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Principal Investigator: James M Otis
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $339,750
Funding agency: National Institute on Drug Abuse
SUMMARY/ABSTRACT
Reward-associated cues are unlikely to provoke reward seeking when that behavior is inappropriate, yet cues
elicit opioid seeking in patients with opioid use disorder (OUD) when that behavior is unproductive or
maladaptive. There is little understanding of how brain systems that can normally suppress unproductive reward
seeking are modified by opioid use and causally contribute to opioid seeking. This is in part due to technical
feasibility, as measuring adaptations in single neurons across the onset, maintenance, and relapse phases of
opioid use is challenging. Here, I overcome this issue using a novel assay developed in my lab, wherein I
longitudinally track activity in precisely defined neurons throughout heroin self-administration, extinction, and
reinstatement using two-photon calcium imaging in head-restrained mice. We test the overarching hypothesis
that a thalamostriatal subcircuit is inhibited by opioid use and by the presentation of stimuli that initiate opioid-
seeking behaviors. In support of this hypothesis, my preliminary data suggest that posterior paraventricular
thalamic neurons that project to the nucleus accumbens (pPVT NAc) become hypoactive and hypoexcitable
as a result of repeated heroin use and display rapid reductions in activity during cue- and drug-induced
reinstatement of heroin seeking. Furthermore, I show that optogenetically mimicking this inhibition during
extinction initiates heroin seeking. To test my specific hypotheses, in Aim 1, I will longitudinally track the activity
dynamics of single pPVT NAc neurons and neuronal ensembles throughout heroin self-administration,
extinction, and reinstatement. In Aim 2, I will evaluate the long-lasting intrinsic and synaptic adaptations among
pPVT NAc neurons at multiple timepoints following heroin self-administration. In Aim 3, I will determine the
function of pPVT NAc neuronal activity for the suppression of heroin seeking during extinction, and expression
of heroin seeking during reinstatement. Overall, this project will identify how a brain circuit that inhibits reward
seeking in inappropriate conditions is modified by opioid use and causally influences opioid-seeking behavior.
Terms: <2-photon><Assay><Behavior><Behavioral><Behavioral Assay><Behavioral Paradigm><Bioassay><Biological Assay><Brain><Brain Nervous System><Calcium><Conflict><Conflict (Psychology)><Consumption><Cues><Data><Diacetylmorphine><Diamorphine><Drug usage><Drugs><Electrophysiology><Electrophysiology (science)><Encephalon><Extinction><Fear><Feeding behaviors><Fright><Head><Health><Heroin><Image><In vivo two-photon calcium imaging><Ingestive Behavior><Knowledge><Laboratories><Literature><Maintenance><Measures><Medication><Mice><Mice Mammals><Motivation><Murine><Mus><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Nucleus Accumbens><Opiates><Opioid><Paraventricular Nucleus of Thalamus><Paraventricular Thalamic Nucleus><Pathway interactions><Patients><Pharmaceutical Preparations><Phase><Publications><Relapse><Research><Rest><Rewards><Saline><Saline Solution><Satiation><Scientific Publication><Self Administered><Self Administration><Slice><Stimulus><Structure of paraventricular nucleus of thalamus><Synapses><Synaptic><System><Testing><Thalamic structure><Thalamus><addiction><addictive disorder><drug use><drug/agent><electrophysiological><experience><experiment><experimental research><experimental study><experiments><feeding><feeding-related behaviors><frontier><heroin intake><heroin use><imaging><in vivo calcium imaging><insight><mu opioid receptors><neurobiological><neuronal><neuronal circuit><neuronal circuitry><neurophysiological><neurophysiology><novel><nutrient intake activity><opiate consumption><opiate drug use><opiate intake><opiate use><opiate use disorder><opioid consumption><opioid drug use><opioid intake><opioid use><opioid use disorder><optogenetics><patch clamp><pathway><relapse prediction><restraint><reward anticipation><satiety><synapse><thalamic><two-photon><μ opioid receptors><μ-OR><μOR>