# Endocrine regulation of alcohol consumption and fear learning

> **NIH VA IK2** · IOWA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

In the United States alcohol use disorder (AUD) affects ~15% of adults. While those numbers alone are striking,
patients diagnosed with post-traumatic stress disorder (PTSD) are 3 times more likely to develop AUD compared
to the population at large. This relationship is even more worrisome in Veteran populations as VA medical records
suggest 63% of Veterans with AUD are co-diagnosed with PTSD. Co-morbid AUD and PTSD represents a major
healthcare issue given that chronic excessive alcohol consumption in Veteran populations with PTSD intensifies
symptoms of PTSD including overgeneralization of the fear response and impaired fear memory extinction.
Clinically, the ability to treat co-morbid AUD and PTSD has not been addressed and our understanding of
maladaptive changes in common neural pathways which contribute to co-morbidity AUD and PTSD is limited.
Therefore, in order to develop effective therapies for co-morbid AUD and PTSD we must improve our knowledge
of why these disorders exhibit a strong relationship by pursuing new hypotheses using cutting edge techniques.
Recently, the endocrine hormone fibroblast growth factor 21 (FGF21), known for its potent metabolic effects,
was illustrated to significantly reduce alcohol consumption via an undescribed mechanism requiring expression
of the obligate FGF21 co-receptor β-klotho (KLB) in the brain. Importantly, single nucleotide polymorphisms in
both FGF21 and KLB genomic loci are highly associated with increased alcohol consumption in humans. Our
preliminary data presented in this proposal illustrates that excessive alcohol consumption promotes FGF21
secretion from the liver. Additionally, mice lacking FGF21 expression in the liver exhibit increased preference for
alcohol suggesting FGF21 signaling in response to alcohol consumption represents a homeostatic feedback
loop to negatively regulate alcohol consumption. Furthermore, we find that FGF21 signaling through KLB
expressing (KLB+) neurons in the basolateral amygdala (BLA) is necessary for FGF21 to suppress alcohol
consumption. Interestingly, FGF21 signaling in the BLA also appears to be necessary for enhanced fear memory
associated with chronic alcohol consumption suggesting FGF21 signaling in the BLA influences both alcohol
consumption and fear memory. In the BLA we have identified two distinct populations of KLB+ neurons which
project to the nucleus accumbens (NAc) or the central amygdala (CeA). Neurons in the BLA which project to
these regions have previously been illustrated to regulate alcohol consumption and fear memory. Relatedly,
these same projection populations have been described to encode the emotional valence of cues associated
with reward and aversion. Thus, in this proposal we hypothesize that FGF21 signaling through KLB+ neurons in
the BLA which project to the NAc or the CeA influences alcohol consumption and fear memory through
modulating the valence encoding properties of these neurons. This proposal takes advantage of optrode
reco...

## Key facts

- **NIH application ID:** 10661072
- **Project number:** 5IK2BX005774-02
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Kyle Harrington Flippo
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10661072

## Citation

> US National Institutes of Health, RePORTER application 10661072, Endocrine regulation of alcohol consumption and fear learning (5IK2BX005774-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10661072. Licensed CC0.

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