Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation

Abstract

Motivation to work for potential rewards is critically dependent on dopamine (DA) in the nucleus accumbens (NAc). DA release from NAc axons can be controlled by at least two distinct mechanisms: 1) action potentials propagating from DA cell bodies in the ventral tegmental area (VTA), and 2) activation of β2* nicotinic receptors by local cholinergic interneurons (CINs). How CIN activity contributes to NAc DA dynamics in behaving animals is not well understood. We monitored DA release in the NAc Core of awake, unrestrained rats using the DA sensor RdLight1, while simultaneously monitoring or manipulating CIN activity at the same location. CIN stimulation rapidly evoked DA release, and in contrast to slice preparations, this DA release showed no indication of short-term depression or receptor desensitization. The sound of unexpected food delivery evoked a brief joint increase in CIN population activity and DA release, with a second joint increase as rats approached the food. In an operant task, we observed fast ramps in CIN activity during approach behaviors, either to start the trial or to collect rewards. These CIN ramps co-occurred with DA release ramps, without corresponding changes in the firing of lateral VTA DA neurons. Finally, we examined the effects of blocking CIN influence over DA release through local NAc infusion of DHβE, a selective antagonist of β2* nicotinic receptors. DHβE dose-dependently interfered with motivated approach decisions, mimicking the effects of a DA antagonist. Our results support a key influence of CINs over motivated behavior via the local regulation of DA release.

Comment on ‘Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation’

“…In their original report of ACh-evoked DA release, Cachope and colleagues (2012) presented an example recording whereby strong optogenetic activation of cholinergic interneurons for several seconds is accompanied by DA elevation in the NAc of a urethane-anesthetized mouse. More recently, we and others showed in mice and rats that the patterns of DA and ACh release in various striatal locations in vivo are strongly correlated on sub-second time-scales in a manner that is consistent with ACh-evoked DA release (Howe et al, 2019;Liu et al, 2022;Chantranupong et al, 2023;Krok et al, 2023;Mohebi et al, 2023). Yet DA dynamics in the dorsal and lateral striatum were found to persist even after molecular, pharmacological and optogenetic interference with ACh signaling (Chantranupong et al, 2023;Krok et al, 2023).…”

“…In addition, our findings call into question the nature of the RdLight1 fluorescent transients reported in Figure 1 of the study by Mohebi et al (2023). Given the similarity of our recordings in terms of response magnitude, timing and dynamics over a variety of stimulation parameters, it is likely that the light-evoked RdLight1 responses reported reflect this photoactivation effect.…”

“…A recent paper in eLife (Mohebi et al, 2023) provided some of the most compelling evidence to date that optogenetic activation of channelrhodopsin-expressing striatal cholinergic interneurons drives DA release in the NAc of awake behaving rats, as measured with the red-shifted DA sensor RdLight1 (Patriarchi et al, 2020). However, one concern with these experiments is that mApple-based fluorescent sensors – including RdLight1 and the GRAB-rDA3 series (Zhuo et al, 2023) – may exhibit photoactivation (also known as ‘photoswitching’ or ‘photoconversion’), a process whereby mApple’s red fluorescence changes in the presence of blue light (Shaner et al, 2008).…”

“…However, evidence for this mechanism in vivo has been less forthcoming. A recent paper in eLife (Mohebi et al ., 2023) reported that, in awake behaving rats, optogenetic activation of striatal cholinergic interneurons with blue light readily evokes dopamine release measured with the red fluorescent sensor RdLight1. Here, we show that blue light alone alters the fluorescent properties of RdLight1 in a manner that may be misconstrued as phasic dopamine release, and that this artefactual photoactivation can account for the effects attributed to cholinergic interneurons.…”

Reward expectation selectively boosts the firing of accumbens D1+ neurons during motivated approach

“…Decisions to work depend critically upon DA modulation of the NAc (7). Blockade of NAc Core dopamine receptors -especially D1r -interferes with the initiation of approach behavior (34,61,62). Mice lacking functional D1r show a deficit in cue-evoked approach, and this deficit is ameliorated by restoring expression of D1r specifically in NAc Core D1+ neurons (63).…”