scholarly journals Biased M1 receptor–positive allosteric modulators reveal role of phospholipase D in M1-dependent rodent cortical plasticity

2019 ◽  
Vol 12 (610) ◽  
pp. eaax2057 ◽  
Author(s):  
Sean P. Moran ◽  
Zixiu Xiang ◽  
Catherine A. Doyle ◽  
James Maksymetz ◽  
Xiaohui Lv ◽  
...  
Keyword(s):  
Phospholipase D ◽  
Cortical Plasticity ◽  
Critical Role ◽  
Muscarinic Acetylcholine Receptor ◽  
Brain Regions ◽  
Allosteric Modulators ◽  
Diverse Range ◽  
Electrophysiological Responses ◽  
Positive Allosteric Modulators

Highly selective, positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer’s disease and schizophrenia. Discovery programs have produced a structurally diverse range of M1 receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M1 receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M1 receptor signaling in native systems, and it is not clear whether biased M1 PAMs display differences in modulating M1-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M1 PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist–induced LTD but also blocked M1-dependent LTD in the PFC. In contrast, biased and nonbiased M1 PAMs acted similarly in potentiating M1-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M1 PAMs to modulate certain central nervous system (CNS) functions and that biased M1 PAMs function differently in brain regions implicated in cognition.

scholarly journals Biased M1 positive allosteric modulators reveal novel role of phospholipase D in M1-dependent rodent cortical plasticity

2019 ◽  
Author(s):  
Sean P. Moran ◽  
Zixiu Xiang ◽  
Catherine A. Doyle ◽  
James Maksymetz ◽  
Xiaohui Lv ◽  
...  
Keyword(s):  
Phospholipase D ◽  
Cortical Plasticity ◽  
Critical Role ◽  
Muscarinic Acetylcholine Receptor ◽  
Brain Regions ◽  
Allosteric Modulators ◽  
Diverse Range ◽  
Positive Allosteric Modulators ◽  
Potential Improvement

AbstractHighly selective positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for the potential improvement of cognitive function in patients suffering from Alzheimer’s disease and schizophrenia. M1 PAM discovery programs have produced a structurally diverse range of M1 PAMs with distinct pharmacological properties, including different levels of agonist activity and differences in signal bias. This includes the recent discovery of novel biased M1 PAMs that can potentiate coupling of M1 to activation of phospholipase C but not phospholipase D (PLD). However, little is known about the role of PLD in M1 signaling in native systems and it is not clear whether biased M1 PAMs will display differences in modulating M1-mediated responses in native tissue. We now report a series of studies using novel PLD inhibitors and PLD knockout mice to show that PLD is necessary for the induction of M1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Importantly, biased M1 PAMs that do not couple to PLD not only fail to potentiate orthosteric agonist-induced LTD but also block M1-dependent LTD in the PFC. In contrast, biased and non-biased M1 PAMs act similarly in potentiating M1-dependent electrophysiological responses that are PLD-independent. These findings demonstrate that PLD plays a critical role in the ability of M1 PAMs to modulate certain CNS functions and that biased M1 PAMs function differently in brain regions implicated in cognition.SummaryWe demonstrate a novel role of phospholipase D in M1-dependent rodent cortical plasticity and M1 PAMs that do not couple to phospholipase D have functionally distinct effects on cortical plasticity than non-biased M1 PAMs.

The role of the cerebellum in creativity and expert stone knapping

2020 ◽  
pp. 105971232096646
Author(s):  
Frederick L Coolidge
Keyword(s):  
Critical Role ◽  
Brain Regions ◽  
Stone Tool ◽  
Fine Motor ◽  
Engagement Theory ◽  
Motor Movements ◽  
And Function ◽  
The Mind ◽  
Stone Knapping

The purpose of this article is to review the evolution and function of the cerebellum, particularly in regard to its role in creativity and expert stone knapping. First, the article reviews the history of the cerebellum, its evolution and phylogenetics, and its concerted evolution with various brain regions. It also notes the critical role of the cerebellum and the cerebro-cerebellar network in its traditionally recognized control of gross and fine motor movements and in its exaptation for basic and higher level cognitive processes, particularly in regard to increasingly more sophisticated stone knapping. Also, reviewed are various theories, advanced over the past three decades, of how the cerebellum tweaks and refines thoughts, images, and ideas just as it refines and smooths motor movements. Baddeley’s working memory model is also prominently featured, as are the works of Ito, Vandervert, and others on the cerebellum’s role in novel problem-solving, insight, and creativity. Finally, this article reviews two “Cognitive Rubicons” in stone tool knapping, Theory of Mind and stone knapping, and Malafouris’ Material Engagement Theory. The article concludes with a novel hypothesis that the automaticity provided by the cerebellum derived from extensive practice in stone knapping may have freed Baddeley’s central executive from its attentional demands and allows the mind to “wander and wonder.”

scholarly journals Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music

2017 ◽  
Vol 28 (11) ◽  
pp. 3939-3950 ◽  
Author(s):  
Frederick S Barrett ◽  
Katrin H Preller ◽  
Marcus Herdener ◽  
Petr Janata ◽  
Franz X Vollenweider
Keyword(s):  
Music Perception ◽  
Critical Role ◽  
Brain Regions ◽  
Neural Response ◽  
Music Listening ◽  
Receptor Signaling ◽  
Tonal Structure ◽  
5Ht2a Receptor ◽  
Serotonin 2A

AbstractClassic psychedelic drugs (serotonin 2A, or 5HT2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences.

Using loss- and gain-of-function approaches to target amygdala-projecting serotonergic neurons in the dorsal raphe nucleus that enhance anxiety-related and conditioned fear behaviors

2020 ◽  
Vol 34 (4) ◽  
pp. 400-411
Author(s):  
Cristian S Bernabe ◽  
Izabela F Caliman ◽  
William A Truitt ◽  
Andrei I Molosh ◽  
Christopher A Lowry ◽  
...  
Keyword(s):  
Dorsal Raphe Nucleus ◽  
Conditioned Fear ◽  
Critical Role ◽  
Brain Regions ◽  
Dorsal Raphe ◽  
Raphe Nucleus ◽  
Selective Lesion ◽  
Anxious Behavior ◽  
Dorsal Raphé

Background: The central serotonergic system originating from the dorsal raphe nucleus (DR) plays a critical role in anxiety and trauma-related disorders such as posttraumatic stress disorder. Although many studies have investigated the role of serotonin (5-HT) within pro-fear brain regions such as the amygdala, the majority of these studies have utilized non-selective pharmacological approaches or poorly understood lesioning techniques which limit their interpretation. Aim: Here we investigated the role of amygdala-projecting 5-HT neurons in the DR in innate anxiety and conditioned fear behaviors. Methods: To achieve this goal, we utilized (1) selective lesion of 5-HT neurons projecting to the amygdala with saporin toxin conjugated to anti-serotonin transporter (SERT) injected into the amygdala, and (2) optogenetic excitation of amygdala-projecting DR cell bodies with a combination of a retrogradely transported canine adenovirus-expressing Cre-recombinase injected into the amygdala and a Cre-dependent-channelrhodopsin injected into the DR. Results: While saporin treatment lesioned both local amygdalar 5-HT fibers and neurons in the DR as well as reduced conditioned fear behavior, optical activation of amygdala-projecting DR neurons enhanced anxious behavior and conditioned fear response. Conclusion: Collectively, these studies support the hypothesis that amygdala-projecting 5-HT neurons in the DR represent an anxiety and fear-on network.

scholarly journals A REVIEW ON THE NEURAL CIRCUITS IN ANXIETY DISORDERS

2016 ◽  
Vol 9 (9) ◽  
pp. 26
Author(s):  
Ashwani Arya ◽  
Gulshan Sindhwani
Keyword(s):  
Anxiety Disorders ◽  
Behavioral Problems ◽  
Social Withdrawal ◽  
Treatment Options ◽  
Brain Regions ◽  
Emotional And Behavioral Problems ◽  
Diverse Range ◽  
Evidence Based Treatment ◽  
Reciprocal Connections

ABSTRACTAnxiety disorders are among the most common mental, emotional, and behavioral problems. These affect one-eighth of the total population worldwide.Anxiety disorders are a group of mental disorders characterized by irritability, fear, insomnia, nervousness, tachycardia, inability to concentrate,poor coping skills, palpitation, sweating, agoraphobia, and social withdrawal. Brain regions and networks involved in anxiety symptomatology isan effort to better understand the mechanism involved and to develop more effective treatments for the anxiety disorders. Thus, neuroanatomicaland neuroimaging research in anxiety disorders has centered on the role of the amygdala, reciprocal connections between the amygdala and theprefrontal cortex, and, most recently, alterations in interoceptive processing by the anterior insula. Anxiety disorders are characterized by alterationsin a diverse range of neurochemical systems, suggesting ample novel targets for drug therapies. The neurotransmitter like corticotropin-releasingfactor, neuropeptides (substance P, neuropeptide Y, oxytocin, orexin, and galanin) are implicated in anxiety pathways. Each of these active areas ofresearch holds promise for expanding and improving evidence-based treatment options for individuals suffering with clinical anxiety. Therefore,this article gives the information on the neurocognitive mechanisms, causes, neurotransmitter involved in anxiety disorders and emphasize on thetherapeutic targets for anxiety disorders.Keywords: Anxiety, Stress, Amygdala, Corticotropin releasing factor, Insula, Thalamus.

scholarly journals An insula-driven network computes decision uncertainty and promotes abstinence in chronic cocaine users

2020 ◽  
Author(s):  
Ju-Chi Yu ◽  
Vincenzo G. Fiore ◽  
Richard W. Briggs ◽  
Jacquelyn Braud ◽  
Katya Rubia ◽  
...  
Keyword(s):  
Ventral Striatum ◽  
Critical Role ◽  
Insular Cortex ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Decision Task ◽  
Dorsal Anterior Cingulate Cortex ◽  
Excitatory Connection ◽  
Chronic Cocaine

AbstractThe anterior insular cortex (AIC) and its interconnected brain regions have been associated with both addiction and decision-making under uncertainty. However, the causal interactions in this uncertainty-encoding neurocircuitry and how these neural dynamics impact relapse remain elusive. Here, we used model-based fMRI to measure choice uncertainty in a motor decision task in 61 individuals with cocaine use disorder (CUD) and 25 healthy controls. CUD participants were assessed before discharge from a residential treatment program and followed for up to 24 weeks. We found that choice uncertainty was tracked by the AIC, dorsal anterior cingulate cortex (dACC), and ventral striatum (VS), across participants. Stronger activations in these regions measured pre-discharge predicted longer abstinence after discharge in individuals with CUD. Dynamic causal modelling revealed an AIC-to-dACC directed connectivity modulated by uncertainty in controls, but a dACC-to-AIC connectivity in CUD participants. This reversal was mostly driven by early-relapsers (<30 days). Furthermore, CUD individuals who displayed a stronger AIC-to-dACC excitatory connection during uncertainty encoding remained abstinent for longer periods. These findings reveal a critical role of an AIC-driven, uncertainty-encoding neurocircuitry in protecting against relapse and promoting abstinence.

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