RESEARCH SUMMARY
Alcohol use disorder (AUD) accounts for the largest percentage of active substance use disorders. One
prominent trait of AUD is compulsive use despite adverse consequences. Previous work has found that animals
who drink alcohol in excess display diminished lateral habenula (LHb) activity, a brain region widely
acknowledged to participate in aversive behaviors, suggesting that LHb hypoactivity may be an integral factor in
compulsive alcohol use. However, mechanisms that contribute to these reductions in LHb activity have not been
fully explored. Comprehensive assessment of LHb plasticity in preclinical models of AUD through the
measurement of afferent neurotransmission dynamics could offer potential insight into a neurobiological basis
for the reduced LHb activity observed in aversion resistance. One afferent region of particular interest is the
ventral pallidum (VP). Recent findings have shown that VP glutamate (VPGlu) neurons, which project extensively
into the LHb, contribute to adaptive constraint of natural reward consumption and reduction of drug-seeking
actions. Yet, there remains a significant knowledge gap concerning potential alterations of LHb-projecting VP
neurons that arise in response to the development of aversion-resistant alcohol use. Clarifying the changes that
occur in both multiregional and VP-specific afferent input is necessary to improve our understanding of
physiological alterations preventing normative aversive behavior in aversion-resistant drinking. Thus, the broad
goal of the proposed work is to elucidate neurobiological adaptations of LHb afferent projections during
compulsive alcohol consumption.
The primary objective of this proposal is twofold: first, to investigate the impact of alcohol use on afferent
neurotransmission into the LHb during aversion resistant alcohol consumption, and second, to explore the
significance of VP-to-LHb projections in this behavior. Given that afferent input from several distinct brain regions
has been shown to influence aversive behavior and alcohol misuse, I hypothesize that LHb afferent
neurotransmission is adaptably dysregulated in animals that exhibit aversion resistant alcohol use,
which may be due in part to changes in activity of VP inputs. To test this hypothesis, I will use in vivo fiber
photometry to record neurotransmitter activity in the LHb and optogenetics to manipulate VP-to-LHb projections
during aversion-resistant alcohol consumption alongside histological techniques to quantify neurochemical
content of LHb projections. Experiments proposed here will advance our understanding of the neural
mechanisms underlying aversion-resistant alcohol use, establishing a foundation for future research examining
LHb-associated neural circuitry in compulsive alcohol use. Throughout this proposal, I will gain valuable training
in the execution of behavioral neuroscience experiments, in vivo neurotransmitter recording methods, neuronal
manipulation techniques, histological processing, and advanced computational strategies. This project will allow
me to build a firm foundation for a successful career as an independent investigator.
