4.8 Article

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

Journal

CELL REPORTS
Volume 39, Issue 9, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2022.110874

Keywords

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Categories

Funding

  1. NSF GRFP
  2. NIH [R01 DA047869, U19 NS104648-01]
  3. ARO [W911NF1710554]
  4. Brain Research Foundation
  5. Simons Collaboration on the Global Brain
  6. New York Stem Cell Foundation
  7. [F32 MH118792]
  8. U.S. Department of Defense (DOD) [W911NF1710554] Funding Source: U.S. Department of Defense (DOD)

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The study revealed that high endogenous acetylcholine event frequency is correlated with greater extinction of cocaine-context associations in male mice, and extinction is related to a weakening of glutamatergic synapses across different MSN subtypes. Manipulating ChIN activity bidirectionally influences the rate of extinction and associated plasticity at MSNs.
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.

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