Wednesday, April 2, 2025
4/2/2025
Prefrontal circuits controlling heroin seeking - PROJECT SUMMARY Opioid use disorder (OUD) can be conceptualized as a two-sided coin, with one side of the pathology characterized by excessive motivational drive for opioids, and on the other side, a weakened ability to suppress opioid-seeking impulses. As the seat of executive function, the prefrontal cortex plays an integral role in the decision ‘to seek or not to seek’ opioids. We have identified two functionally opposing prefrontal subcircuits that drive versus limit opioid seeking. The infralimbic (IL) prefrontal cortex projection to the lateral hypothalamus (ILàLH) drives heroin seeking, whereas the IL projection to the nucleus accumbens shell (ILàNAshell) limits it. We also discovered that these distinct IL ensembles encode heroin cue-learning, a process that contributes to subsequent relapse triggered by heroin cues encountered in the environment. Relapse is an important metric of OUD pathology, but our data suggest that heroin choice, the tendency to choose heroin reward over non-drug reward, is a separate metric of OUD pathology that does not always respond to treatments aimed at reducing relapse. Thus, we will employ a preclinical model of OUD that captures multiple metrics of OUD pathology, including heroin choice and relapse. Furthermore, the downstream target of the IL driver includes LH orexin neurons, which we hypothesize are a biomarker of OUD pathology, as current evidence suggests the number of these neurons increases after repeated opioid exposure and this number positively correlates with heroin motivation. Our preliminary data indicate that the ILàLH driver subcircuit is more responsive to orexin than the ILàNAshell limiter subcircuit, posing the possibility that a positive feedback loop in the ILàLH driver subcircuit is engaged to perpetuate opioid seeking. Importantly, orexin antagonists have been a major focus in the search for new OUD medications, and this newly identified driver circuit could be a major mechanism through which orexin drives opioid seeking. The goals of this proposal are to determine whether the recruitment of the IL driver circuit is a hallmark of heroin-induced pathology, whether this IL subcircuit engages a positive feedback loop via the orexin system to further exacerbate heroin seeking, and whether simultaneously targeting both IL subcircuits to normalize IL output can be used to reverse this pathology. The discovery of distinct IL driver and limiter circuits that control heroin seeking is highly significant because it points to novel interventions aimed at shifting the balance between these circuits as potential anti-addiction treatment strategies. We will also identify how the orexin system interacts with this circuitry and whether this may be another potential point of intervention. The information gained from these experiments could have profound implications for OUD treatment by identifying multiple ways to restore adaptive functionality in these prefrontal circuits and ameliorate OUD pathology, either by reducing excessive motivational drive for opioids or by strengthening inhibitory control over impulses to seek opioids, or both.
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