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72
result(s) for
"Sutton, Laurie"
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Sword of the dragon
Wonder Woman sees a message in the clouds instructing her to go to Stonehenge, where she finds a group of tourists being held hostage by Morgaine Le Fey, who demands Wonder Woman steal the Star Sword of Merlin.
Book
NF1-cAMP signaling dissociates cell type–specific contributions of striatal medium spiny neurons to reward valuation and motor control
The striatum plays a fundamental role in motor learning and reward-related behaviors that are synergistically shaped by populations of D1 dopamine receptor (D1R)- and D2 dopamine receptor (D2R)-expressing medium spiny neurons (MSNs). How various neurotransmitter inputs converging on common intracellular pathways are parsed out to regulate distinct behavioral outcomes in a neuron-specific manner is poorly understood. Here, we reveal that distinct contributions of D1R-MSNs and D2R-MSNs towards reward and motor behaviors are delineated by the multifaceted signaling protein neurofibromin 1 (NF1). Using genetic mouse models, we show that NF1 in D1R-MSN modulates opioid reward, whereas loss of NF1 in D2R-MSNs delays motor learning by impeding the formation and consolidation of repetitive motor sequences. We found that motor learning deficits upon NF1 loss were associated with the disruption in dopamine signaling to cAMP in D2R-MSN. Restoration of cAMP levels pharmacologically or chemogenetically rescued the motor learning deficits seen upon NF1 loss in D2R-MSN. Our findings illustrate that multiplex signaling capabilities of MSNs are deployed at the level of intracellular pathways to achieve cell-specific control over behavioral outcomes.
Journal Article
The Penguin's crime wave
The Penguin hijacks a luxury yacht with his penguin-shaped submarine and it is up to Batman to stop him and rescue the passengers and crew.
Book
Homeostatic cAMP regulation by the RGS7 complex controls depression-related behaviors
Affective disorders arise from abnormal responses of the brain to prolonged exposure to challenging environmental stimuli. Recent work identified the orphan receptor GPR158 as a molecular link between chronic stress and depression. Here we reveal a non-canonical mechanism by which GPR158 exerts its effects on stress-induced depression by the complex formation with Regulator of G protein Signaling 7 (RGS7). Chronic stress promotes membrane recruitment of RGS7 via GPR158 in the medial prefrontal cortex (mPFC). The resultant complex suppresses homeostatic regulation of cAMP by inhibitory GPCRs in the region. Accordingly, RGS7 loss in mice induces an antidepressant-like phenotype and resiliency to stress, whereas its restoration within the mPFC is sufficient to rescue this phenotype in a GPR158-dependent way. These findings mechanistically link the unusual orphan receptor-RGS complex to a major stress mediator, the cAMP system and suggest new avenues for pharmacological interventions in affective disorders.
Journal Article
Fear the Shark
When the Shark, who feeds on human fear, rises from the ocean near Coast City, it is up to Hal Jordan of the Green Lantern Corps to use his power ring to defeat the Shark's fear-inspiring weapons, and stop the tsunami rushing toward the city.
Book
Orphan receptor GPR158 controls stress-induced depression
Stress can be a motivational force for decisive action and adapting to novel environment; whereas, exposure to chronic stress contributes to the development of depression and anxiety. However, the molecular mechanisms underlying stress-responsive behaviors are not fully understood. Here, we identified the orphan receptor GPR158 as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression. GPR158 is highly upregulated in the PFC of human subjects with major depressive disorder. Exposure of mice to chronic stress also increased GPR158 protein levels in the PFC in a glucocorticoid-dependent manner. Viral overexpression of GPR158 in the PFC induced depressive-like behaviors. In contrast GPR158 ablation, led to a prominent antidepressant-like phenotype and stress resiliency. We found that GPR158 exerts its effects via modulating synaptic strength altering AMPA receptor activity. Taken together, our findings identify a new player in mood regulation and introduce a pharmacological target for managing depression.
Journal Article
The Light King strikes!
Hal Jordan must put an end to the light king's reign, or it'll be lights out for him as well.
Book
The dopamine D2 receptor regulates Akt and GSK-3 via Dvl-3
The dopamine D2 receptor (D2DR) regulates Akt and may also target the Wnt pathway, two signalling cascades that inhibit glycogen synthase kinase-3 (GSK-3). This study examined whether the Wnt pathway is regulated by D2DR and the role of Akt and dishevelled-3 (Dvl-3) in regulating GSK-3 and the transcription factor β-catenin in the rat brain. Western blotting showed that subchronic treatment of raclopride (D2DR antagonist) increase phosphorylated Akt, Dvl-3, GSK-3, phosphorylated GSK-3 and β-catenin, whereas subchronic treatment of quinpirole (D2DR agonist) induced the opposite response. Co-immunopreciptations revealed an association between GSK-3 and the D2DR complex that was altered following raclopride and quinpirole, albeit in opposite directions. SCH23390 (D1DR antagonist) and nafadotride (D3DR antagonist) were also used to determine if the response was specific to the D2DR. Neither subchronic treatment affected Dvl-3, GSK-3, Akt nor β-catenin protein levels, although nafadotride altered the phosphorylation state of Akt and GSK-3. In addition, in-vitro experiments were conducted to manipulate Akt and Dvl-3 activity in SH-SY5Y cells to elucidate how the pattern of change observed following manipulation of D2DR developed. Results indicate that Akt affects the phosphorylation state of GSK-3 but has no effect on β-catenin levels. However, altering Dvl-3 levels resulted in changes in Akt and the Wnt pathway similar to what was observed following raclopride or quinpirole treatment. Collectively, the data suggests that the D2DR very specifically regulates Wnt and Akt signalling via Dvl-3.
Journal Article
Blossom battle!
Batman and Batgirl have to rescue Poison Ivy when her experimental plant food turns regular plants into menacing monsters she cannot control.
Book
Regulation of Akt and Wnt Signalling by the Dopamine D2 Receptor and Metabotropic Glutamate Receptor 2/3
Akt and the Wnt pathway, two cascades that regulate GSK-3, have been implicated in schizophrenia and antipsychotic drug action. Although it is known that antipsychotic drugs alleviate psychosis by blocking the dopamine D2 receptor (D2DR) and that metabotropic glutamate receptor 2/3 (mGluR2/3) agonists may improve some of the symptoms of schizophrenia, it is unclear if both classes of drugs exert their effects through Akt, GSK-3 and/or the Wnt pathway or if changes in these pathways are mediated through the D2DR and mGluR2/3 respectively. In addition to antipsychotics, mood stabilizers and antidepressants also target GSK-3, suggesting that there must be something unique in the way GSK-3 is targeted by antipsychotics since neither mood stabilizers nor antidepressants alleviate psychosis. The current study examined whether Akt and the Wnt pathway are regulated by the D2DR and mGluR2/3 and investigated the role of Akt and Dvl-3, a key activator in the Wnt pathway, in regulating GSK-3 in the rat brain. The study also compared the effects of antipsychotic, mood stabilizers and antidepressants on Akt and Wnt pathway proteins to determine if antipsychotics have unique effects on these signalling proteins. Results showed that raclopride (D2DR antagonist) regulated Akt and the Wnt pathway via Dvl-3 and the response was identical to antipsychotic treatment. Administration of the mGluR2/3 agonist, LY379268 also targeted Akt and the Wnt pathway and induced a similar response as antipsychotics. In addition, repeated amphetamine treatment, an established animal model for the positive symptoms of schizophrenia, quinpirole (D2DR agonist) and LY341495 (mGluR2/3 antagonist) induced similar changes in Akt and Wnt signalling that parallel alterations reported in schizophrenia. Furthermore, systemic inhibition of GSK-3 was able to attenuate the increase in locomotion induced by LY341495, a behavioural measure that models the positive symptoms of schizophrenia. The study also showed that clozapine and haloperidol (antipsychotics) induced a common Wnt response that was not mimicked by the mood stabilizers or antidepressants tested but that all neuropsychiatric drugs tested induced changes in Akt. Collectively the data shows that the Wnt pathway is regulated specifically by drugs with antipsychotic properties and may represent a novel target for pharmaceutical intervention.
Dissertation