DREADDs (Designer Receptors Exclusively Activated by Designer Drugs): Chemogenetic Tools with Therapeutic Utility

Urban, Daniel J.; Roth, Bryan L.

doi:10.1146/annurev-pharmtox-010814-124803

Cited by 551 publications

(509 citation statements)

References 100 publications

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“…Such manipulations will enable study of how normal developmental contributions produce long-lasting impacts on attention, and additionally, how aberrant developmental signaling could be targeted to prevent attentional deficits in preclinical models. DREADD can be expressed in cell-type and circuit-specific manners via viral approaches (Urban and Roth, 2015). Because of this capability, our study provides a template for future studies to chemogenetically dissect the neural circuit basis of attentional behavior in mice.…”

Section: Discussionmentioning

confidence: 99%

“…The utility of this approach is substantiated in accumulating studies that have applied technology to specific cell types and neural circuits in the context of behavioral assays of brain function following its inception (Urban and Roth, 2015). Human M4 muscarinic DREADD receptor coupled to Gi (hM4Di) has been used to silence neuronal firing in vivo (Ferguson et al, 2011;Krashes et al, 2011), and has successfully elucidated neural mechanisms mediating complex cognitive processes, such as goal-directed behavior (Parnaudeau et al, 2013;Parnaudeau et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Chemogenetic Inactivation of Dorsal Anterior Cingulate Cortex Neurons Disrupts Attentional Behavior in Mouse

Koike

Demars

Short

et al. 2015

Neuropsychopharmacol

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Attention is disrupted commonly in psychiatric disorders, yet mechanistic insight remains limited. Deficits in this function are associated with dorsal anterior cingulate cortex (dACC) excitotoxic lesions and pharmacological disinhibition; however, a causal relationship has not been established at the cellular level. Moreover, this association has not yet been examined in a genetically tractable species such as mice. Here, we reveal that dACC neurons causally contribute to attention processing by combining a chemogenetic approach that reversibly suppresses neural activity with a translational, touchscreen-based attention task in mice. We virally expressed inhibitory hM4Di DREADD (designer receptor exclusively activated by a designer drug) in dACC neurons, and examined the effects of this inhibitory action with the attention-based five-choice serial reaction time task. DREADD inactivation of the dACC neurons during the task significantly increased omission and correct response latencies, indicating that the neuronal activities of dACC contribute to attention and processing speed. Selective inactivation of excitatory neurons in the dACC not only increased omission, but also decreased accuracy. The effect of inactivating dACC neurons was selective to attention as response control, motivation, and locomotion remain normal. This finding suggests that dACC excitatory neurons play a principal role in modulating attention to task-relevant stimuli. This study establishes a foundation to chemogenetically dissect specific cell-type and circuit mechanisms underlying attentional behaviors in a genetically tractable species.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemogenetic Inactivation of Dorsal Anterior Cingulate Cortex Neurons Disrupts Attentional Behavior in Mouse

Koike

Demars

Short

et al. 2015

Neuropsychopharmacol

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“…Chemogenetics refers to the approach of using engineered receptors that can inhibit (Armbruster et al, 2007) or activate (Alexander et al, 2009) neurons when an otherwise inert ligand binds to them (Urban and Roth, 2015). DREADDs (designer receptors exclusively activated by designer drugs) are chemogenetic tools with therapeutic utility (Urban and Roth, 2015) and have been used to manipulate cell signaling within diverse cell types (Rogan and Roth, 2011). However, the dependency on the same chemical actuator clozapine-N-oxide (CNO) has restricted the ability to use DREADDs to selectively either inhibit or activate neuronal activity in the same animal.…”

Section: Introductionmentioning

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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“…Optogenetics uses light-activated channels, while chemogenetics uses receptors responsive only to the designed ligand [105,106]. Here, we discuss the variety of genetic tools available, and the advantages and disadvantages in using each; these are summarized in Table 2.…”

Section: Genetic Toolbox For Circuit Manipulationmentioning

confidence: 99%

“…This chemogenetic tool employs design-based drugs to activate G protein-coupled receptors that have been modified to respond only to the novel ligand [106,141]. G proteincoupled receptors play crucial roles as modulator in many physiological processes [142][143][144].…”

Section: Designer Receptor Exclusively Activated By Designer Drugmentioning

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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DREADDs (Designer Receptors Exclusively Activated by Designer Drugs): Chemogenetic Tools with Therapeutic Utility

Cited by 551 publications

References 100 publications

Chemogenetic Inactivation of Dorsal Anterior Cingulate Cortex Neurons Disrupts Attentional Behavior in Mouse

Chemogenetic Inactivation of Dorsal Anterior Cingulate Cortex Neurons Disrupts Attentional Behavior in Mouse

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

Selective Manipulation of Neural Circuits

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