AgRP Neurons as Modulators of Drug Reactivity

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ABSTRACT Drug abuse and addiction are serious mental health problems that impose severe economic and social burdens on our community. It has been known for decades that physiological states (hunger and satiety) can influence drug seeking, taking, and relapse. Previous studies showed that hunger-mediating hormones enhance drug use, collectively implying that hunger can be a risk factor for enhanced drug response. However, the interaction between hunger-mediating neurons and drug response remains unclear. Among multiple neuronal populations related to hunger, neurons expressing Agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus are known to be a central mediator of hunger. Despite its central role in evoking hunger, there is a gap in our knowledge of the effect of AgRP neuronal activity on drug response. Our overall goal is to determine the role of AgRP neurons in modulating drug behavioral responsivity and drug- directed behavior through recruitment of mesolimbic reward circuitry which, in turn, modulates motor outputs. As an initial exploratory step, the PI seeks to determine the effect of AgRP neuronal activity on stimulant-driven motor outputs to measure alterations in behavioral sensitivity to abused drugs using zebrafish larvae as an optically tractable model. Our central hypothesis is that the activation of AgRP neurons potentiates motor- neuronal and behavioral responses to psychostimulant drugs. Our specific aim is to determine the effect of AgRP neuronal activity on stimulant-driven responses. We will use transgenic zebrafish lines that express a genetically encoded neural activity indicator in spinal motor neurons, and also a genetically encoded optogenetic actuator or silencer in AgRP neurons. To determine whether the activation of AgRP neurons is sufficient or necessary to increase drug responses, stimulant-driven motor neuronal activity and behavioral responses will be monitored while optogenetically activating or suppressing AgRP neurons. A better understanding of the role of AgRP neurons on drug response could lead to the discovery of novel therapeutic opportunities that control the AgRP neuronal excitability in order to mitigate drug addiction.