Abstract
BackgroundPrelimbic cortical projections to the nucleus accumbens core are critical for cue-induced cocaine seeking, but the identity of the accumbens neuron(s) targeted by this projection, and the transient neuroadaptations contributing to relapse within these cells, remain unknown.MethodsMale Sprague-Dawley rats underwent cocaine or sucrose self-administration, extinction, and cue-induced reinstatement. Pathway-specific chemogenetics, patch-clamp electrophysiology, in vivo electrochemistry, and high-resolution confocal microscopy were used to identify and characterize a small population of nucleus accumbens core neurons that receive dense prelimbic cortical input to determine their role in regulating cue-induced cocaine and natural reward seeking.ResultsChemogenetic inhibition of prelimbic cortical projections to the nucleus accumbens core suppressed cue-induced cocaine relapse and normalized real-time cue-evoked increases in accumbens glutamate release to that of sucrose seeking animals. Furthermore, chemogenetic inhibition of the population of nucleus accumbens core neurons receiving the densest prelimbic cortical input suppressed cocaine, but not sucrose seeking. These neurons also underwent morphological plasticity during the peak of cocaine seeking in the form of dendritic spine expansion and increased ensheathment by astroglial processes at large spines.ConclusionWe identified and characterized a unique subpopulation of nucleus accumbens neurons that receive dense prelimbic cortical input. The functional specificity of this subpopulation is underscored by their ability to mediate cue-induced cocaine relapse, but not sucrose seeking. This subset of cells represents a novel target for addiction therapeutics revealed by anterograde targeting to interrogate functional circuits imbedded within a known network.
Highlights
Relapse to cocaine use can be precipitated by cues or contexts predicting cocaine (Kosten et al, 2006) which activate key cortical and limbic regions involved in craving (Childress et al, 1999)
To test whether PrL neurons projecting to the nucleus accumbens core (NAcore) (PrLNAcore) are required for cue-induced reinstatement and increased glutamate release in the NAcore, we expressed inhibitory hM4Di-DREADDs in PrLNAcore neurons using an intersectional chemogenetic approach (Figure 1A)
Cocaine seeking was measured as the number of non-reinforced presses of the lever formerly paired with cocaine (i.e., “active” lever presses or Active lever presses (ALP))
Summary
Relapse to cocaine use can be precipitated by cues or contexts predicting cocaine (Kosten et al, 2006) which activate key cortical and limbic regions involved in craving (Childress et al, 1999). Cue-mediated activation of prelimbic (PrL) cortical glutamatergic neurons, their projection to the nucleus accumbens core (NAcore), is required for reinstatement of cocaine seeking after extinction (Kalivas et al, 2005; McGlinchey et al, 2016). PrL inputs represent a major driver of NAcore neurons (Finch, 1996) and neural processes within the NAcore that guide motivated behavior are known to be disrupted by cocaine (see Carelli, 2002; Kalivas, 2008; Kalivas and O’Brien, 2008 for reviews). When relatively weak PFC stimulation is employed, ∼20% of NAcore neurons exhibit spike firing, suggesting that a subpopulation of NAcore neurons receives the majority of PrL inputs (Finch, 1996) and that there is heterogeneity of functional innervation of NAcore MSNs by PrL neurons. Prelimbic cortical projections to the nucleus accumbens core are critical for cue-induced cocaine seeking, but the identity of the accumbens neuron(s) targeted by this projection, and the transient neuroadaptations contributing to relapse within these cells, remain unknown
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