Cortical functional hyperconnectivity in a mouse model of depression and selective network effects of ketamine

McGirr, Alexander; LeDue, Jeffrey; Chan, Alex Siu Wing; Xie, Yicheng; Murphy, Timothy H.

doi:10.1093/brain/awx142

Cited by 54 publications

(44 citation statements)

References 67 publications

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“…Receptor-based sensors also recognize a host of drug molecules, precluding their simultaneous use with imaging. Meanwhile, PBP-based indicators have few such restrictions, which has allowed use of TBOA, ketamine, NBQX, and other drugs with iGluSnFR 24,25,84,85 , vigabatrin and isoflurane with iGABASnFR 26 , and here, tacrine, donepezil, oxotremorine and eserine with iAChSnFR.…”

Section: Discussionmentioning

confidence: 99%

A fast genetically encoded fluorescent sensor for faithfulin vivoacetylcholine detection in mice, fish, worms and flies

Zhang

Shivange

et al. 2020

Preprint

138

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Here we design and optimize a genetically encoded fluorescent indicator, iAChSnFR, for the ubiquitous neurotransmitter acetylcholine, based on a bacterial periplasmic binding protein. iAChSnFR shows large fluorescence changes, rapid rise and decay kinetics, and insensitivity to most cholinergic drugs. iAChSnFR revealed large transients in a variety of slice and in vivo preparations in mouse, fish, fly and worm. iAChSnFR will be useful for the study of acetylcholine in all animals. IntroductionAcetylcholine (ACh) is a critical neurotransmitter in all animals. Among invertebrates, it is the most prevalent excitatory transmitter in the brain, sensory ganglia, and frequently the neuromuscular junction (NMJ). Among vertebrates, only a minority of neurons release ACh, but these signals play varying key roles. For instance, ACh signals at the NMJ, in the autonomic nervous system, and in subsets of the central nervous system, particularly projections arising from the brainstem and basal forebrain. Other cholinergic neuron populations in the brain include striatal interneurons, the stria vascularis-medial habenula-interpeduncular nucleus pathway, and sparse, incompletely characterized cell types such as intrinsic cholinergic interneurons in cortex 1 and hippocampus 2 . ACh helps to regulate attention 3 and wakefulness 4 , and participates in memory formation and consolidation 5 . ACh is also an important transmitter in glia, and between the nervous and immune systems 6 .Acetylcholine is synthesized pre-synaptically from choline and acetyl-CoA by choline acetyltransferase (ChAT), then packaged into synaptic vesicles by the vesicular acetylcholine transporter (VAChT). A key, partially understood aspect of cholinergic signaling is co-release with other neurotransmitters, including GABA, ATP, and glutamate 7,8 . To understand the role of co-release, one must measure ACh release alongside emerging measurements of other neurotransmitters.Acetylcholine receptors are among the most diverse neurotransmitter receptor families. Humans possess five muscarinic G protein-coupled receptors (GPCRs) for ACh (mAChRs) with diverse expression in the brain and smooth, cardiac, and skeletal muscle. Vertebrate nicotinic ACh receptors (nAChRs) are pentameric ligand-gated cation channels. Humans have a total of 17 nAChR subunit genes, in five classes: 10 a, 4 b, and one each of g, d, and e. nAChRs occur with many subunit combinations 9 , and others may be undiscovered. Invertebrates also have AChgated chloride channels. On neurons, receptors can be localized pre-, post-, and extrasynaptically, often with different isoforms in each place 10

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Section: Discussionmentioning

confidence: 99%

A fast genetically encoded fluorescent sensor for faithfulin vivoacetylcholine detection in mice, fish, worms and flies

Zhang

Shivange

et al. 2020

Preprint

138

View full text Add to dashboard Cite

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“…In contrast to long‐term NMDA receptor antagonism which appears to be able to drive a depressive phenotype (Zimmer et al, ), acute treatment with the NMDA receptor antagonist ketamine has been shown to reduce symptoms of depression (McGirr et al, ) and depressive‐like phenotypes (McGirr, LeDue, Chan, Xie, & Murphy, ). One study investigated the effects of stress on cortical connectivity in situ using mesoscale cortical imaging of glutamatergic transmission in rodent model of depression.…”

Section: Introductionmentioning

confidence: 99%

“…One study investigated the effects of stress on cortical connectivity in situ using mesoscale cortical imaging of glutamatergic transmission in rodent model of depression. Following chronic stress the authors found aberrant cortical connectivity associated with alterations in glutamatergic signaling, which could be rapidly reversed with brief, low‐dose ketamine exposure (McGirr et al, ). This data mimics the rapid antidepressant effects of ketamine in human patients (McGirr et al, ).…”

Section: Introductionmentioning

confidence: 99%

Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress

Murphy-Royal

Gordon

Bains

2019

Glia

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An organism's response to stress requires activation of multiple brain regions. This can have long‐lasting effects on synaptic transmission and plasticity that likely provide adaptive benefits. Recent evidence implicates not only neurones, but also glial cells in the regulation of the central response to stress. Intense, repeated or uncontrolled stress has been implicated in the emergence of multiple neuropsychiatric conditions. Human studies have consistently observed glial dysfunction in mood and stress disorders such as major depression. Interestingly animal models of stress have recapitulated glial abnormalities that are comparable to the human condition, validating the use of rodent models for the study of stress disorders. In this review we will focus upon one family of glia, the astrocytes, and describe the evidence to date that links astrocytes to possible stress‐related disorders.

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“…Similar to the experiments in humans, spatially overlapping results from stimulation and ICA analysis confirm the involvement of areas detected by ICA in particular sensory or motor functions. In comparison, existing imaging methods usually derive coordinates of ROI from sensory evoked responses or the stereotactic coordinates retrieved from brain atlases (3,(44)(45)(46)(47). In contrast, ICA-derived coordinates provide functional ROI, where ROI determination and experimental investigation of associated parameters such as functional connectivity can be accomplished in the same in vivo experiment.…”

Section: Discussionmentioning

confidence: 99%

In vivo widefield calcium imaging of the mouse cortex for analysis of network connectivity in health and brain disease

Cramer¹,

Gesierich²,

Roth³

et al. 2018

Preprint

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The organization of brain areas in functionally connected networks, their dynamic changes, and perturbations in disease states are subject of extensive investigations. Research on functional networks in humans predominantly uses functional magnetic resonance imaging (fMRI). However, adopting fMRI and other functional imaging methods to mice, the most widely used model to study brain physiology and disease, poses major technical challenges and faces important limitations.Hence, there is great demand for alternative imaging modalities for network characterization. Here, we present a refined protocol for in vivo widefield calcium imaging of both cerebral hemispheres in mice expressing a calcium sensor in excitatory neurons. We implemented a stringent protocol for minimizing anesthesia and excluding movement artifacts which both imposed problems in previous approaches. We further adopted a method for unbiased identification of functional cortical areas using independent component analysis (ICA) on resting-state imaging data. Biological relevance of identified components was confirmed using stimulus-dependent cortical activation. To explore this novel approach in a model of focal brain injury, we induced photothrombotic lesions of the motor cortex, determined changes in inter-and intrahemispheric connectivity at multiple time points up to 56 days post-stroke and correlated them with behavioral deficits. We observed a severe loss in interhemispheric connectivity after stroke, which was partially restored in the chronic phase and associated with corresponding behavioral motor deficits. Taken together, we present an improved widefield calcium imaging tool accounting for anesthesia and movement artifacts, adopting an advanced analysis pipeline based on human fMRI algorithms and with superior sensitivity to recovery mechanisms in mouse models compared to behavioral tests. This tool will enable new studies on interhemispheric connectivity in murine models with comparability to human imaging studies for a wide spectrum of neuroscience applications in health and disease.

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Cortical functional hyperconnectivity in a mouse model of depression and selective network effects of ketamine

Cited by 54 publications

References 67 publications

A fast genetically encoded fluorescent sensor for faithfulin vivoacetylcholine detection in mice, fish, worms and flies

A fast genetically encoded fluorescent sensor for faithfulin vivoacetylcholine detection in mice, fish, worms and flies

Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress

In vivo widefield calcium imaging of the mouse cortex for analysis of network connectivity in health and brain disease

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