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Designer Receptor Exclusively Activated by a Designer Drug (DREADD)

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
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
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
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
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...
October 3, 2016: NMR in Biomedicine
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
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
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
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
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
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
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
Tamar L Ben-Shaanan, Hilla Azulay-Debby, Tania Dubovik, Elina Starosvetsky, Ben Korin, Maya Schiller, Nathaniel L Green, Yasmin Admon, Fahed Hakim, Shai S Shen-Orr, Asya Rolls
Positive expectations contribute to the clinical benefits of the placebo effect. Such positive expectations are mediated by the brain's reward system; however, it remains unknown whether and how reward system activation affects the body's physiology and, specifically, immunity. Here we show that activation of the ventral tegmental area (VTA), a key component of the reward system, strengthens immunological host defense. We used 'designer receptors exclusively activated by designer drugs' (DREADDs) to directly activate dopaminergic neurons in the mouse VTA and characterized the subsequent immune response after exposure to bacteria (Escherichia coli), using time-of-flight mass cytometry (CyTOF) and functional assays...
August 2016: Nature Medicine
Ike Dela Peña, Wei-Xing Shi
Clinical evidence suggests that the prefrontal cortex (PFC) is hypofunctional in disorders including schizophrenia, drug addiction, and attention-deficit/hyperactivity disorder (ADHD). In schizophrenia, hypofrontality has been further suggested to cause both the negative and cognitive symptoms, and overactivity of dopamine neurons that project to subcortical areas. The latter may contribute to the development of positive symptoms of the disorder. Nevertheless, what causes hypofrontality and how it alters dopamine transmission in subcortical structures remain unclear due, in part, to the difficulty in modeling hypofrontality using previous techniques (e...
August 2016: Medical Hypotheses
Peter M Grace, Keith A Strand, Erika L Galer, Daniel J Urban, Xiaohui Wang, Michael V Baratta, Timothy J Fabisiak, Nathan D Anderson, Kejun Cheng, Lisa I Greene, Debra Berkelhammer, Yingning Zhang, Amanda L Ellis, Hang Hubert Yin, Serge Campeau, Kenner C Rice, Bryan L Roth, Steven F Maier, Linda R Watkins
Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β)...
June 14, 2016: Proceedings of the National Academy of Sciences of the United States of America
Paul D Whissell, Sarasa Tohyama, Loren J Martin
A central goal in understanding brain function is to link specific cell populations to behavioral outputs. In recent years, the selective targeting of specific neural circuits has been made possible with the development of new experimental approaches, including chemogenetics. This technique allows for the control of molecularly defined subsets of cells through engineered G protein-coupled receptors (GPCRs), which have the ability to activate or silence neuronal firing. Through chemogenetics, neural circuits are being linked to behavioral outputs at an unprecedented rate...
2016: Frontiers in Genetics
Hu Zhu, Dipendra K Aryal, Reid H J Olsen, Daniel J Urban, Amanda Swearingen, Stacy Forbes, Bryan L Roth, Ute Hochgeschwender
DREADDs, designer receptors exclusively activated by designer drugs, are engineered G protein-coupled receptors (GPCR) which can precisely control GPCR signaling pathways (for example, Gq, Gs, and Gi). This chemogenetic technology for control of GPCR signaling has been successfully applied in a variety of in vivo studies, including in mice, to remotely control GPCR signaling, for example, in neurons, glia cells, pancreatic β-cells, or cancer cells. In order to fully explore the in vivo applications of the DREADD technology, we generated hM3Dq and hM4Di strains of mice which allow for Cre recombinase-mediated restricted expression of these pathway-selective DREADDs...
August 2016: Genesis: the Journal of Genetics and Development
Tatsuya Hattori, Takuya Osakada, Ayaka Matsumoto, Naoki Matsuo, Sachiko Haga-Yamanaka, Takaya Nishida, Yuji Mori, Kazutaka Mogi, Kazushige Touhara, Takefumi Kikusui
Exocrine gland-secreting peptide 1 (ESP1) released into male tear fluids is a male pheromone that stimulates sexually receptive behavior in female mice via the vomeronasal sensory system. ESP1 also induces c-Fos expression in male brain regions distinct from those in females. However, behavior in males following ESP1 exposure has not been examined. In the present study, we show that ESP1, in conjunction with unfamiliar male urine, enhances male aggression via the specific vomeronasal receptor V2Rp5. In addition, male mice that secrete ESP1 but lack V2Rp5 exhibit a lower level of aggressiveness than do mice that express V2Rp5...
May 9, 2016: Current Biology: CB
Xianglong Zhu, David Ottenheimer, Ralph J DiLeone
While weight gain is clearly promoted by excessive energy intake and reduced expenditure, the underlying neural mechanisms of energy balance remain unclear. The nucleus accumbens (NAc) is one brain region that has received attention for its role in the regulation of energy balance; its D1 and D2 receptor containing neurons have distinct functions in regulating reward behavior and require further examination. The goal of the present study is to investigate how activation and inhibition of D1 and D2 neurons in the NAc influences behaviors related to energy intake and expenditure...
2016: Frontiers in Behavioral Neuroscience
Carmen Varela, Sarah Weiss, Retsina Meyer, Michael Halassa, Joseph Biedenkapp, Matthew A Wilson, Ki Ann Goosens, Daniel Bendor
The hippocampus is critical for the storage of new autobiographical experiences as memories. Following an initial encoding stage in the hippocampus, memories undergo a process of systems-level consolidation, which leads to greater stability through time and an increased reliance on neocortical areas for retrieval. The extent to which the retrieval of these consolidated memories still requires the hippocampus is unclear, as both spared and severely degraded remote memory recall have been reported following post-training hippocampal lesions...
2016: PloS One
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