Chemogenetics revealed: DREADD occupancy and activation via converted clozapine

Gómez, Juan L.; Bonaventura, Jordi; Lesniak, Wojciech; Mathews, William B.; Sysa‐Shah, Polina; Rodriguez, Lionel A.; Ellis, Randall J.; Richie, Christopher T.; Harvey, Brandon K.; Dannals, Robert F.; Pomper, Martin G.; Bonci, Antonello; Michaelides, Michael

doi:10.1126/science.aan2475

Cited by 837 publications

(940 citation statements)

References 21 publications

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“…Importantly, CNO treatment had no effect on the behavior or body weight of Nts Cre ;NtsR1 ++ mice expressing channel rhodopsin (ChR) in LHA Nts neurons instead of hM3Dq-mCherry (Fig. S3), confirming that our results are not due to off-target effects of CNO or its metabolite clozapine (Gomez et al, 2017). Interestingly, activation of LHA Nts neurons in Nts Cre ;NtsR1 KOKO mice also induced sustained weight loss over 5 days (Fig.…”

Section: Resultssupporting

confidence: 70%

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

et al. 2017

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SUMMARY The central mechanism by which neurotensin (Nts) potentiates weight loss has remained elusive. We leveraged chemogenetics to reveal that Nts-expressing neurons of the lateral hypothalamic area (LHA) promote weight loss in mice by increasing volitional activity and restraining food intake. Intriguingly, these dual weight loss behaviors are mediated by distinct signaling pathways: Nts action via NtsR1 is essential for the anorectic effect of the LHA Nts circuit, but not for regulation of locomotor or drinking behavior. Furthermore, although LHA Nts neurons cannot reduce intake of freely available obesogenic foods, they effectively restrain motivated feeding in hungry, weight-restricted animals. LHA Nts neurons are thus vital mediators of central Nts action, particularly in the face of negative energy balance. Enhanced action via LHA Nts neurons may therefore be useful to suppress the increased appetitive drive that occurs after lifestyle-mediated weight loss, and hence to prevent weight regain.

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Section: Resultssupporting

confidence: 70%

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

et al. 2017

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“…Additional work is needed to make AAV vectors more efficient to reduce their required dose, and to make compact cell-type specific promoters that work robustly in primates 24 . Finally, ongoing studies of the pharmacokinetics of CNO and clozapine 62 will enable the optimization of ligand dosing for DREADD activation or motivate the use of available alternative ligands 63 or chemogenetic receptors 64,65 . These improvements will facilitate the development and translation of ATAC as a paradigm for precise noninvasive control of neural circuits.…”

Section: Discussionmentioning

confidence: 99%

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

et al. 2018

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Neurological and psychiatric diseases often involve the dysfunction of specific neural circuits in particular regions of the brain. Existing treatments, including drugs and implantable brain stimulators, aim to modulate the activity of these circuits, but are typically not cell type-specific, lack spatial targeting or require invasive procedures. Here, we introduce an approach to modulating neural circuits noninvasively with spatial, cell-type and temporal specificity. This approach, called acoustically targeted chemogenetics, or ATAC, uses transient ultrasonic opening of the blood brain barrier to transduce neurons at specific locations in the brain with virally-encoded engineered G-protein-coupled receptors, which subsequently respond to systemically administered bio-inert compounds to activate or inhibit the activity of these neurons. We demonstrate this concept in mice by using ATAC to noninvasively modify and subsequently activate or inhibit excitatory neurons within the hippocampus, showing that this enables pharmacological control of memory formation. This technology allows a brief, noninvasive procedure to make one or more specific brain regions capable of being selectively modulated using orally bioavailable compounds, thereby overcoming some of the key limitations of conventional brain therapies.

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“…Recent work has brought into question the exclusivity of CNO as the ligand for DREADDs and demonstrated that rodents are capable of CNO to clozapine back metabolism (Gomez et al 2017). While it has been shown that CNO is not significantly back metabolized to clozapine in mice, it is possible that the limited clozapine produced is sufficient to induce DREADD activity reported in Gomez et al, while being subthreshold for off-target effects (Guettier et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

et al. 2018

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Propensity to relapse, even following long periods of abstinence, is a key feature in substance use disorders. Relapse and relapse-like behaviors are known to be induced, in part, by re-exposure to drug-associated cues. Yet, while many critical nodes in the neural circuitry contributing to relapse have been identified and studied, a full description of the networks driving reinstatement of drug-seeking behaviors is lacking. One area that may provide further insight to the mechanisms of relapse is the habenula complex, an epithalamic region composed of lateral and medial (MHb) substructures, each with unique cell and target populations. Although well conserved across vertebrate species, the functions of the MHb are not well understood. Recent research has demonstrated that the MHb regulates nicotine aversion and withdrawal. However, it remains undetermined whether MHb function is limited to nicotine and aversive stimuli or if MHb circuit regulates responses to other drugs of abuse. Advances in circuit-level manipulations now allow for cell-type and temporally specific manipulations during behavior, specifically in spatially restrictive brain regions, such as the MHb. In this study, we focus on the response of the MHb to reinstatement of cocaine-associated behavior, demonstrating that cocaine-primed reinstatement of conditioned place preference engages habenula circuitry. Using chemogenetics, we demonstrate that MHb activity is sufficient to induce reinstatement behavior. Together, these data identify the MHb as a key hub in the circuitry underlying reinstatement and may serve as a target for regulating relapse-like behaviors.

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Chemogenetics revealed: DREADD occupancy and activation via converted clozapine

Cited by 837 publications

References 21 publications

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

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