Abstract
Opioid use disorder (OUD) is characterized by high relapse rates, underscoring an urgent need to identify neurobiological mechanisms of opioid seeking. The paraventricular thalamus (PVT) is a key brain region implicated in drug seeking in humans and rodents. While the role of its downstream targets is beginning to be clarified, the upstream inputs that regulate PVT activity during opioid seeking remain poorly understood. The prelimbic cortex (PL) provides substantial excitatory input to the PVT and has a well-established role in cue-guided behaviors and drug seeking. However, the contribution of the PL→PVT pathway to heroin seeking is yet to be elucidated. To address this knowledge gap, we trained male and female rats to self-administer heroin for 12 days and then used a pathway-specific chemogenetic approach to transiently inhibit PL→PVT projections during a cued heroin seeking test following 14 days of abstinence. We found that chemogenetic inhibition of this pathway significantly reduced heroin seeking. We next examined synaptic plasticity at PL→PVT synapses ex vivo on withdrawal day 14 and found that abstinence from heroin self-administration induced an increase in AMPA/NMDA ratio compared to saline controls. Importantly, the increase in synaptic strength was normalized by applying an ex vivo optogenetic long-term depression (LTD) protocol. Finally, we applied the same optogenetic LTD protocol in vivo immediately before the cued seeking test and found that depotentiation of PL→PVT synaptic activity significantly reduced heroin seeking. These findings identify PL→PVT inputs as key drivers of heroin seeking and demonstrate that weakening this pathway reduces opioid seeking.
Significance Statement The persistent nature of relapse presents a major obstacle in the effective long-term treatment of opioid use disorder (OUD). This study identifies a specific neural circuit, from the prelimbic cortex to the paraventricular nucleus of the thalamus (PL→PVT), as a key regulator of heroin seeking in rats after abstinence. We demonstrate that suppressing the activity of this pathway, either by temporarily silencing its neurons or by inducing a lasting form of synaptic depotentiation (LTD), reduces cued heroin seeking. These findings establish the PL as a key upstream driver of PVT activity in promoting cued heroin seeking. Thus, interventions targeting cortico-thalamic synaptic strength may represent a promising avenue for future therapeutic development for OUD.
Footnotes
The authors declare no competing financial interests.
We thank Jorge Flores and Emma Ames for excellent technical assistance. The authors would like to thank the NIDA Drug Supply Program for supplying diamorphine HCl (Heroin) for these studies. This work was supported by the National Institute On Drug Abuse/National Institutes of Health Grant R00 DA048974 to G.G.
