Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

Augustin, Shana M.; Chancey, Jessica Hotard; Lovinger, David M.

doi:10.1016/j.celrep.2018.08.042

Cited by 52 publications

(52 citation statements)

References 52 publications

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“…The pause elongation observed in NAc CINs in our slice recordings following D2R upregulation is consistent with the reverse effect on CIN pausing previously reported with bath-applied D2R antagonists 33,34,41 . The effect is also in line with recent slice physiology studies showing that dorsal striatal CINs from mice lacking D2Rs in ChAT-expressing cells lack pausing but show no gross alterations in CIN firing 36,37 . However, a lack of D2Rs since early in development could give rise to a wide range of unidentified adaptations.…”

Section: Discussionsupporting

confidence: 89%

“…Slice physiology data support a role for DA, as pharmacological blockade of D2Rs eliminates CIN pauses induced by DA neuron optogenetic stimulation and by DA uncaging [33][34][35][36] . Pauses evoked by DA or electrical striatal stimulation are similarly abolished in brain slices from mice with CIN-specific deletion of D2Rs 36,37 . Complicating matters, CINs also receive inputs from motor cortical and centromedial and parafascicular thalamic areas (CM-Pf).…”

Section: Introductionmentioning

confidence: 82%

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Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning

Gallo

Greenwald

Teboul

et al. 2020

Preprint

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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).

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 82%

Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning

Gallo

Greenwald

Teboul

et al. 2020

Preprint

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“…This result was somewhat surprising because D2R activation is required for eCB-dependent LTD in the DLS (Calabresi et al, 1992) and quinpirole inhibits evoked EPSCs in MSNs in a frequency and CB1R-dependent manner (Wang et al, 2012;. In the context of HFS-LTD, D2Rs expressed on CINs promote eCB signaling by limiting ACh release and subsequent activation of M1Rs located on MSNs (Augustin et al, 2018;Wang et al, 2006), which is opposite to the mechanism uncovered in our study. These independent findings, although seemingly contradictory, suggest that M1Rs can either inhibit or augment eCB production, depending on the level of neural activity, and D2Rs regulate the magnitude of eCB modulation by M1Rs regardless of the sign.…”

Section: Discussioncontrasting

confidence: 93%

“…Activation of dopamine D2Rs is required for the expression of HFS-LTD in the dorsal striatum. The mechanism by which D2Rs participate in HFS-LTD has been debated in the literature, however it's clear that D2Rs on cholinergic interneurons are required for inhibiting ACh release and M1R activation (Augustin et al, 2018;Wang et al, 2006). In contrast to HFS-LTD, we found that brief synaptic stimulation requires M1R activation for 2-AG generation.…”

Section: Dopamine D2 Receptors On Cholinergic Interneurons Inhibit 2-contrasting

confidence: 56%

2-Arachidonoylglycerol mobilization following brief synaptic stimulation in the dorsal lateral striatum requires glutamatergic and cholinergic neurotransmission

Liput

Puhl

Dong

et al. 2020

Preprint

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Several forms of endocannabinoid (eCB) signaling have been described in the dorsal lateral striatum (DLS), however most experimental protocols used to induce plasticity do not recapitulate the firing patterns of striatal-projecting pyramidal neurons in the cortex or firing patterns of striatal medium spiny neurons. Therefore, it is unclear if current models of eCB signaling in the DLS provide a reliable description of mechanisms engaged under physiological conditions. To address this uncertainty, we investigated mechanisms of eCB mobilization following brief synaptic stimulation that mimics in vivo patterns of neural activity in the DLS. To monitor eCB mobilization, the novel genetically encoded fluorescent eCB biosensor, GRABeCB2.0, was expressed in corticostriatal afferents of C57BL6J mice and evoked eCB transients were measured in the DLS using a brain slice photometry technique. We found that brief bouts of synaptic stimulation induce long lasting eCB transients. Inhibition of monoacylglycerol lipase, prolonged the duration of the eCB transient, while inhibition of diacylglycerol lipase inhibited the peak amplitude, suggesting that 2-AG is the predominate eCB generated following brief synaptic stimulation. 2-AG transients were robustly inhibited by AMPA and NMDA receptor antagonists, DNQX and DL-AP5 respectively. Additionally, the 2-AG transient was inhibited by the muscarinic M1 receptor (M1R) antagonist, VU 0255035, and augmented by the M1R positive allosteric modulator, VU 0486846, indicating that acetylcholine (ACh) release is required for efficient 2-AG production. The dopamine D2 receptor (D2R) agonist, quinpirole, inhibited the 2-AG transient. However, in slices from mice lacking D2Rs on cholinergic interneurons (CINs), quinpirole did not inhibit the 2-AG transient, demonstrating that D2Rs on CINs can modulate 2-AG production. The AMPA receptor or NMDA receptor antagonists, DNQX or DL-AP5 respectively, occluded 2-AG augmentation by VU 0486846 suggesting that converging glutamatergic and cholinergic signals are required for efficient 2-AG production following brief synaptic stimulation. Collectively, these data uncover unrecognized mechanisms underlying 2-AG mobilization in the DLS.

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“…D2Rs are also found in striatal cholinergic interneurons (CINs), where they regulate corticostriatal plasticity, and on pre‐synaptic dopaminergic terminals, where they regulate dopamine release . The presence of D2Rs in non‐MSN cell types complicates the interpretation of pharmacological effects on striatal function since at least three different cell populations can be simultaneously affected .…”

Section: Introductionmentioning

confidence: 99%

Emerging roles of striatal dopamine D2 receptors in motivated behaviour: Implications for psychiatric disorders

Olivetti

Balsam

Simpson

et al. 2019

Basic Clin Pharma Tox

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Impaired motivation has been a long recognized negative symptom of schizophrenia, as well as a common feature of non-psychotic psychiatric disorders, responsible for a significant share of functional burden, and with limited treatment options. The striatum and dopamine signalling system play a central role in extracting motivationally relevant information from the environment, selecting which behavioural direction the animal should follow, and the vigour with which to engage it. Much of this function relies on striatal projection neurons, known as medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2Rs), or D2-MSNs. However, determining the precise nature of D2-MSNs in regulating motivated behaviour in both healthy individuals and experimental manipulations of D2-MSN function has at times yielded a somewhat confusing picture since their activity has been linked to either enhancement or dampening of motivation in animal models. In this MiniReview, we describe the latest data from rodent studies that investigated how D2Rs exert their modulatory effect on motivated behaviour by regulating striatal indirect pathway neuronal activity. We will include a discussion about how functional selectivity of D2Rs towards G protein-dependent or β-arrestin-dependent signalling differentially affects motivated behaviour. Lastly, we will describe a recent preclinical attempt to improve motivation by exploiting serotonin receptor-mediated modulation of dopamine transmission in the striatum. K E Y W O R D SD2 receptors, dopamine, indirect pathway, motivation, striatum

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Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

Cited by 52 publications

References 52 publications

Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning

Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning

2-Arachidonoylglycerol mobilization following brief synaptic stimulation in the dorsal lateral striatum requires glutamatergic and cholinergic neurotransmission

Emerging roles of striatal dopamine D2 receptors in motivated behaviour: Implications for psychiatric disorders

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