of behavioral CO2 reactivity and orexin activation are the best predictors of extinction memory.