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Designer Receptor Exclusively Activated by a Designer Drug (DREADD)

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https://www.readbyqxmd.com/read/29763576/g-i-protein-functions-in-thalamic-neurons-to-decrease-orofacial-nociceptive-response
#1
Jennifer Strand, Crystal Stinson, Larry L Bellinger, Yuan Peng, Phillip R Kramer
Orofacial pain includes neuronal pathways that project from the trigeminal nucleus to and through the thalamus. What role the ventroposterior thalamic complex (VP) has on orofacial pain transmission is not understood. To begin to address this question an inhibitory G protein (Gi) designer receptor exclusively activated by a designer drug (DREADD) was transfected in cells of the VP using adeno-associated virus isotype 8. Virus infected cells were identified by a fluorescent tag and immunostaining. Cells were silenced after injecting the designer drug clozapine-n-oxide, which binds the designer receptor activating Gi ...
May 12, 2018: Brain Research
https://www.readbyqxmd.com/read/29754898/replay-of-episodic-memories-in-the-rat
#2
Danielle Panoz-Brown, Vishakh Iyer, Lawrence M Carey, Christina M Sluka, Gabriela Rajic, Jesse Kestenman, Meredith Gentry, Sydney Brotheridge, Isaac Somekh, Hannah E Corbin, Kjersten G Tucker, Bianca Almeida, Severine B Hex, Krysten D Garcia, Andrea G Hohmann, Jonathon D Crystal
Vivid episodic memories in people have been characterized as the replay of multiple unique events in sequential order [1-3]. The hippocampus plays a critical role in episodic memories in both people and rodents [2, 4-6]. Although rats remember multiple unique episodes [7, 8], it is currently unknown if animals "replay" episodic memories. Therefore, we developed an animal model of episodic memory replay. Here, we show that rats can remember a trial-unique stream of multiple episodes and the order in which these events occurred by engaging hippocampal-dependent episodic memory replay...
April 21, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29686629/critical-role-for-g-i-o-protein-activity-in-the-dorsal-striatum-in-the-reduction-of-voluntary-alcohol-intake-in-c57bl-6-mice
#3
Meridith T Robins, Terrance Chiang, Kendall L Mores, Doungkamol Alongkronrusmee, Richard M van Rijn
The transition from non-dependent alcohol use to alcohol dependence involves increased activity of the dorsal striatum. Interestingly, the dorsal striatum expresses a large number of inhibitory G-protein-coupled receptors (GPCRs), which when activated may inhibit alcohol-induced increased activity and can decrease alcohol consumption. Here, we explore the hypothesis that dorsal striatal Gi/o -protein activation is sufficient to reduce voluntary alcohol intake. Using a voluntary, limited-access, two-bottle choice, drink-in-the-dark model of alcohol (10%) consumption, we validated the importance of Gi/o signaling in this region by locally expressing neuron-specific, adeno-associated-virus encoded Gi/o -coupled muscarinic M4 designer receptors exclusively activated by designer drugs (DREADD) in the dorsal striatum and observed a decrease in alcohol intake upon DREADD activation...
2018: Frontiers in Psychiatry
https://www.readbyqxmd.com/read/29668112/pharmacogenetic-manipulation-of-the-nucleus-accumbens-alters-binge-like-alcohol-drinking-in-mice
#4
Kush Purohit, Puja K Parekh, Joseph Kern, Ryan W Logan, Zheng Liu, Yanhua Huang, Colleen A McClung, John C Crabbe, Angela R Ozburn
BACKGROUND: Chronic alcohol intake leads to long-lasting changes in reward- and stress-related neuronal circuitry. The nucleus accumbens (NAc) is an integral component of this circuitry. Here, we investigate the effects of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) on neuronal activity in the NAc and binge-like drinking. METHODS: C57BL/6J mice were stereotaxically injected with AAV2 hSyn-HA hM3Dq, -hM4Di, or -eGFP bilaterally into NAc [core + shell, core or shell]...
April 18, 2018: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/29662948/reduced-orexin-system-function-contributes-to-resilience-to-repeated-social-stress
#5
Laura A Grafe, Darrell Eacret, Jane Dobkin, Seema Bhatnagar
Exposure to stress increases the risk of developing affective disorders such as depression and post-traumatic stress disorder (PTSD). However, these disorders occur in only a subset of individuals, those that are more vulnerable to the effects of stress, whereas others remain resilient. The coping style adopted to deal with the stressor, either passive or active coping, is related to vulnerability or resilience, respectively. Important neural substrates that mediate responses to a stressor are the orexins. These neuropeptides are altered in the cerebrospinal fluid of patients with stress-related illnesses such as depression and PTSD...
March 2018: ENeuro
https://www.readbyqxmd.com/read/29660441/silencing-the-insular-striatal-circuit-decreases-alcohol-self-administration-and-increases-sensitivity-to-alcohol
#6
Anel A Jaramillo, Kalynn Van Voorhies, Patrick A Randall, Joyce Besheer
Internal drug states/cues can impact drug taking, as pretreatment with a moderate to high alcohol dose (i.e., loading dose) can decrease subsequent alcohol self-administration, alcohol-seeking, and relapse-like drinking. The insular cortex (IC) is implicated in processing information about internal states and findings show that silencing the IC and its projections to the nucleus accumbens core (AcbC) enhance sensitivity to the interoceptive effects of alcohol. Therefore, the goal of the present work was to determine the functional role of IC-AcbC projections in modulating the effects of alcohol pretreatment on operant alcohol self-administration...
April 13, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/29571824/dose-dependent-reduction-in-cocaine-induced-locomotion-by-clozapine-n-oxide-in-rats-with-a-history-of-cocaine-self-administration
#7
Yasmin Padovan-Hernandez, Lori A Knackstedt
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are novel tools for the dissection of circuitry mediating behavior and neural function. Designer receptors based on the muscarinic M3 and M4 subtypes were designed to be activated by clozapine-N-oxide (CNO), a ligand previously shown to be an inert metabolite of clozapine. However, recent work in rats has shown that CNO is reverse metabolized to its parent compound. Furthermore, CNO administration (5 mg/kg IP) attenuates amphetamine-induced locomotion and the evoked dopamine response that accompanies it...
March 20, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29530713/dreadded-microglia-in-pain-implications-for-spinal-inflammatory-signaling-in-male-rats
#8
Peter M Grace, Xiaohui Wang, Keith A Strand, Michael V Baratta, Yingning Zhang, Erika L Galer, Hang Yin, Steven F Maier, Linda R Watkins
The absence of selective pharmacological tools is a major barrier to the in vivo study of microglia. To address this issue, we developed a Gq - and Gi -coupled Designer Receptor Exclusively Activated by a Designer Drug (DREADD) to enable selective stimulation or inhibition of microglia, respectively. DREADDs under a CD68 (microglia/macrophage) promoter were intrathecally transfected via an AAV9 vector. Naïve male rats intrathecally transfected with Gq (stimulatory) DREADDs exhibited significant allodynia following intrathecal administration of the DREADD-selective ligand clozapine-N-oxide (CNO), which was abolished by intrathecal interleukin-1 receptor antagonist...
June 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29516036/inhibition-of-a-descending-prefrontal-circuit-prevents-ketamine-induced-stress-resilience-in-females
#9
S D Dolzani, M V Baratta, J M Moss, N L Leslie, S G Tilden, A T Sørensen, L R Watkins, Y Lin, S F Maier
Stress is a potent etiological factor in the onset of major depressive disorder and posttraumatic stress disorder (PTSD). Therefore, significant efforts have been made to identify factors that produce resilience to the outcomes of a later stressor, in hopes of preventing untoward clinical outcomes. The NMDA receptor antagonist ketamine has recently emerged as a prophylactic capable of preventing neurochemical and behavioral outcomes of a future stressor. Despite promising results of preclinical studies performed in male rats, the effects of proactive ketamine in female rats remains unknown...
January 2018: ENeuro
https://www.readbyqxmd.com/read/29507292/fear-extinction-requires-infralimbic-cortex-projections-to-the-basolateral-amygdala
#10
Daniel W Bloodgood, Jonathan A Sugam, Andrew Holmes, Thomas L Kash
Fear extinction involves the formation of a new memory trace that attenuates fear responses to a conditioned aversive memory, and extinction impairments are implicated in trauma- and stress-related disorders. Previous studies in rodents have found that the infralimbic prefrontal cortex (IL) and its glutamatergic projections to the basolateral amygdala (BLA) and basomedial amygdala (BMA) instruct the formation of fear extinction memories. However, it is unclear whether these pathways are exclusively involved in extinction, or whether other major targets of the IL, such as the nucleus accumbens (NAc) also play a role...
March 6, 2018: Translational Psychiatry
https://www.readbyqxmd.com/read/29507147/activity-dependent-myelination-of-parvalbumin-interneurons-mediated-by-axonal-morphological-plasticity
#11
Jeffrey Stedehouder, Demi Brizee, Guy Shpak, Steven A Kushner
Axonal myelination of neocortical pyramidal neurons is modulated dynamically by neuronal activity. Recent studies have shown that a substantial proportion of neocortical myelin content is contributed by fast-spiking, parvalbumin (PV)-positive interneurons. However, it remains unknown whether the myelination of PV+ interneurons is also modulated by intrinsic activity. Here, we used cell-type-specific Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in adult mice to activate a sparse population of medial prefrontal cortex (mPFC) PV+ interneurons...
April 11, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29500819/cyclic-amp-producing-chemogenetic-activation-of-indirect-pathway-striatal-projection-neurons-and-the-downstream-effects-on-the-globus-pallidus-and-subthalamic-nucleus-in-freely-moving-mice
#12
Safa Bouabid, Fu-Ming Zhou
The indirect pathway striatal medium spiny projection neurons (iMSNs) are critical to motor and cognitive brain functions. These neurons express a high level of cAMP-increasing adenosine A2a receptors. However, the potential effects of cAMP production on iMSN spiking activity have not been established, and recording identified iMSNs in freely moving animals is challenging. Here, we show that in the transgenic mice expressing cAMP-producing G protein Gs -coupled designer receptor exclusively activated by designer drug (Gs-DREADD) in iMSNs, the baseline spike firing in MSNs is normal, indicating DREADD expression does not affect the normal physiology of these neurons...
March 3, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29497149/the-dreadd-agonist-clozapine-n-oxide-cno-is-reverse-metabolized-to-clozapine-and-produces-clozapine-like-interoceptive-stimulus-effects-in-rats-and-mice
#13
Daniel F Manvich, Kevin A Webster, Stephanie L Foster, Martilias S Farrell, James C Ritchie, Joseph H Porter, David Weinshenker
Clozapine-N-oxide (CNO) has long been the ligand of choice for selectively activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). However, recent studies have challenged the long-held assertion that CNO is otherwise pharmacologically inert. The present study aimed to 1) determine whether CNO is reverse-metabolized to its parent compound clozapine in mice (as has recently been reported in rats), and 2) determine whether CNO exerts clozapine-like interoceptive stimulus effects in rats and/or mice...
March 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29396448/ventromedial-prefrontal-cortex-mediates-sex-differences-in-persistent-cognitive-drive-for-food
#14
Lauren C Anderson, Gorica D Petrovich
Contemporary environments are saturated with food cues that stimulate appetites in the absence of hunger, which leads to maladaptive eating. These settings can induce persistent drive to eat, as learned behaviors can reappear after extinction. Behavioral paradigms of responding renewal provide a valuable framework to study how food cues contribute to the inability to resist palatable foods and change maladaptive eating habits. Using a rat model for this persistent food motivation, we determined sex differences in the causal function for the ventromedial prefrontal cortex (vmPFC) during context-mediated renewal of responding to food cues...
February 2, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29356147/kisspeptin-neurones-in-the-posterodorsal-medial-amygdala-modulate-sexual-partner-preference-and-anxiety-in-male-mice
#15
D A Adekunbi, X F Li, G Lass, K Shetty, O A Adegoke, S H Yeo, W H Colledge, S L Lightman, K T O'Byrne
The posterodorsal medial amygdala (MePD) is a neural site in the limbic brain involved in regulating emotional and sexual behaviours. There is, however, limited information available on the specific neuronal cell type in the MePD functionally mediating these behaviours in rodents. The recent discovery of a significant kisspeptin neurone population in the MePD has raised interest in the possible role of kisspeptin and its cognate receptor in sexual behaviour. The present study therefore tested the hypothesis that the MePD kisspeptin neurone population is involved in regulating attraction towards opposite sex conspecifics, sexual behaviour, social interaction and the anxiety response by selectively stimulating these neurones using the novel pharmacosynthetic DREADDs (designer receptors exclusively activated by designer drugs) technique...
March 2018: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/29338070/the-use-of-chemogenetics-in-behavioural-neuroscience-receptor-variants-targeting-approaches-and-caveats
#16
REVIEW
Erin J Campbell, Nathan J Marchant
The last decade has seen major advances in neuroscience tools allowing us to selectively modulate cellular pathways in freely moving animals. Chemogenetic approaches such as designer receptors exclusively activated by designer drugs (DREADDs) permit the remote control of neuronal function by systemic drug administration. These approaches have dramatically advanced our understanding of the neural control of behaviour. Here, we review the different techniques and genetic approaches available for the restriction of chemogenetic receptors to defined neuronal populations...
April 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29336819/identification-of-a-corticohabenular-circuit-regulating-socially-directed-behavior
#17
Madhurima Benekareddy, Tevye Jason Stachniak, Andreas Bruns, Frederic Knoflach, Markus von Kienlin, Basil Künnecke, Anirvan Ghosh
BACKGROUND: The prefrontal cortex (PFC) has been implicated in the pathophysiology of social dysfunction, but the specific circuit partners mediating PFC function in health and disease are unclear. METHODS: The excitatory designer receptor exclusively activated by designer drugs (DREADD) hM3Dq was used to induce PFC activation during social behavior measured in the three-chamber sociability assay (rats/mice). Functional magnetic resonance imaging was combined with hM3Dq-mediated PFC activation to identify novel nodes in the "social brain" in a hypothesis-free manner...
April 1, 2018: Biological Psychiatry
https://www.readbyqxmd.com/read/29335360/activity-in-the-ventral-medial-prefrontal-cortex-is-necessary-for-the-therapeutic-effects-of-extinction-in-rats
#18
Elizabeth A Fucich, Denisse Paredes, Madeleine O Saunders, David A Morilak
Poor response and high relapse rates remain problematic in the treatment of stress-related psychiatric disorders such as depression and post-traumatic stress disorder. Although mechanisms of pharmacotherapies are intensely studied, little is known about mechanisms of behavioral therapy that could inform improved treatments. We have previously demonstrated the therapeutic effects of extinction learning as a behavioral intervention modeling exposure therapy in rats. In the present study, we tested the hypothesis that activity in the ventral medial prefrontal cortex (vmPFC) during extinction is necessary for its therapeutic effects...
February 7, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29333487/activation-of-the-medial-prefrontal-cortex-reverses-cognitive-and-respiratory-symptoms-in-a-mouse-model-of-rett-syndrome
#19
C James Howell, Michael P Sceniak, Min Lang, Wenceslas Krakowiecki, Fatimah E Abouelsoud, Saloni U Lad, Heping Yu, David M Katz
Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2; Amir et al., 1999), a transcriptional regulatory protein (Klose et al., 2005). Mouse models of RTT ( Mecp2 mutants) exhibit excitatory hypoconnectivity in the medial prefrontal cortex (mPFC; Sceniak et al., 2015), a region critical for functions that are abnormal in RTT patients, ranging from learning and memory to regulation of visceral homeostasis (Riga et al...
November 2017: ENeuro
https://www.readbyqxmd.com/read/29317484/chemogenetic-excitation-of-accumbens-projecting-infralimbic-cortical-neurons-blocks-toluene-induced-conditioned-place-preference
#20
Wesley N Wayman, John J Woodward
Abuse rates for inhalants among adolescents continue to be high, yet preclinical models for studying mechanisms underlying inhalant abuse remain limited. Our laboratory has previously shown that, in male rats, an acute binge-like exposure to toluene vapor that mimics human solvent abuse modifies the intrinsic excitability of mPFC pyramidal neurons projecting to the NAc. These changes showed region (infralimbic; IL vs prelimbic; PRL), layer (shallow; 2/3 vs deep; 5/6), target (core vs shell), and age (adolescent vs adult) dependent differences (Wayman and Woodward, 2017)...
February 7, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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