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

> **NIH NIH F31** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $45,771

## Abstract

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...

## Key facts

- **NIH application ID:** 10834068
- **Project number:** 5F31AA030936-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Marissa Renee Raskin
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,771
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834068

## Citation

> US National Institutes of Health, RePORTER application 10834068, CO2 reactivity and orexin activation as predictors of extinction phenotype to fear and reward cues (5F31AA030936-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10834068. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*