The nucleus accumbens dorsomedial column: distinct anterior-posterior inputs and activation inversely associated with opioid relapse

Abstract

Anatomical studies suggest that a dorsomedial region of nucleus accumbens (dmACB) forms a basal ganglia-like closed-loop circuit with medial ventral pallidum (mVP), lateral hypothalamic area (LHA), and paraventricular thalamic nucleus (PVT). The topographic organization of the circuit is unknown. We first used anterograde (Phaseolus vulgaris leucoagglutinin, PHAL) and retrograde (cholera-toxin B, CTB) tracers to map this organization. We then used immunoreactivity for Fos phosphorylated at serine 32 (pSer32-Fos-ir) as a proxy for the activation marker Fos (thus, we refer to pSer32-Fos hereafter as 'Fos') to determine whether the time-dependent increase (incubation) of oxycodone seeking after electric barrier-induced abstinence is associated with dmACB activation. In Experiment 1, we injected rats with PHAL into the anterior PVT (aPVT) and CTB into either the mVP or the anterior LHA (LHAa) to determine the distribution of their connections within the dmACB. We also injected CTB into anterior and posterior dmACB to identify afferent inputs. In Experiment 2, we trained rats to self-administer oxycodone for two weeks and counted Fos-labeled cells in anterior and posterior dmACB, the surrounding ACB, and dorsal striatum regions after drug-seeking tests on either abstinence day 1 or day 15 following electric barrier-induced abstinence. PHAL-labeled aPVT axons and CTB-labeled mVP and LHA neurons were confined to dmACB, forming a longitudinal column along the anterior-posterior axis of ACB. Inputs to anterior and posterior dmACB came from different cortical and subcortical regions. dmACB Fos+ cell counts were higher after oxycodone-seeking tests on day 1 than on day 15 and were negatively correlated with oxycodone seeking. These results characterize a connection-defined dmACB circuit and show that incubation of opioid-seeking is unexpectedly associated with reduced dmACB activation.