Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning

Abstract

Cholinergic interneurons (CINs) in the striatum respond to salient stimuli with a multiphasic response, including a pause, in neuronal activity. Slice physiology experiments have shown the importance of dopamine D2 receptors (D2Rs) in regulating CIN pausing yet the behavioral significance of the CIN pause and its regulation by dopamine in vivo is still unclear. Here, we show that D2R upregulation in CINs of the nucleus accumbens (NAc) lengthens the pause in CIN activity ex vivo and enlarges a stimulus-evoked decrease in acetylcholine (ACh) levels during behavior. This enhanced dip in ACh levels is associated with a selective deficit in the learning to inhibit responding in a Go/No-Go task. Our data demonstrate, therefore, the importance of CIN D2Rs in modulating the CIN response induced by salient stimuli and points to a role of the pause in inhibitory learning. This work has important implications for brain disorders with altered striatal dopamine and ACh function, including schizophrenia and attention-deficit hyperactivity disorder (ADHD).

Continuous cholinergic-dopaminergic updating in the nucleus accumbens underlies approaches to reward-predicting cues

“…This is particularly important considering that tonically-active CINs also co-release glutamate, and in vivo electrophysiological methods cannot distinguish the consequences of ACh and glutamate release. Consistent with a previous report using a Go/No-Go task in mice 102 , we observed that NAc ACh dynamics in control mice performing the Autoshaping task are mainly characterised by a transient reward-evoked decrease in cholinergic tone, likely reflecting the pause of activity of CINs electrophysiologically detected in vivo. This profound decrease of cholinergic signals correlates with the acquisition of approach behaviours, suggesting a relevant gating mechanism necessary for the acquisition or maintenance of cue-motivated learning behaviours.…”

GPCR-Based Dopamine Sensors—A Detailed Guide to Inform Sensor Choice for In Vivo Imaging

“…In Table 1 you will find a summary of currently available DA biosensors as well as their main properties, which are further detailed in Section 5 . DA biosensors have already generated key findings in the basic understanding of reward behavior [ 101 , 102 , 103 , 104 , 105 , 106 , 107 ], thirst regulation [ 108 ], feeding behavior [ 109 ], addiction [ 38 , 110 , 111 ], aversive learning [ 112 ], depressive-like behavior [ 98 ], sleep-wake cycle [ 113 ] or to dissect neuromodulator mechanisms in disease models [ 114 , 115 ] using a variety of in vivo imaging modalities shown in Figure 1 . DA biosensors can also be used to understand DA release dynamics in vitro or ex vivo [ 58 , 59 , 60 , 61 ], as shown for example in Reference [ 116 ] where dLight1 was used to understand the metabolic demands and bioenergetic roles of the mitochondria in governing phasic DA release.…”

“…Next, among the sensors selected, it is best to favor a sensor with maximal dynamic range (if possible, >250–300%). We found that dLight1.1, dLight1.2 and RdLight1 displayed an optimal combination of medium ligand affinity (330 nM, 765 nM and 860 nM, respectively) and good dynamic range (230%, 340% and 250%, respectively), making them ideally suited for in vivo bulk (photometry) imaging of large DA transients in response to rewards or cues in the heavily innervated striatum or NAc [ 58 , 59 ], see also: [ 107 , 110 , 111 , 112 , 113 , 115 , 224 , 225 ]. On the other hand, sensors with high and extremely high affinity such as GRAB-DA2m (K d = 90 nM; dFFmax = 340%; validated in vivo), GRAB-DA2h (K d = 7 nM; dFFmax = 280%; validated in vivo) [ 61 ] and dLight1.4 (K d = 4.1 nM; dFFmax = 170%; not validated in vivo yet) [ 58 ]; as well as other sensors in development (not shown) are ideally suited to detect DA release in brain regions with sparser and extremely sparse innervation or may potentially be used to track tonic DA changes in the nanomolar range [ 11 ] (this remains to be determined).…”

“…In Supplementary Table S2 we present an overview of previously published in vivo applications of DA biosensors from the dLight, RdLight and GRAB-DA families in rodent animal models [ 38 , 58 , 60 , 61 , 98 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 224 , 226 , 227 , 228 ]. The large majority of experiments was performed in either the dorsal striatum or the NAc where the DA concentration reaches its maximal levels.…”

Dopamine D2 receptors in nucleus accumbens cholinergic interneurons increase impulsive choice

“…First, CINs influence striatal output by modulating cortico-striatal plasticity in SPNs [26,27], which are thought to play key roles in action selection and reward valuation [28,29]. Second, CINs not only powerfully control local dopamine release [30][31][32], but their cue-evoked firing activity and acetylcholine release is, in turn, sensitive to dopamine actions on D2Rs [33][34][35]. Third, recent work involving systemic administration of cholinergic receptor agonists and antagonists has suggested a complex involvement of acetylcholine in delay and probabilistic discounting tasks [36][37][38][39].…”