The M1/M4 preferring muscarinic agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain

Montani, Caterina; Canella, Carola; Schwarz, Adam J.; Li, Jennifer; Gilmour, Gary; Galbusera, Alberto; Wafford, Keith A.; Gutierrez-Barragan, Daniel; McCarthy, Andrew; Shaw, David B.; Knitowski, Karen M.; McKinzie, David L.; Gozzi, Alessandro; Felder, Christian C.

doi:10.1038/s41386-020-00916-0

Cited by 37 publications

(33 citation statements)

References 89 publications

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“…The focal topographic reconfiguration observed in awake state is of interest as it highlights functional substrates that are critically sensitive to the effect of general anesthesia, and that as such may putatively govern a transition between stimulus-unresponsive to wakeful, conscious states in the rodent brain. In this respect, the observed heightened functional connectivity in basal forebrain-hypothalamic areas and their increased cross-talk with other cortical modules is fully consistent with the established role of these regions as key mediators of arousal and vigilance in the mammalian brain (Lee and Dan, 2012;Xu et al, 2015;Montani et al, 2020). As conscious perception relies upon the ability to integrate information across specialized communities of brain regions, our finding that rsfMRI network structure in awake states shows increased interareal cross-talk is important, as it reconstitutes in mice a dominant functional configuration that has been associated with conscious states in other species (Barttfeld et al, 2015;Ma et al, 2017).…”

Section: Discussionsupporting

confidence: 80%

Unique spatiotemporal fMRI dynamics in the awake mouse brain

Singh

Gutierrez-Barragan

Alvino

et al. 2021

Preprint

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Resting state fMRI (rsfMRI) mapping in the mouse is typically performed under light anesthesia, preventing a full characterization of how the ensuing network architecture reconfigures under wakeful, conscious states. Leveraging a robust protocol for rsfMRI mapping in non-anesthetized, head-fixed mice, we provide a comprehensive description of the functional topography and dynamic structure of rsfMRI activity in awake mice. We find that rsfMRI networks in the awake state, while anatomically comparable to those observed under anesthesia, are topologically configured to maximize interregional communication, departing from the underlying community structure of the axonal connectome. We further report that rsfMRI activity in wakeful animals exhibits unique spatiotemporal dynamics characterized by a state-dependent, dominant occurrence of coactivation states encompassing functional anti-coordination between visual-auditory and default mode network areas, and a prominent participation of arousal-related forebrain nuclei. We finally show that rsfMRI dynamics in awake mice exhibits a stereotypical temporal structure, in which state-dominant coactivation states are configured as leading network attractors. These findings suggest that spontaneous brain activity in awake mice is critically shaped by state-specific involvement of basal forebrain arousal systems, and document that its dynamic structure recapitulates distinctive, evolutionarily-relevant principles that are predictive of conscious states in higher mammalian species.

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Section: Discussionsupporting

confidence: 80%

Unique spatiotemporal fMRI dynamics in the awake mouse brain

Singh

Gutierrez-Barragan

Alvino

et al. 2021

Preprint

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“…Please cite this article in press as: Gutierrez-Barragan et al, Unique spatiotemporal fMRI dynamics in the awake mouse brain, Current Biology (2021), https://doi.org/10.1016/j.cub.2021.12.015 Article connectivity in basal forebrain-hypothalamic areas and their increased cross-talk with cortical modules are fully consistent with the established role of these regions as key mediators of arousal and vigilance in the mammalian brain. [32][33][34] As conscious perception relies upon the ability to integrate information across specialized communities of brain regions, our finding that rsfMRI network structure in awake states shows increased interareal crosstalk is important, as it reconstitutes in mice a dominant functional configuration that has been associated with conscious conditions in other species. 14,35 This finding is also consistent with the postulates of prevailing theories of consciousness, 36,37 according to which functional networks that support awake, conscious states must exhibit global integration, evidenced in our data as greater functional coupling between cortical and subcortical network systems.…”

Section: Discussionmentioning

confidence: 86%

Unique spatiotemporal fMRI dynamics in the awake mouse brain

et al. 2022

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“…Disruption of cholinergic signals through muscarinic receptors has been associated with various pathologies including AD [ 62 ]. M1/M4 muscarinic receptors are potential targets of AD [ 63 ]. In a rodent model, activation of mGlu5 and M1 muscarinic acetylcholine receptor (mAChR) positive allogenic modulator (PAMs) induces a long-term depression (mLTD) in the mouse prefrontal cortex (PFC).…”

Section: Ad Relation To the Cholinergic Systemmentioning

confidence: 99%

Role of Cholinergic Signaling in Alzheimer’s Disease

et al. 2022

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Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer’s disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is complex and remains unclear, being affected by various factors. The cholinergic hypothesis is the earliest theory about the pathogenesis of AD. Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD. In addition, abnormal central cholinergic changes can also induce abnormal phosphorylation of ttau protein, nerve cell inflammation, cell apoptosis, and other pathological phenomena, but the exact mechanism of action is still unclear. Due to the complex and unclear pathogenesis, effective methods to prevent and treat AD are unavailable, and research to explore novel therapeutic drugs is various and active in the world. This review summaries the role of cholinergic signaling and the correlation between the cholinergic signaling pathway with other risk factors in AD and provides the latest research about the efficient therapeutic drugs and treatment of AD.

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The M1/M4 preferring muscarinic agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain

Cited by 37 publications

References 89 publications

Unique spatiotemporal fMRI dynamics in the awake mouse brain

Unique spatiotemporal fMRI dynamics in the awake mouse brain

Unique spatiotemporal fMRI dynamics in the awake mouse brain

Role of Cholinergic Signaling in Alzheimer’s Disease

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