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Principal Investigator: Kyle Harrington Flippo
Organization: IOWA CITY VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
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
recording, in vivo calcium imaging, and optogenetics to investigate how FGF21 signaling in projection defined
populations of KLB+ neurons in the BLA influences valence encoding, alcohol consumption, and fear
conditioning to improve our understanding of how shared neural substrates contribute to AUD and PTSD. As a
postdoctoral research fellow with experience investigating how FGF21 signaling in the brain regulates
physiological homeostasis I will perform the experiments described in this proposal under the mentorship of Dr.
Matthew Potthoff and Dr. Ted Abel. The career development plan accompanying this proposal is designed to
achieve my long-term goal of becoming an independent VA-funded researcher. Immediate goals associated with
this proposal, such as learning optrode recording and calcium imaging, as well as obtaining a tenure track faculty
position will facilitate accomplishing my long-term career goal. Key aspects of the career development plan
include technical and professional mentorship provided by my mentors and a Scientific Advisory Committee
designed specifically to accomplish the goals of this proposal. Formal courses on scientific writing and leadership
as well as research conferences will supplement the training provided by my Scientific Advisory Committee.
Terms: <21+ years old><Address><Adult><Adult Human><Advisory Committees><Affect><Alcohol Chemical Class><Alcohol Drinking><Alcohol consumption><Alcohols><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Autoregulation><Brain><Brain Nervous System><Calcium><Cell Communication and Signaling><Cell Signaling><Chronic><Clinical><Cues><Data><Development Plans><Diagnosis><Disease><Disorder><Emotional><Encephalon><Endocrine><Endocrine Gland Secretion><EtOH drinking><EtOH use><Exhibits><Extinction><FGF-21><Faculty><Fear><Feedback><Fright><Funding><General Population><General Public><Genes><Genetic Diversity><Genetic Variation><Goals><Healthcare><Heavy Drinking><Homeostasis><Hormones><Human><Image><Impairment><In vivo two-photon calcium imaging><Intracellular Communication and Signaling><Investigators><Knowledge><Leadership><Learning><Liver><Medical Records><Mentors><Mentorship><Metabolic><Mice><Mice Mammals><Modern Man><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neural Pathways><Neurocyte><Neurons><Nucleus Accumbens><PTSD><Patients><Physiological Homeostasis><Population><Population Forecasts><Population Projection><Position><Positioning Attribute><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Postdoc><Postdoctoral Fellow><Posttraumatic Neuroses><Property><Receptor Protein><Regulation><Research><Research Associate><Research Personnel><Researchers><Rewards><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Single Base Polymorphism><Single Nucleotide Polymorphism><Symptoms><Task Forces><Techniques><Therapeutic Hormone><Training><United States><Veterans><Writing><adulthood><advisory team><alcohol co-morbidity><alcohol comorbidity><alcohol ingestion><alcohol intake><alcohol product use><alcohol response><alcohol use><alcohol use disorder><alcoholic beverage consumption><alcoholic drink intake><amygdaloid nuclear complex><biological signal transduction><career><career development><chronic EtOH drinking><chronic alcohol consumption><chronic alcohol drinking><chronic alcohol ingestion><chronic alcohol use><chronic ethanol consumption><chronic ethanol drinking><chronic ethanol ingestion><conditioned fear><conference><convention><design><designing><drink heavily><effective therapy><effective treatment><ethanol consumption><ethanol drinking><ethanol ingestion><ethanol intake><ethanol product use><ethanol response><ethanol use><ethanol use disorder><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><experience><experiment><experimental research><experimental study><experiments><extreme drinking><fear conditioning><fear memory><fibroblast growth factor 21><gene locus><genetic locus><genomic location><genomic locus><health care><heavy alcohol use><hepatic body system><hepatic organ system><imaging><improved><in vivo calcium imaging><military veteran><neural><neuronal><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><optogenetics><post-doc><post-doctoral><post-doctoral trainee><post-trauma stress disorder><posttrauma stress disorder><preference><receptor><research associates><response><response to alcohol><response to ethanol><single nucleotide variant><summit><symposia><symposium><tenure process><tenure track><traumatic neurosis><veteran population>