Regional Heterogeneity of D2-Receptor Signaling in the Dorsal Striatum and Nucleus Accumbens

Marcott, Pamela F.; Gong, Sheng; Donthamsetti, Prashant; Grinnell, Steven G.; Nelson, Melissa; Newman, Amy Hauck; Birnbaumer, Lutz; Martemyanov, Kirill A.; Javitch, Jonathan A.; Ford, Christopher P.

doi:10.1016/j.neuron.2018.03.038

Cited by 57 publications

(76 citation statements)

References 73 publications

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“…In this regard, a recent study unveiled that D2R from the AcbSh have a higher sensitivity for DA than those from the DS. This difference has been attributed to postsynaptic signaling molecules that differ between the two regions 35 . In support of this hypothesis, our study revealed significant differences in expression of genes encoding for postsynaptic molecules that belong to G protein signaling and RGS family, which could account for the region-dependent D2R sensitivity to DA.…”

Section: Discussionmentioning

confidence: 99%

Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum

et al. 2020

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Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.

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Section: Discussionmentioning

confidence: 99%

Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum

et al. 2020

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“…It is evident that differential signaling properties of GPCRs, to which DRD2 belongs, contribute to striatal heterogeneity. Distinct signaling properties in striatal domains can thereby shape physiological changes of the striatal circuit and ultimately result in different behavioral readouts (Marcott et al, ).…”

Section: Emerging Complexity Of Striatal Functionmentioning

confidence: 99%

Genetic tools to study complexity of striatal function

Ciriachi

Svane‐Petersen

Rickhag

2019

J of Neuroscience Research

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As the main input structure of the basal ganglia (BG), the striatum collects and integrates information from several brain areas and funnels them forward to other BG nuclei. The striatal projection neurons are medium‐sized spiny neurons classified in two main subpopulations, based on their neurochemical characterization and projection targets. These subpopulations are segregated into two distinct circuits, the direct and the indirect pathway, which originate in the striatum and interconnect the BG, ultimately reaching their output nuclei. In this review, we discuss current opinions on the striatal circuit and present different strategies to decipher this circuit complexity by utilizing cell ablation, opto‐ and chemogenetics, tetanus toxin‐induced neuronal silencing, and calcium imaging techniques. We also describe genetically encoded biosensors to monitor signaling dynamics in the striatal circuit with high spatial and temporal resolution by targeting both glutamate and dopamine transmission together with downstream signaling effectors. Recent findings revealing transcriptional, functional diversity, and regionally distinct signaling properties of spiny projection neurons argue that refined interrogation will be pertinent for a deeper understanding of this circuit. Moreover, future mapping the G‐protein–coupled receptor repertoire in SPNs will potentially enable pathway‐specific modulation of SPN activity and provide a novel framework for targeting BG diseases. Overall, these tools will be critical for designing next‐generation treatments for BG diseases.

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“…The discovery of GPCR signalling through G protein–independent mechanisms, as well as preferential coupling to specific Gα subunits, has spurred new avenues of research that offer a more nuanced view of how D2 receptors may generate sub–cell‐type specificity to drive different responses to midbrain dopamine with distinct behavioural consequences . Using exogenous GIRK channels expressed in indirect D2‐MSNs in the NAc or dorsal striatum to obtain functional readouts of D2R activity, Marcott and colleagues revealed regional differences in how dopamine signals via D2 receptors.…”

Section: Introductionmentioning

confidence: 99%

“…Cellular responses to dopamine in the NAc exhibited slower kinetics and less sensitivity to dopamine compared to D2‐MSNs in the dorsal striatum. These differences were driven by D2R preferential coupling to Gα o as opposed to Gα i subunits in the NAc . How regional D2R functional selectivity with respect to G proteins affects D2R‐dependent behaviours, including motivation, remains to be determined.…”

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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Regional Heterogeneity of D2-Receptor Signaling in the Dorsal Striatum and Nucleus Accumbens

Cited by 57 publications

References 73 publications

Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum

Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum

Genetic tools to study complexity of striatal function

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

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