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Principal Investigator: Adam G Gordon-Fennell
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $173,167
Funding agency: National Institute on Drug Abuse
Project Summary/Abstract
Opioid use has reached epidemic proportions and is now the leading cause of preventable death in the United
States. Beyond the risk of death, opioid use disorder causes an incalculable amount of suffering as it devastates
the lives of individuals and their communities. The heightened motivation for drug rewards compared to non-
drug rewards stems in part from changes in the brain circuity associated with motivation. A greater understanding
of this circuitry may lead to targeted interventions that can attenuate drug motivation. Decades of research
demonstrate that the lateral hypothalamus (LHA), and its modulation of the dopamine system, plays a crucial
role motivation. Multiple species of animals will work tirelessly to obtain electrical stimulation of the LHA, and
lesions of the LHA reduce motivation across a broad spectrum of behaviors. Recent research has revealed
complexity in the function of the LHA, as subpopulations of neurons can drive discrete or even opposing
behavioral phenotypes. Despite the established role in motivation broadly, the role of the LHA subpopulations in
motivation for opioids remains largely unknown. This proposal seeks to investigate the behavioral function
and spatiotemporal signaling dynamics of multiple LHA subpopulations and downstream dopaminergic
signaling during the development and expression of motivation for opioids. During the K99 period, I will
receive world-class training in the theory of opioid pharmacology and self-administration, techniques for
longitudinal recording using 2-photon imaging, and advanced analysis of the relationships between neuronal
signaling dynamics and behavior. In Aim 1 (K99), I will determine the causal behavioral function of multiple LHA
subpopulations during motivation for opioids using transient inhibition or excitation of neurotransmitter defined
neuron populations. In Aim 2 (K99), I will determine the relation between bulk signaling dynamics in the LHA
subpopulations and downstream dopamine signaling using fiber-photometry and the single cell dynamics of LHA
subpopulations using 2-photon imaging throughout the development and expression motivation for opioids. By
recording throughout the experiment, I will have the power to characterize bulk and single-cell signals based on
activity across each stage of opioid self-administration. In Aim 3 (R00), as I transition to developing my own
research lab, I will investigate the caudal circuit effects of transient stimulation of LHA subpopulations during
motivation for opioids. Altogether, the results of the proposed aims will deepen our understanding of the role of
the LHA in mediating motivation for drugs of abuse and related neuronal circuitry. The training I will receive
throughout the K99/R00 period will facilitate my development into an independent researcher investigating the
behavioral function and spatiotemporal signaling dynamics related to substance use disorder.
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