Dissecting the role of dorsal hippocampus to nucleus accumbens circuits in opioid seeking behavior

Although significant advances in the treatment of opiate addiction have been made, relapse to opiate use after abstinence continues to impede successful treatment, highlighting the need for efforts to dissect the mechanism of opiate-dependent changes in brain function. Long-lasting associations between opiates and the context in which they are taken result in cues that lead to drug craving and ultimately relapse. The hippocampus represents a key structure in the integration of emotional processing, learning and memory, and reward-related behaviors. While the ventral subdivision of the hippocampus (vHPC) is involved in processing emotional values of salient stimuli and goal-directed behaviors, the dorsal hippocampus (dHPC) plays a critical role in episodic, spatial, and associative memory. In addition, it has been shown that the dHPC is necessary for context- and cue-associated reward behaviors, including the expression of reward seeking. Further, we found that chemogenetic inhibition of glutamatergic dHPC neurons reduces cue-induced morphine-seeking in an instrumental model of relapse. Together, these findings indicate that the dHPC is important for the development and maintenance of opioid-cue associations necessary for drug-seeking behavior. Integration of rewarding and aversive stimuli relies on the mesolimbic reward circuit, where the nucleus accumbens (NAc) plays a crucial role. The NAc facilitates reward seeking by integrating dopaminergic reinforcement signals with glutamate-encoded environmental and cue stimuli. Although glutamatergic inputs to the NAc from the ventral hippocampus have been reported, our preliminary data show that dense projections to the NAc also originate in the dHPC. Interestingly, we found that photo-stimulation of excitatory dHPC neurons is rewarding and reinforcing using a real-time place preference test and instrumental self-stimulation, respectively. Interestingly, this dHPC stimulation was accompanied by enhanced activity of accumbal neurons and evoked local field potentials within the NAc. No studies have examined whether the dHPCNAc is involved in opioid-seeking behavior. Characterization of the cellular mechanisms initiated by the alterations in glutamatergic transmission from the dHPC to the NAc observed during opioid self-administration is necessary to identify novel molecular targets that might prevent drug relapse triggered by the exposure to drug-associated cues. Therefore, the overall goal of this proposal is to investigate the role of excitatory transmission from the dHPC to the NAc in opioid-seeking behavior and identify novel molecular targets that may mitigate the influence of drug-cue associations on relapse. Accordingly, the aims here will 1) determine whether dHPC to NAc projecting neurons are necessary and sufficient for fentanyl-seeking; 2) examine the effects of fentanyl-seeking behavior on function and plasticity of NAc neurons downstream of dHPC projections; 3) determine the role of dHPCNAc dynorphin- or enkephalin-containing synapses in fentanyl-seeking behavior. Findings generated from this project will have significant translational potential for understanding the mechanisms of drug relapse.