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Cholinergic interneurons mediate cocaine extinction in male mice through plasticity across medium spiny neuron subtypes
Journal article   Open access   Peer reviewed

Cholinergic interneurons mediate cocaine extinction in male mice through plasticity across medium spiny neuron subtypes

Weston Fleming, Junuk Lee, Brandy A. Briones, Scott S. Bolkan and Ilana B. Witten
Cell reports (Cambridge), Vol.39(9), pp.110874-110874
05/31/2022
DOI: 10.1016/j.celrep.2022.110874
PMCID: PMC9196889
PMID: 35649378
url
https://doi.org/10.1016/j.celrep.2022.110874View
Published (Version of record) Open Access

Abstract

Cholinergic interneurons (ChINs) in the nucleus accumbens (NAc) have been implicated in the extinction of drug associations, as well as related plasticity in medium spiny neurons (MSNs). However, since most previous work relied on artificial manipulations, whether endogenous acetylcholine signaling relates to drug associations is unclear. Moreover, despite great interest in the opposing effects of dopamine on MSN subtypes, whether ChIN-mediated effects vary by MSN subtype is also unclear. Here, we find that high endogenous acetylcholine event frequency correlates with greater extinction of cocaine-context associations across male mice. Additionally, extinction is associated with a weakening of glutamatergic synapses across MSN subtypes. Manipulating ChIN activity bidirectionally controls both the rate of extinction and the associated plasticity at MSNs. Our findings indicate that NAc ChINs mediate drug-context extinction by reducing glutamatergic synaptic strength across MSN subtypes, and that natural variation in acetylcholine signaling may contribute to individual differences in extinction. [Display omitted] •NAc acetylcholine signaling correlates with cocaine extinction•Cocaine extinction decreases glutamatergic presynaptic strength at D1R and D2R MSNs•Activation of ChINs promotes extinction and associated plasticity•Inhibition of ChINs blocks extinction and associated plasticity Fleming et al. show that individual differences in nucleus accumbens (NAc) acetylcholine signaling correlate with extinction of a cocaine-context association. Manipulations of NAc cholinergic interneuron activity support a model where acetylcholine release weakens glutamatergic presynaptic strength at NAc D1R and D2R medium spiny neurons, promoting cocaine-context extinction.
 acetylcholine cocaine nucleus accumbens plasticity

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