Source 1primary paper2024MED
Toolkit/hM4D(Gi)
hM4D(Gi)
Also known as: designer receptor, hM4Di
Taxonomy: Mechanism Branch / Architecture. Workflows sit above the mechanism and technique branches rather than replacing them.
Summary
Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation.
Usefulness & Problems
Why this is useful
hM4D(Gi) is the Gi-coupled DREADD variant used here for pan-neuronal cortical chemogenetic manipulation. The study reports unexpectedly excitatory effects in a significant portion of neurons after deschloroclozapine administration.; pan-neuronal chemogenetic inhibition attempts in cortex; testing in vivo electrophysiological consequences of Gi-coupled DREADD actuation; hM4D(Gi) is the inhibitory designer receptor used to chemogenetically silence the rat lateral hypothalamus in this study. Its stimulation was assessed by measuring reduced food intake after re-feeding.; chemogenetic inhibition of the lateral hypothalamus; in vivo proof-of-concept testing of chemogenetic treatments; hM4D(Gi) is an inhibitory DREADD used in the study for chemogenetic silencing of peripheral afferents. The summary states that its expression was associated with CNO-dependent increases in mechanical and thermal thresholds.; chemogenetic inhibition of peripheral nociceptors; increasing mechanical and thermal pain thresholds
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hM4D(Gi) is the Gi-coupled DREADD variant used here for pan-neuronal cortical chemogenetic manipulation. The study reports unexpectedly excitatory effects in a significant portion of neurons after deschloroclozapine administration.
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pan-neuronal chemogenetic inhibition attempts in cortex
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testing in vivo electrophysiological consequences of Gi-coupled DREADD actuation
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hM4D(Gi) is the inhibitory designer receptor used to chemogenetically silence the rat lateral hypothalamus in this study. Its stimulation was assessed by measuring reduced food intake after re-feeding.
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chemogenetic inhibition of the lateral hypothalamus
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in vivo proof-of-concept testing of chemogenetic treatments
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hM4D(Gi) is an inhibitory DREADD used in the study for chemogenetic silencing of peripheral afferents. The summary states that its expression was associated with CNO-dependent increases in mechanical and thermal thresholds.
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chemogenetic inhibition of peripheral nociceptors
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increasing mechanical and thermal pain thresholds
Problem solved
It is used to perturb cortical networks through a Gi-coupled chemogenetic receptor.; provides a Gi-coupled chemogenetic receptor for perturbing cortical networks; It enables a controllable in vivo silencing paradigm for testing whether chemogenetic inhibition of LH can reduce food intake.; provides a receptor-based means to silence LH activity in a rat efficacy assay; It offers a chemogenetic route to suppress pain signaling without relying on light delivery.; provides non-optical inhibitory control of pain-related peripheral afferents
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It is used to perturb cortical networks through a Gi-coupled chemogenetic receptor.
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provides a Gi-coupled chemogenetic receptor for perturbing cortical networks
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It enables a controllable in vivo silencing paradigm for testing whether chemogenetic inhibition of LH can reduce food intake.
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provides a receptor-based means to silence LH activity in a rat efficacy assay
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It offers a chemogenetic route to suppress pain signaling without relying on light delivery.
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provides non-optical inhibitory control of pain-related peripheral afferents
Problem links
provides a Gi-coupled chemogenetic receptor for perturbing cortical networks
LiteratureIt is used to perturb cortical networks through a Gi-coupled chemogenetic receptor.
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It is used to perturb cortical networks through a Gi-coupled chemogenetic receptor.
provides a receptor-based means to silence LH activity in a rat efficacy assay
LiteratureIt enables a controllable in vivo silencing paradigm for testing whether chemogenetic inhibition of LH can reduce food intake.
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It enables a controllable in vivo silencing paradigm for testing whether chemogenetic inhibition of LH can reduce food intake.
provides non-optical inhibitory control of pain-related peripheral afferents
LiteratureIt offers a chemogenetic route to suppress pain signaling without relying on light delivery.
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It offers a chemogenetic route to suppress pain signaling without relying on light delivery.
Published Workflows
Objective: Validate a robust but simple in vivo efficacy assay in rats to support chemogenetic drug discovery and preclinical proof-of-concept testing.
Why it works: The workflow tests methodological parameters by reading out the food-intake-reducing effect of LH chemogenetic inhibition, allowing the authors to identify conditions that give a quick, simple, and reliable in vivo efficacy signal.
general chemogenetic silencing of the lateral hypothalamushM4D(Gi) designer receptor stimulationAAV serotype comparisonactuator drug comparisondose investigationapplication route investigationbehavioral endpoint optimization
Stages
- 1.Methodological parameter investigation in rat in vivo assay(broad_screen)
This stage exists to compare AAV serotype, actuator drug, dose, and application route in a rat model using food-intake reduction as the efficacy readout.
Selection: food-intake-reducing effect after chemogenetic inhibition of the lateral hypothalamus
- 2.Endpoint timing optimization after re-feeding(decision_gate)
This stage exists to identify the optimal experimental endpoint for the in vivo assay.
Selection: strongest food-intake effect window
Objective: Investigate the in vivo electrophysiological consequences of pan-neuronal DREADD actuation by deschloroclozapine on spontaneous firing rate and local field potential oscillations in anterior cingulate cortex.
Why it works: The study pairs chemogenetic receptor actuation with in vivo electrophysiological recording to directly observe how pan-neuronal cortical perturbation changes firing and oscillatory activity.
Gq-coupled DREADD actuationGi-coupled DREADD actuationindirect local network perturbation effects under non-uniform receptor expressionchemogenetic manipulationin vivo electrophysiological recording
Objective: Develop and apply optogenetic and chemogenetic strategies for sustained inhibition of pain through peripheral nociceptor control.
Why it works: The study combines peripheral viral delivery of inhibitory actuators with in vivo behavioral testing, allowing direct comparison of optical and ligand-gated inhibition strategies in pain-related afferents.
optogenetic inhibition of peripheral nociceptorschemogenetic inhibition of peripheral nociceptorsAAV-mediated peripheral deliveryin vivo behavioral assay
Taxonomy & Function
Primary hierarchy
Mechanism Branch
Architecture: A reusable architecture pattern for arranging parts into an engineered system.
Mechanisms
chemogenetic receptor activation by exogenous small-molecule actuatorsgi-coupled inhibitory signalingnetwork-level modulation of neuronal activityTechniques
Computational DesignTarget processes
No target processes tagged yet.
Input: Chemical
Implementation Constraints
cofactor dependency: cofactor requirement unknownencoding mode: hybridimplementation constraint: context specific validationimplementation constraint: payload burdenoperating role: actuator
It requires neuronal transduction, deschloroclozapine actuation, and in vivo electrophysiological recording of firing rate and LFP oscillations.; requires transduction of cortical neurons; requires deschloroclozapine administration for actuation; The abstract indicates that hM4D(Gi) required AAV transfection into rats and administration of actuator drugs such as deschloroclozapine or clozapine-N-oxide.; requires transfection with an AAV vector; requires administration of a chemogenetic actuator drug; used in rats targeting the lateral hypothalamus; The study context indicates AAV6-hSyn vector delivery to peripheral afferents and administration of CNO.; AAV6-hSyn delivery to peripheral afferents; CNO administration
It does not ensure purely inhibitory outcomes in vivo when local network effects and biased receptor expression influence the response.; produced excitatory effects in a significant portion of neurons despite being a Gi-coupled DREADD; interpretation is complicated by indirect network effects and non-uniform expression; The abstract does not show that hM4D(Gi) alone solves translational delivery or clinical validation challenges beyond this rat proof-of-concept assay.; in vivo effectiveness depends on actuator choice, dose, application route, and AAV serotype; The provided evidence does not establish that it removes the need for exogenous ligand dosing or viral transduction.; requires ligand administration; requires viral delivery
Validation
Cell-freeBacteriaMammalianMouseHumanTherapeuticIndep. Replication
Supporting Sources
Source 2primary paper2024MED
Ranked Claims
AAV5, oral deschloroclozapine, and clozapine-N-oxide were effective but slightly less potent than the strongest reported condition.
AAV5, oral administration of deschloroclozapine, and clozapine-N-oxide were also effective but with slightly less potency.
Subcutaneous deschloroclozapine in AAV9-transfected rats produced a substantial reduction in food intake comparable to exenatide.
Subcutaneous deschloroclozapine in rats transfected with AAV9 resulted in a substantial reduction of food-intake, comparable to the efficacy of exenatide.
Chemogenetic inhibition of the lateral hypothalamus by hM4D(Gi) stimulation reduces food intake in rats.
Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation.
Deschloroclozapine actuation of pan-neuronal hM3D(Gq) in rat anterior cingulate cortex produced inhibitory effects in a significant portion of neurons in vivo.
Unexpectedly, in response to the administration of deschloroclozapine, we observed inhibitory effects with pan-neuronal hM3D(Gq) stimulation
Deschloroclozapine actuation of pan-neuronal hM4D(Gi) in rat anterior cingulate cortex produced excitatory effects in a significant portion of neurons in vivo.
and excitatory effects with pan-neuronal hM4D(Gi) stimulation in a significant portion of neurons
In this study, the majority of cells transduced with both hM3D(Gq) and hM4D(Gi) were GABAergic.
In the current study, for instance, the majority of cells that were transduced with both hM3D(Gq) and hM4D(Gi) were GABAergic.
General chemogenetic silencing of the lateral hypothalamus can serve as a fast and reliable in vivo experimental model for preclinical proof-of-concept validation of chemogenetic treatments.
This study demonstrates that general chemogenetic silencing of the LH can be utilized as an optimal, fast and reliable in vivo experimental model for conducting preclinical proof-of-concept studies in order to validate the in vivo effectiveness of novel chemogenetic treatments.
Panneuronal cortical chemogenetic modulation can profoundly alter oscillatory neuronal activity.
we found that panneuronal cortical chemogenetic modulation can profoundly alter oscillatory neuronal activity
DREADDs are valuable tools in neuroscience research.
Chemogenetic techniques, specifically the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have become invaluable tools in neuroscience research.
Approval Evidence
3 sources7 linked approval claimsfirst-pass slug hm4d-gi
Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation.
Source:
Unexpectedly, in response to the administration of deschloroclozapine, we observed excitatory effects with pan-neuronal hM4D(Gi) stimulation in a significant portion of neurons.
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PMC text for the anchor paper explicitly shows AAV6-hSyn-HA-hM4D(Gi)-IRES-mCitrine expression in peripheral afferents and CNO-dependent increases in mechanical and thermal thresholds.
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efficacysupports
Chemogenetic inhibition of the lateral hypothalamus by hM4D(Gi) stimulation reduces food intake in rats.
Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation.
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electrophysiology effectsupports
Deschloroclozapine actuation of pan-neuronal hM4D(Gi) in rat anterior cingulate cortex produced excitatory effects in a significant portion of neurons in vivo.
and excitatory effects with pan-neuronal hM4D(Gi) stimulation in a significant portion of neurons
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expression biassupports
In this study, the majority of cells transduced with both hM3D(Gq) and hM4D(Gi) were GABAergic.
In the current study, for instance, the majority of cells that were transduced with both hM3D(Gq) and hM4D(Gi) were GABAergic.
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model utilitysupports
General chemogenetic silencing of the lateral hypothalamus can serve as a fast and reliable in vivo experimental model for preclinical proof-of-concept validation of chemogenetic treatments.
This study demonstrates that general chemogenetic silencing of the LH can be utilized as an optimal, fast and reliable in vivo experimental model for conducting preclinical proof-of-concept studies in order to validate the in vivo effectiveness of novel chemogenetic treatments.
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applicationsupports
The study used optogenetic and chemogenetic strategies in peripheral nociceptors to achieve sustained inhibition of pain.
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deliverysupports
AAV6-hSyn delivery was used to express inhibitory optogenetic and chemogenetic constructs in peripheral afferents.
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mechanism or performancesupports
hM4D(Gi) expression in peripheral afferents increased mechanical and thermal thresholds in a CNO-dependent manner.
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Comparisons
Source-stated alternatives
The paper directly contrasts hM4D(Gi) with the Gq-coupled hM3D(Gq) receptor.; The abstract contrasts actuator and vector choices around the same receptor system, including deschloroclozapine versus clozapine-N-oxide and AAV9 versus AAV5.; The paper pairs this chemogenetic strategy with optogenetic inhibition using SwiChR and iC1C2.
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The paper directly contrasts hM4D(Gi) with the Gq-coupled hM3D(Gq) receptor.
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The abstract contrasts actuator and vector choices around the same receptor system, including deschloroclozapine versus clozapine-N-oxide and AAV9 versus AAV5.
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The paper pairs this chemogenetic strategy with optogenetic inhibition using SwiChR and iC1C2.
Source-backed strengths
supports strong modulation of oscillatory neuronal activity at the network level; supports measurable reduction of food intake in rats when stimulated with tested actuators; reported CNO-dependent increases in mechanical and thermal thresholds
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supports strong modulation of oscillatory neuronal activity at the network level
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supports measurable reduction of food intake in rats when stimulated with tested actuators
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reported CNO-dependent increases in mechanical and thermal thresholds
Compared with chemogenetic circuit manipulation
The paper pairs this chemogenetic strategy with optogenetic inhibition using SwiChR and iC1C2.
Shared frame: source-stated alternative in extracted literature
Strengths here: supports strong modulation of oscillatory neuronal activity at the network level; supports measurable reduction of food intake in rats when stimulated with tested actuators; reported CNO-dependent increases in mechanical and thermal thresholds.
Relative tradeoffs: produced excitatory effects in a significant portion of neurons despite being a Gi-coupled DREADD; interpretation is complicated by indirect network effects and non-uniform expression; in vivo effectiveness depends on actuator choice, dose, application route, and AAV serotype.
Source:
The paper pairs this chemogenetic strategy with optogenetic inhibition using SwiChR and iC1C2.
Compared with iC1C2
The paper pairs this chemogenetic strategy with optogenetic inhibition using SwiChR and iC1C2.
Shared frame: source-stated alternative in extracted literature
Strengths here: supports strong modulation of oscillatory neuronal activity at the network level; supports measurable reduction of food intake in rats when stimulated with tested actuators; reported CNO-dependent increases in mechanical and thermal thresholds.
Relative tradeoffs: produced excitatory effects in a significant portion of neurons despite being a Gi-coupled DREADD; interpretation is complicated by indirect network effects and non-uniform expression; in vivo effectiveness depends on actuator choice, dose, application route, and AAV serotype.
Source:
The paper pairs this chemogenetic strategy with optogenetic inhibition using SwiChR and iC1C2.
Compared with optogenetic
The paper pairs this chemogenetic strategy with optogenetic inhibition using SwiChR and iC1C2.
Shared frame: source-stated alternative in extracted literature
Strengths here: supports strong modulation of oscillatory neuronal activity at the network level; supports measurable reduction of food intake in rats when stimulated with tested actuators; reported CNO-dependent increases in mechanical and thermal thresholds.
Relative tradeoffs: produced excitatory effects in a significant portion of neurons despite being a Gi-coupled DREADD; interpretation is complicated by indirect network effects and non-uniform expression; in vivo effectiveness depends on actuator choice, dose, application route, and AAV serotype.
Source:
The paper pairs this chemogenetic strategy with optogenetic inhibition using SwiChR and iC1C2.
Compared with SwiChR
The paper pairs this chemogenetic strategy with optogenetic inhibition using SwiChR and iC1C2.
Shared frame: source-stated alternative in extracted literature
Strengths here: supports strong modulation of oscillatory neuronal activity at the network level; supports measurable reduction of food intake in rats when stimulated with tested actuators; reported CNO-dependent increases in mechanical and thermal thresholds.
Relative tradeoffs: produced excitatory effects in a significant portion of neurons despite being a Gi-coupled DREADD; interpretation is complicated by indirect network effects and non-uniform expression; in vivo effectiveness depends on actuator choice, dose, application route, and AAV serotype.
Source:
The paper pairs this chemogenetic strategy with optogenetic inhibition using SwiChR and iC1C2.
Ranked Citations
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