A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior

Vardy, Eyal; Robinson, J. Elliott; Li, Chia; Olsen, Reid H.J.; DiBerto, Jeffrey F.; Giguère, Patrick M.; Sassano, Flori M.; Huang, Xi Ping; Zhu, Hongguang; Urban, Daniel J.; White, Kate L.; Rittiner, Joseph E.; Crowley, Nicole A.; Pleil, Kristen E.; Mazzone, Christopher M.; Mosier, Philip D.; Song, Juan; Kash, Thomas L.; Malanga, C. J.; Krashes, Michael J.; Roth, Bryan L.

doi:10.1016/j.neuron.2015.03.065

Cited by 347 publications

(364 citation statements)

References 47 publications

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“…Male mice expressing Cre specifically in AgRP neurons (Agrp ires-Cre ) received bilateral stereotactic injection of the Cre-dependent AAV9-hSyn-DIO-HA-KOR expressing the newly designed Gi-coupled DREADD using the kappa-opioid receptor (KORD) activated by the salvinorin B (SalB): a pharmacologically inert ligand (Vardy et al, 2015). SalB-mediated AgRP neuron silencing was assessed during spontaneous feeding at the onset of the dark period and in response to a fast on both chow and HFHS diet.…”

Section: Feeding Relies On Food Palatability and Dopamine Tone When Amentioning

confidence: 99%

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Palatability Can Drive Feeding Independent of AgRP Neurons

Denis¹,

Joly‐Amado²,

Webber³

et al. 2017

Cell Metabolism

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Section: Feeding Relies On Food Palatability and Dopamine Tone When Amentioning

confidence: 99%

“…Diphtheria toxin (DT, 50 µg/kg; List Biological Laboratories, Campbell, CA) or vehicle injection was administered via subcutaneous or intramuscular routes in neonates or adult animal respectively. Salvorin B (SalB) was dissolved in DMSO and injected IP at 10mg/kg as described in (Vardy et al, 2015).…”

Section: Drugs and Peptidesmentioning

confidence: 99%

Palatability Can Drive Feeding Independent of AgRP Neurons

Denis¹,

Joly‐Amado²,

Webber³

et al. 2017

Cell Metabolism

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“…One widely used chemogenetic method in mice and rats is the DREADD (designer receptors exclusively activated by designer drugs) system in which a mutated muscarinic G protein-coupled receptor is activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Recently, the Roth laboratory developed a novel inhibitory DREADD in which a mutated kappa-opioid receptor (KORD) is activated by the pharmacologically inert drug salvinorin B (SalB; Vardy et al, 2015). They demonstrated the feasibility of using KORD to study brain circuits involved in motivated behavior in mice.…”

mentioning

confidence: 99%

Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats

Marchant

Whitaker²,

Bossert³

et al. 2015

Neuropsychopharmacol

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In the past decade, novel methods using engineered receptors have enabled researchers to manipulate neuronal activity with increased spatial and temporal specificity. One widely used chemogenetic method in mice and rats is the DREADD (designer receptors exclusively activated by designer drugs) system in which a mutated muscarinic G protein-coupled receptor is activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Recently, the Roth laboratory developed a novel inhibitory DREADD in which a mutated kappa-opioid receptor (KORD) is activated by the pharmacologically inert drug salvinorin B (SalB; Vardy et al, 2015). They demonstrated the feasibility of using KORD to study brain circuits involved in motivated behavior in mice. Here, we used behavioral, electrophysiological, and neuroanatomical methods to demonstrate the feasibility of using the novel KORD to study brain circuits involved in motivated behavior in rats. In Exp. 1, we show that SalB dose-dependently decreased spontaneous and cocaine-induced locomotor activity in rats expressing KORD to midbrain (ventral tegmental area/substantia nigra). In Exp. 2, we show that SalB completely inhibited tonic firing in KORDexpressing putative dopamine neurons in midbrain. In Exp. 3, we used a 'retro-DREADD' dual-virus approach to restrict expression of KORD in ventral subiculum neurons that project to nucleus accumbens shell. We show that KORD activation selectively decreased novel context-induced Fos expression in this projection. Our results indicate that the novel KORD is a promising tool to selectively inactivate brain areas and neural circuits in rat studies of motivated behavior.

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“…To overcome this limitation, a new set of receptor and ligand was recently developed [152,153]. KORD, the new DREADD, is a kappa-opioid receptor coupled to inhibitory Gi protein and selectively responsive to an inert ligand, salvinorin B [153][154][155].…”

Section: Designer Receptor Exclusively Activated By Designer Drugmentioning

confidence: 99%

“…In terms of choosing of tools for experiments, optogenetics allow precise temporal alterations of function. Chemogenetics, especially DREADDs are more appropriate than optogenetics for changes of behaviors, which requires prolonged testing as DREADD activity is sustained for several hours after 1 injection of the ligand [41,150,151,153]. In addition, chemogenetics also can be done without a headmounted light source and invasive fiber optics.…”

Section: Engineered Ligand-gated Ion Channelsmentioning

confidence: 99%

Selective Manipulation of Neural Circuits

Park

Carmel

2016

Neurotherapeutics

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Unraveling the complex network of neural circuits that form the nervous system demands tools that can manipulate specific circuits. The recent evolution of genetic tools to target neural circuits allows an unprecedented precision in elucidating their function. Here we describe two general approaches for achieving circuit specificity. The first uses the genetic identity of a cell, such as a transcription factor unique to a circuit, to drive expression of a molecule that can manipulate cell function. The second uses the spatial connectivity of a circuit to achieve specificity: one genetic element is introduced at the origin of a circuit and the other at its termination. When the two genetic elements combine within a neuron, they can alter its function. These two general approaches can be combined to allow manipulation of neurons with a specific genetic identity by introducing a regulatory gene into the origin or termination of the circuit. We consider the advantages and disadvantages of both these general approaches with regard to specificity and efficacy of the manipulations. We also review the genetic techniques that allow gain-and loss-of-function within specific neural circuits. These approaches introduce light-sensitive channels (optogenetic) or drug sensitive channels (chemogenetic) into neurons that form specific circuits. We compare these tools with others developed for circuit-specific manipulation and describe the advantages of each. Finally, we discuss how these tools might be applied for identification of the neural circuits that mediate behavior and for repair of neural connections.

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A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior

Cited by 347 publications

References 47 publications

Palatability Can Drive Feeding Independent of AgRP Neurons

Palatability Can Drive Feeding Independent of AgRP Neurons

Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats

Selective Manipulation of Neural Circuits

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