Linking Cholinergic Interneurons, Synaptic Plasticity, and Behavior during the Extinction of a Cocaine-Context Association

Abstract

Despite the fact that cholinergic interneurons are a key cell-type within the nucleus accumbens, a relationship between synaptic plasticity and the in vivo activity of cholinergic interneurons remains to be established. Here, we identify a three-way link between the activity of cholinergic interneurons, synaptic plasticity, and learning in mice undergoing the extinction of a cocaine-context association. We found that activity of cholinergic interneurons regulates extinction learning for a cocaine-context association and generates a sustained reduction in glutamatergic presynaptic strength onto medium spiny neurons. Interestingly, activation of cholinergic interneurons does not support reinforcement learning nor plasticity by itself, suggesting that these neurons have a modulatory rather than a reinforcing function.

Transient synaptic potentiation in nucleus accumbens shell during refraining from cocaine seeking

“…Overall, these results suggest that depression of spontaneous glutamate release onto NAshell MSNs occurs during reexposure to context regardless of whether that context is associated with extinction or self-administration alone. Similar results have been described for D1-MSNs in NAcore 27 and in nucleus accumbens when mice underwent extinction of conditioned place preference 15.…”

“…Extinction decreases pre-synaptic glutamate release in nucleus accumbens. 15 The expression of calcium permeable (CP)-AMPARs in spines of NAshell MSNs contacted by infralimbic prefrontal cortex (PFC) after prolonged withdrawal oppose drug seeking. 9 Finally, NMDA glutamate receptor (NMDAR) signaling in nucleus accumbens enhances extinction learning.…”

Combined Social and Spatial Coding in a Descending Projection from the Prefrontal Cortex

“…Given that plasticity of PL synapses in NAc is thought to be a site of reward-related learning (Britt et al 2012; Otis et al 2017; McFarland et al 2003; Pascoli et al 2014; J. Lee et al 2016), we hypothesized that these neurons could support the formation of social-spatial associations by providing information to the NAc about the location of social encounters.…”

“…In mice, a large number of distributed but interconnected brain areas have been implicated, including the prelimbic cortex (PL, part of the medial prefrontal cortex) and several of its projection targets (e.g. the amygdala, ventral tegmental area, NAc) (Okuyama et al 2016; Wong et al 2016; Lin et al 2011; Hitti & Siegelbaum 2014; Yizhar et al 2011; E. Lee et al 2016; van Kerkhof et al 2013; Takahashi et al 2014; Wang et al 2011; Bicks et al 2015; Gunaydin et al 2014; Felix-Ortiz et al 2016; Amadei et al 2017).…”

Molecular Mechanisms of Reward and Aversion

“…In this context, it is not too surprising that newer studies have revealed striatal acetylcholine to have a modulatory role rather than directly reinforcing properties. Neither optogenetic activation nor inhibition of choline acetyltransferase (ChAT)-positive neurons in the NAc is capable of inducing place preference or avoidance (Lee et al, 2016).…”