Modulating Dopamine Signaling and Behavior with Chemogenetics: Concepts, Progress, and Challenges

Runegaard, Annika H.; Fitzpatrick, Ciarán Martin; Andreasen, Jesper T.; Sørensen, Andreas T.; Gether, Ulrik

doi:10.1124/pr.117.013995

Cited by 39 publications

(35 citation statements)

References 211 publications

(311 reference statements)

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“…In the present study, we aimed at further document the in vivo properties of C21 by extending its DREADDs application to transgenic TH-Cre rats. Indeed, TH-Cre rats are frequently used in combination to DREADDs as they appear as a powerful tool for the investigation of tonic modulation of mesolimbic and nigrostriatal dopaminergic (DA) systems in motivated, cognitive and affective behaviors (Beloate et al, 2016;Boekhoudt et al, 2016;Mahler et al, 2014;Runegaard et al, 2019). However, no one has tested yet the potential efficiency and selectivity of C21 in this experimental model.…”

Section: Introductionmentioning

confidence: 99%

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats

Goutaudier

Coizet

Carcenac

et al. 2020

Preprint

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Although Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) represent a technical revolution in integrative neuroscience, the first ligands used were not as selective as expected. Compound 21 (C21) was recently proposed as an alternative, but in vivo characterization of its properties is not sufficient yet. Here, we evaluated its potency to selectively modulate the activity of nigral dopaminergic (DA) neurons through the canonical DREADD receptor hM4Di using TH-Cre rats. In males, 1 mg.kg -1 of C21 strongly increased nigral neurons activity in control animals, indicative of a significant off-target effect. Reducing the dose to 0.5 mg.kg -1 circumvented this aspecific effect, while activated the inhibitory DREADDs and selectively reduced nigral neurons firing. In females, 0.5 mg.kg -1 of C21 induced a transient and residual off-target effect that may mitigated the inhibitory DREADDs-mediated effect.This study raises up the necessity to test selectivity and efficacy of chosen ligands for each new experimental condition.

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Section: Introductionmentioning

confidence: 99%

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats

Goutaudier

Coizet

Carcenac

et al. 2020

Preprint

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Section: Discussionmentioning

confidence: 99%

“…The VTA plays a significant role in motor activity and locomotor sensitization (5,67). Chemogenetic inhibition of VTA DA neurons reduced basal and cocaine-induced locomotion (89), while exciting VTA DA neurons, or the VTA-to-NAc projection, elevated basal locomotion (67,(89)(90)(91)(92). mPFC pyramidal neurons synapse onto VTA DA neurons (60,93,94) and activation of the mPFC (95,96) or intra-VTA infusion of glutamatergic agonists (97,98) induces burst-spiking of VTA DA neurons in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…We next used a projection-specific viral chemogenetic approach to manipulate PL neurons projecting to the BLA, NAc, or VTA (59-62). These brain regions were selected because they receive glutamatergic input from the PL and given their involvement in fear learning and/or motor activity (5,(63)(64)(65)(66)(67)(68). We infused an AAV2retro-based (69) Cre vector (AAV2retro-hSyn-Cre-GFP) into the downstream target of interest, and a Cre-dependent vector (AAV8-hSyn-DIO-hM3Dq(mCherry) or AAV8-hSyn-DIO-mCherry)…”

Section: Chemogenetic Activation Of Distinct Pl Projectionsmentioning

confidence: 99%

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Divergent behavioral consequences of manipulations enhancing pyramidal neuron excitability in the prelimbic cortex

Rose

Velasco

et al. 2020

Preprint

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BackgroundDrug-induced neuroadaptations in the prefrontal cortex are thought to underlie impaired executive functions that reinforce addictive behaviors. Repeated cocaine exposure increased layer 5/6 pyramidal neuron excitability in the mouse prelimbic cortex (PL), an adaptation attributable to a suppression of G protein-gated inwardly rectifying K + (GIRK/Kir3) channel activity. GIRK channel suppression in the PL of drug-naïve mice enhanced the motor-stimulatory effect of cocaine. The impact of cocaine on PL GABA neurons, key pyramidal neuron regulators, and the behavioral relevance of increased PL pyramidal neuron excitability, remain unclear. MethodsThe effect of repeated cocaine on mouse layer 5/6 PL GABA neurons was assessed using slice electrophysiology. Adaptations enhancing PL pyramidal neuron excitability were modeled in drug-naïve mice using persistent viral Cre ablation and acute chemogenetic approaches. The impact of these manipulations on PL-dependent behavior was assessed in motor activity and trace fear conditioning tests. ResultsRepeated cocaine treatment did not impact GIRK channel activity in, or excitability of, layer 5/6 PL GABA neurons. GIRK channel ablation in PL pyramidal neurons enhanced the motor-stimulatory effect of cocaine but did not impact baseline activity or fear learning. In contrast, direct or indirect chemogenetic activation of PL pyramidal neurons increased baseline and cocaine-induced motor activity and disrupted fear learning. These effects were mirrored by chemogenetic activation of PL pyramidal neurons projecting to the ventral tegmental area. ConclusionsManipulations enhancing the excitability of PL pyramidal neurons, including those projecting to the VTA, recapitulate behavioral hallmarks of repeated cocaine exposure.

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“…The chemogenetic platform allows remote control of neuronal activity in subsets of neuronal populations to deconstruct circuits implicated in behavioral outcome (Farrell & Roth, ; Runegaard et al, ; Urban & Roth, ). DREADDs associated to G s (rM3Ds, excitatory), G q (hM3Dq, excitatory), and G i (hM4Di, inhibitory) proteins have been used for investigations in the CNS (Roth, ).…”

Section: Interventional Approachesmentioning

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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Modulating Dopamine Signaling and Behavior with Chemogenetics: Concepts, Progress, and Challenges

Cited by 39 publications

References 211 publications

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats

Divergent behavioral consequences of manipulations enhancing pyramidal neuron excitability in the prelimbic cortex

Genetic tools to study complexity of striatal function

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