Cholinergic interneurons mediate cocaine extinction through similar plasticity across medium spiny neuron subtypes

Cholinergic interneurons (ChINs) in the nucleus accumbens (NAc) have been implicated in the acquisition and extinction of drug associations, as well as related plasticity in medium spiny neurons (MSNs). However, since most previous work has relied on artificial manipulations, if and how endogenous patterns of cholinergic signaling relate to drug associations is unknown. Moreover, despite great interest in the opposing effects of dopamine on MSN subtypes, whether ChIN-mediated effects are similar or different across MSN subtypes is also unknown. Here, we find that endogenous acetylcholine event frequency during extinction negatively correlates with the strength and persistence of cocaine-context associations across individuals, consistent with effects of artificial manipulation of ChIN activity during extinction. Moreover, ChIN activation during extinction produces a reduction in excitatory synaptic strength on both MSN subtypes, similar to the effect of multiple extinction sessions in the absence of ChIN manipulations. Together, our findings indicate that natural variation in NAc acetylcholine may contribute to individual differences in drug-context extinction by modulating glutamatergic presynaptic strength similarly at both D1R and D2R MSN subtypes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/458113v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@14b4cc1org.highwire.dtl.DTLVardef@9c5224org.highwire.dtl.DTLVardef@d4bff3org.highwire.dtl.DTLVardef@1862150_HPS_FORMAT_FIGEXP M_FIG C_FIG