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Designer Receptor Exclusively Activated by a Designer Drug (DREADD)

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https://www.readbyqxmd.com/read/27922009/pet-imaging-guided-chemogenetic-silencing-reveals-a-critical-role-of-primate-rostromedial-caudate-in-reward-evaluation
#1
Yuji Nagai, Erika Kikuchi, Walter Lerchner, Ken-Ichi Inoue, Bin Ji, Mark A G Eldridge, Hiroyuki Kaneko, Yasuyuki Kimura, Arata Oh-Nishi, Yukiko Hori, Yoko Kato, Toshiyuki Hirabayashi, Atsushi Fujimoto, Katsushi Kumata, Ming-Rong Zhang, Ichio Aoki, Tetsuya Suhara, Makoto Higuchi, Masahiko Takada, Barry J Richmond, Takafumi Minamimoto
The rostromedial caudate (rmCD) of primates is thought to contribute to reward value processing, but a causal relationship has not been established. Here we use an inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drug) to repeatedly and non-invasively inactivate rmCD of macaque monkeys. We inject an adeno-associated viral vector expressing the inhibitory DREADD, hM4Di, into the rmCD bilaterally. To visualize DREADD expression in vivo, we develop a non-invasive imaging method using positron emission tomography (PET)...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27917685/phosphodiesterase-10-inhibitors-in-clinical-development-for-cns-disorders
#2
Hugo Geerts, Athan Spiros, Patrick Roberts
Phosphodiesterase 10 inhibitors (PDE10-I), are conceptually attractive drugs with a potential great therapeutic window as their enriched striatal localization may likely stimulate D1R and reduce D2R downstream effects. However, so far selective PDE10-I with efficacy in animal models have not shown benefit in clinical trials and unexpectedly revealed a substantial dyskinesia motor side-effect. Areas covered: This paper reviews the underlying biological rationale of PDE10 as a target in schizophrenia, Parkinson's and Huntington's disease based on peer-reviewed published articles, the status of the different PDE10-I in clinical development for various CNS indications and explores possible reasons for the clinical trial failures and translational disconnect...
December 3, 2016: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/27911758/multimodal-imaging-for-dreadd-expressing-neurons-in-living-brain-and-their-application-to-implantation-of-ipsc-derived-neural-progenitors
#3
Bin Ji, Hiroyuki Kaneko, Takafumi Minamimoto, Haruhisa Inoue, Hiroki Takeuchi, Katsushi Kumata, Ming-Rong Zhang, Ichio Aoki, Chie Seki, Maiko Ono, Masaki Tokunaga, Satoshi Tsukamoto, Koji Tanabe, Ryong-Moon Shin, Takeharu Minamihisamatsu, Seiji Kito, Barry J Richmond, Tetsuya Suhara, Makoto Higuchi
: Chemogenetic manipulation of neuronal activities has been enabled by a designer receptor (designer receptor exclusively activated by designer drugs, DREADD) that is activated exclusively by clozapine-N-oxide (CNO). Here, we applied CNO as a functional reporter probe to positron emission tomography (PET) of DREADD in living brains. Mutant human M4 DREADD (hM4Di) expressed in transgenic (Tg) mouse neurons was visualized by PET with microdose [(11)C]CNO. Deactivation of DREADD-expressing neurons in these mice by nonradioactive CNO at a pharmacological dose could also be captured by arterial spin labeling MRI (ASL-MRI)...
November 9, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27909096/excitatory-hindbrain-forebrain-communication-is-required-for-cisplatin-induced-anorexia-and-weight-loss
#4
Amber L Alhadeff, Ruby A Holland, Huiyuan Zheng, Linda Rinaman, Harvey J Grill, Bart C De Jonghe
: Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN), and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We previously demonstrated that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we use neuroanatomical tracing, immunofluorescence and confocal imaging to demonstrate that virtually all NTS→lPBN and lPBN→CeA CGRP projections co-express vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation...
December 1, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27890661/studying-brain-regulation-of-immunity-with-optogenetics-and-chemogenetics-a-new-experimental-platform
#5
REVIEW
Tamar Ben-Shaanan, Maya Schiller, Asya Rolls
The interactions between the brain and the immune system are bidirectional. Nevertheless, we have far greater understanding of how the immune system affects the brain than how the brain affects immunity. New technological developments such as optogenetics and chemogenetics (using DREADDs; Designer Receptors Exclusively Activated by Designer Drugs) can bridge this gap in our understanding, as they enable an unprecedented mechanistic and systemic analysis of the communication between the brain and the immune system...
November 24, 2016: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/27866960/ethanol-seeking-behavior-is-expressed-directly-through-an-extended-amygdala-to-midbrain-neural-circuit
#6
Melanie M Pina, Christopher L Cunningham
Abstinent alcohol-dependent individuals experience an enduring sensitivity to cue-induced craving and relapse to drinking. There is considerable evidence indicating that structures within the midbrain and extended amygdala are involved in this process. Individually, the ventral tegmental area (VTA) and the bed nucleus of the stria terminalis (BNST) have been shown to modulate cue-induced ethanol-seeking behavior. It is hypothesized that cue-induced seeking is communicated through a direct projection from the BNST to VTA...
November 17, 2016: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/27822508/clozapine-n-oxide-administration-produces-behavioral-effects-in-long-evans-rats-implications-for-designing-dreadd-experiments
#7
Duncan A A MacLaren, Richard W Browne, Jessica K Shaw, Sandhya Krishnan Radhakrishnan, Prachi Khare, Rodrigo A España, Stewart D Clark
Clozapine N-oxide (CNO) is a ligand for a powerful chemogenetic system that can selectively inhibit or activate neurons; the so-called Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system. This system consists of synthetic G-protein-coupled receptors, which are not believed to be activated by any endogenous ligand, but are activated by the otherwise inert CNO. However, it has previously been shown that the administration of CNO in humans and rats leads to detectable levels of the bioactive compounds clozapine and N-desmethylclozapine (N-Des)...
September 2016: ENeuro
https://www.readbyqxmd.com/read/27798132/gi-dreadd-expression-in-peripheral-nerves-produces-ligand-dependent-analgesia-as-well-as-ligand-independent-functional-changes-in-sensory-neurons
#8
Jami L Saloman, Nicole N Scheff, Lindsey M Snyder, Sarah E Ross, Brian M Davis, Michael S Gold
: Designer receptors exclusively activated by designer drugs (DREADDs) are an advanced experimental tool that could potentially provide a novel approach to pain management. In particular, expression of an inhibitory (Gi-coupled) DREADD in nociceptors might enable ligand-dependent analgesia. To test this possibility, TRPV1-cre mice were used to restrict expression of Gi-DREADDs to predominantly C-fibers. Whereas baseline heat thresholds in both male and female mice expressing Gi-DREADD were normal, 1 mg/kg clozapine-N-oxide (CNO) produced a significant 3 h increase in heat threshold that returned to baseline by 5 h after injection...
October 19, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27759104/single-and-transient-ca-2-peaks-in-podocytes-do-not-induce-changes-in-glomerular-filtration-and-perfusion
#9
Sybille Koehler, Sebastian Brähler, Alexander Kuczkowski, Julia Binz, Matthias J Hackl, Henning Hagmann, Martin Höhne, Merly C Vogt, Claudia M Wunderlich, F Thomas Wunderlich, Frank Schweda, Bernhard Schermer, Thomas Benzing, Paul T Brinkkoetter
Chronic alterations in calcium (Ca(2+)) signalling in podocytes have been shown to cause proteinuria and progressive glomerular diseases. However, it is unclear whether short Ca(2+) peaks influence glomerular biology and cause podocyte injury. Here we generated a DREADD (Designer Receptor Exclusively Activated by a Designer Drug) knock-in mouse line to manipulate intracellular Ca(2+) levels. By mating to a podocyte-specific Cre driver we are able to investigate the impact of Ca(2+) peaks on podocyte biology in living animals...
October 19, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27733612/sustained-gq-protein-signaling-disrupts-striatal-circuits-via-jnk
#10
Luigi Bellocchio, Andrea Ruiz-Calvo, Anna Chiarlone, Magali Cabanas, Eva Resel, Jean-René Cazalets, Cristina Blázquez, Yoon H Cho, Ismael Galve-Roperh, Manuel Guzmán
: The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. The functionality of striatal neurons is tightly controlled by various metabotropic receptors. Whereas the Gs/Gi-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of Gq-protein-dependent signals remain poorly understood. Here, using different experimental approaches, especially designer receptor exclusively activated by designer drug (DREADD) chemogenetic technology, we found that sustained activation of Gq-protein signaling impairs the functionality of striatal neurons and we unveil the precise molecular mechanism underlying this process: a phospholipase C/Ca(2+)/proline-rich tyrosine kinase 2/cJun N-terminal kinase pathway...
October 12, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27721502/calcium-dysregulation-contributes-to-neurodegeneration-in-ftld-patient-ipsc-derived-neurons
#11
Keiko Imamura, Naruhiko Sahara, Nicholas M Kanaan, Kayoko Tsukita, Takayuki Kondo, Yumiko Kutoku, Yutaka Ohsawa, Yoshihide Sunada, Koichi Kawakami, Akitsu Hotta, Satoshi Yawata, Dai Watanabe, Masato Hasegawa, John Q Trojanowski, Virginia M-Y Lee, Tetsuya Suhara, Makoto Higuchi, Haruhisa Inoue
Mutations in the gene MAPT encoding tau, a microtubules-associated protein, cause a subtype of familial neurodegenerative disorder, known as frontotemporal lobar degeneration tauopathy (FTLD-Tau), which presents with dementia and is characterized by atrophy in the frontal and temporal lobes of the brain. Although induced pluripotent stem cell (iPSC) technology has facilitated the investigation of phenotypes of FTLD-Tau patient neuronal cells in vitro, it remains unclear how FTLD-Tau patient neurons degenerate...
October 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27712862/chemogenetic-activation-of-dopamine-neurons-in-the-ventral-tegmental-area-but-not-substantia-nigra-induces-hyperactivity-in-rats
#12
Linde Boekhoudt, Azar Omrani, Mieneke C M Luijendijk, Inge G Wolterink-Donselaar, Ellen C Wijbrans, Geoffrey van der Plasse, Roger A H Adan
Hyperactivity is a core symptom in various psychiatric disorders, including attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorders, and anorexia nervosa. Although hyperactivity has been linked to dopaminergic signalling, the causal relationship between midbrain dopamine neuronal activity and locomotor hyperactivity remains unknown. In this study, we test whether increased dopamine neuronal activity is sufficient to induce locomotor hyperactivity. To do so, we used designer receptors exclusively activated by designer drugs (DREADD) to chemogenetically enhance neuronal activity in two main midbrain dopamine neuron populations, i...
October 3, 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27696530/stimulation-induced-transient-changes-in-neuronal-activity-blood-flow-and-n-acetylaspartate-content-in-rat-prefrontal-cortex-a-chemogenetic-fmrs-bold-study
#13
Morris H Baslow, Christopher K Cain, Robert Sears, Donald A Wilson, Alvin Bachman, Scott Gerum, David N Guilfoyle
Brain activation studies in humans have shown the dynamic nature of neuronal N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) based on changes in their MRS signals in response to stimulation. These studies demonstrated that upon visual stimulation there was a focal increase in cerebral blood flow (CBF) and a decrease in NAA or in the total of NAA and NAAG signals in the visual cortex, and that these changes were reversed upon cessation of stimulation. In the present study we have developed an animal model in order to explore the relationships between brain stimulation, neuronal activity, CBF and NAA...
December 2016: NMR in Biomedicine
https://www.readbyqxmd.com/read/27639988/pharmacogenetic-reactivation-of-the-original-engram-evokes-an-extinguished-fear-memory
#14
Takahiro Yoshii, Hiroshi Hosokawa, Naoki Matsuo
Fear memory extinction has several characteristic behavioral features, such as spontaneous recovery, renewal, and reinstatement, suggesting that extinction training does not erase the original association between the conditioned stimulus (CS) and the unconditioned stimulus (US). However, it is unclear whether reactivation of the original physical record of memory (i.e., memory trace) is sufficient to produce conditioned fear response after extinction. Here, we performed pharmacogenetic neuronal activation using transgenic mice expressing hM3Dq DREADD (designer receptor exclusively activated by designer drug) under the control of the activity-dependent c-fos gene promoter...
September 14, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27605603/resolving-behavioral-output-via-chemogenetic-designer-receptors-exclusively-activated-by-designer-drugs
#15
C Joseph Burnett, Michael J Krashes
Designer receptors exclusively activated by designer drugs (DREADDs) have proven to be highly effective neuromodulatory tools for the investigation of neural circuits underlying behavioral outputs. They exhibit a number of advantages: they rely on cell-specific manipulations through canonical intracellular signaling pathways, they are easy and cost-effective to implement in a laboratory setting, and they are easily scalable for single-region or full-brain manipulations. On the other hand, DREADDs rely on ligand-G-protein-coupled receptor interactions, leading to coarse temporal dynamics...
September 7, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27477013/a-powerful-dreadd-revealing-structural-drivers-of-functional-dynamics
#16
Ankit N Khambhati, Danielle S Bassett
In this issue of Neuron, Grayson et al. (2016) report how inhibition of amygdala impacts amygdalocortical and corticocortical functional connectivity. Their study predicts changes in functional brain topology, induced by pharmacologic modulation of neuroanatomical circuits using designer receptors exclusively activated by designer drugs (DREADDs), through virtual lesioning of amygdala in structural brain networks.
July 20, 2016: Neuron
https://www.readbyqxmd.com/read/27461084/constitutive-and-acquired-serotonin-deficiency-alters-memory-and-hippocampal-synaptic-plasticity
#17
Sebastian P Fernandez, Aude Muzerelle, Sophie Scotto-Lomassese, Jacques Barik, Agnès Gruart, José M Delgado-García, Patricia Gaspar
Serotonin (5-HT) deficiency occurs in a number of brain disorders that affect cognitive function. However, a direct causal relationship between 5-HT hypo-transmission and memory, and underlying mechanisms, has not been established. We used mice with a constitutive depletion of 5-HT brain levels, (Pet1KO mice) to analyze the contribution of 5-HT to different forms of learning and memory. Pet1KO mice exhibited a striking deficit in novel object recognition memory, a hippocampal-dependent task. No alterations were found in tasks for social recognition, procedural learning or fear memory...
July 27, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27416078/dreadds-suppress-seizure-like-activity-in-a-mouse-model-of-pharmacoresistant-epileptic-brain-tissue
#18
N Avaliani, M Andersson, A H Runegaard, D Woldbye, M Kokaia
Epilepsy is a neurological disorder with a prevalence of ≈1% of general population. Available antiepileptic drugs (AEDs) have multiple side effects and are ineffective in 30% of patients. Therefore, development of effective treatment strategies is highly needed, requiring drug-screening models that are relevant and reliable. We investigated novel chemogenetic approach, using DREADDs (designer receptors exclusively activated by designer drugs) as possible inhibitor of epileptiform activity in organotypic hippocampal slice cultures (OHSCs)...
August 4, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27404844/chemogenetic-silencing-of-the-midline-and-intralaminar-thalamus-blocks-amygdala-kindled-seizures
#19
Evan Wicker, Patrick A Forcelli
Temporal lobe epilepsy is the most common form of medically-intractable epilepsy. While seizures in TLE originate in structures such as hippocampus, amygdala, and temporal cortex, they propagate through a crucial relay: the midline/intralaminar thalamus. Prior studies have shown that pharmacological inhibition of midline thalamus attenuates limbic seizures. Here, we examined a recently developed technology, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), as a means of chemogenetic silencing to attenuate limbic seizures...
September 2016: Experimental Neurology
https://www.readbyqxmd.com/read/27381463/use-of-designer-g-protein-coupled-receptors-to-dissect-metabolic-pathways
#20
Jürgen Wess
G protein-coupled receptors (GPCRs) regulate virtually all metabolic processes, including glucose and energy homeostasis. Recently, the use of designer GPCRs referred to as designer receptors exclusively activated by designer drug (DREADDs) has made it possible to dissect metabolically relevant GPCR signaling pathways in a temporally and spatially controlled fashion in vivo.
September 2016: Trends in Endocrinology and Metabolism: TEM
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