Endocrine regulation of alcohol consumption and fear learning

Iowa City Va Medical Center, Iowa City IA

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Linked publications & trials

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 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.