Dopamine and glutamate regulate striatal acetylcholine in decision-making

Abstract

Striatal dopamine and acetylcholine are essential for the selection and reinforcement of motor actions and decision-making1. In vitro studies have revealed an intrastriatal circuit in which acetylcholine, released by cholinergic interneurons (CINs), drives the release of dopamine, and dopamine, in turn, inhibits the activity of CINs through dopamine D2 receptors (D2Rs). Whether and how this circuit contributes to striatal function in vivo is largely unknown. Here, to define the role of this circuit in a living system, we monitored acetylcholine and dopamine signals in the ventrolateral striatum of mice performing a reward-based decision-making task. We establish that dopamine and acetylcholine exhibit multiphasic and anticorrelated transients that are modulated by decision history and reward outcome. Dopamine dynamics and reward encoding do not require the release of acetylcholine by CINs. However, dopamine inhibits acetylcholine transients in a D2R-dependent manner, and loss of this regulation impairs decision-making. To determine how other striatal inputs shape acetylcholine signals, we assessed the contribution of cortical and thalamic projections, and found that glutamate release from both sources is required for acetylcholine release. Altogether, we uncover a dynamic relationship between dopamine and acetylcholine during decision-making, and reveal multiple modes of CIN regulation. These findings deepen our understanding of the neurochemical basis of decision-making and behaviour.

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).…”

“…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).…”

Corticotropin releasing factor alters the functional diversity of accumbal cholinergic interneurons

“…The mechanisms driving changes in firing motifs remain controversial. The preponderance of the literature indicates that these burst-pause events are driven by a combination of glutamatergic inputs and intrinsic ChI properties and are reliant on activation of dopamine D2 receptors localized to ChIs (Chantranupong et al, 2023; Chuhma et al, 2014; Ding et al, 2010; Zhang and Cragg, 2017; Zucca et al, 2018). We propose that the composition of ChI firing motifs differentially poises the cells to respond to different inputs and neuromodulators.…”

Engineering, applications, and future perspectives of GPCR‐based genetically encoded fluorescent indicators for neuromodulators

“…This is a limitation since they cannot be easily combined to monitor two different neuromodulators in the same region. Although green GPCRbased GEFIs are commonly combined with a red calcium indicator, the combination of a red and green GPCR-based GEFIs has only been done in a few studies (Chantranupong et al, 2023;Krok et al, 2023;Liu et al, 2022). One challenging limitation of the red indicators is that they are less bright and have a lower dynamic range than their green counterparts (Labouesse & Patriarchi, 2021).…”