Organizing principles of astrocytic nanoarchitecture in the mouse cerebral cortex

Salmon, Christopher; Syed, Tabish A.; Kacerovsky, J. Benjamin; Alivodej, Nensi; Schober, Alexandra L.; Sloan, Tyler F.W.; Pratte, Michael T.; Rosen, Michael P.; Green, Miranda; Chirgwin-Dasgupta, Adario; Mehta, Sachin; Jilani, Affan; Wang, Yanan; Vali, Hojatollah; Mandato, Craig A.; Siddiqi, Kaleem; Murai, Keith K.

doi:10.1016/j.cub.2023.01.043

Cited by 31 publications

(10 citation statements)

References 85 publications

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“…However, a recent report demonstrated a relatively even distribution of synapses near distal processes and astrocytic soma. 56 An alternative explanation is that distal astrocytic processes have a higher surface-to-volume ratio (SVR). 36 High SVR increases the amplitudes of [Ca 2+ ] i elevations induced by Ca 2+ entry through the plasma membrane and consequently increases the probability of Ca 2+ -dependent Ca 2+ release from endogenous stores.…”

Section: Discussionmentioning

confidence: 99%

Dissociation Between Neuronal and Astrocytic Calcium Activity in Response to Locomotion in Mice

et al. 2023

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Orchestrated activity of different cell types and their interactions within the brain active milieu provide the cellular basis for brain functions. Locomotion triggers a coordinated response of both neurons and astrocytes in various brain regions. Here we performed calcium (Ca2+) imaging of these two cell types in the somatosensory cortex in head-fixed mice moving on the airlifted platform. Ca2+ activity in astrocytes significantly increased during locomotion from a low baseline level during animal quiescence. Ca2+ signals first appeared in the distal processes and then propagated to astrocytic somata. In somata, Ca2+ concentration ([Ca2+]i) elevations became significantly larger and exhibited oscillatory behaviour. Hence, astrocytic soma operates as both integrator and amplifier of Ca2+ signal. In contrast to astrocytes, pronounced Ca2+ activity was detected in neurons in quiescent periods, and it further increased during locomotion. Neuronal [Ca2+]i rose almost immediately following the onset of locomotion, whereas astrocytic Ca2+ signals lagged by several seconds. Such a long lag suggests that astrocytic [Ca2+]i elevations are unlikely to be triggered by the activity of synapses among local neurons. Next, we compared Ca2+ responses to pairs of consecutive episodes of locomotion (paired-run ratio). Neurons reliably responded to each episode, whereas [Ca2+]i elevations in astrocytes were significantly diminished in response to the second locomotion. This refractory period in astrocytes may arise from distinct mechanisms underlying Ca2+ signal generation. In neurons, the bulk of Ca2+ enters through the Ca2+ channels in the plasma membrane allowing for steady-level Ca2+ elevations in repetitive runs. Astrocytic Ca2+ responses originate from the intracellular stores, the depletion of which affects subsequent Ca2+ signals. Functionally, neuronal Ca2+ response is primary and reflects sensory input processed by neurons. Astrocytic Ca2+ dynamics is secondary and likely to participate in regulation of metabolic and homeostatic support of intercellular communication and plasticity within the brain active milieu.

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Section: Discussionmentioning

confidence: 99%

Dissociation Between Neuronal and Astrocytic Calcium Activity in Response to Locomotion in Mice

et al. 2023

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“…Another important application of our approach will be the investigation of mitochondrial turnover and resulting distributions in astrocytes [ 73 , 74 ]. Despite these limitations, we demonstrate the general importance and feasibility of physiological simulations by integrating molecular properties, spatial intracellular orchestration and morphology.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic multiscale modelling of energy metabolism in human astrocytes reveals the impact of morphology changes in Alzheimer’s Disease

Farina,

Voorsluijs,

Fixemer

et al. 2023

PLoS Comput Biol

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Astrocytes with their specialised morphology are essential for brain homeostasis as metabolic mediators between blood vessels and neurons. In neurodegenerative diseases such as Alzheimer’s disease (AD), astrocytes adopt reactive profiles with molecular and morphological changes that could lead to the impairment of their metabolic support and impact disease progression. However, the underlying mechanisms of how the metabolic function of human astrocytes is impaired by their morphological changes in AD are still elusive. To address this challenge, we developed and applied a metabolic multiscale modelling approach integrating the dynamics of metabolic energy pathways and physiological astrocyte morphologies acquired in human AD and age-matched control brain samples. The results demonstrate that the complex cell shape and intracellular organisation of energetic pathways determine the metabolic profile and support capacity of astrocytes in health and AD conditions. Thus, our mechanistic approach indicates the importance of spatial orchestration in metabolism and allows for the identification of protective mechanisms against disease-associated metabolic impairments.

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“…Considering how popular astrocyte calcium imaging has become, there is thus a need for new or adapted methods and models to analyze calcium activity in such recordings. Owing to the constrains enumerated above, such methods need to be 1) comprehensive, to capture all activity in the cell, 2) unbiased, rather than restricted to user-defined regions of interest, 3) agnostic, to make no or minimal assumptions regarding the spatio-temporal properties of underlying Ca 2+ fluxes, and 4) with instrument-limited accuracy, to favor detailed investigations consistent with the structured nature of astrocytes architecture 10 .…”

Section: Overviewmentioning

confidence: 99%

STARDUST: a pipeline for the unbiased analysis of astrocyte regional calcium dynamics

Wu,

Dai,

Lefton

et al. 2024

Preprint

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SummaryCalcium imaging has become an increasingly popular way to probe the activity of astrocytes. However, the governing principles of astrocyte calcium dynamics are still elusive and their relationship to cellular events ill-defined. Useful assumptions and ‘shortcuts’ commonly applied to neuronal recordings therefore do not hold true for astrocytes. The imaging of astrocyte calcium activity per se can be relatively straightforward, subsequent analysis methods that adequately capture the richness and complexity of calcium dynamics remain scant. Here, we introduce STARDUST, a pipeline and python-based data processing for the Spatio-Temporal Analysis of Regional Dynamics & Unbiased Sorting of Transients from astrocyte calcium recordings. STARDUST builds upon AQuA to identify patches of active signals, from which it builds a data-driven map of regions of activity (ROAs) that can be combined with cell-segmentation and/or correlated to cellular morphology. For each ROA, STARDUST extracts fluorescence time-series, and performs signal identification and features extraction. STARDUST is agnostic to cell morphology (or cells altogether) and putative calcium propagation across ROAs. Instead, it focuses on decomposing calcium dynamics in a regionalized fashion by treating ROAs as independent units, for instance allowing investigations by signal feature-based ROA rank. STARDUST also identifies ROAs as “stable” (active throughout), “ON” (turned on during drug application) and “OFF” (turned off during drug application) in pharmacology experiments, permitting studies of astrocyte calcium “micro-domains” based on their functional responses. With a systematic set of instructions and troubleshooting tips, and minimal computational/coding background required, STARDUST is a user-friendly addition to the growing toolbox for the exploration of astrocyte calcium dynamics.

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Organizing principles of astrocytic nanoarchitecture in the mouse cerebral cortex

Cited by 31 publications

References 85 publications

Dissociation Between Neuronal and Astrocytic Calcium Activity in Response to Locomotion in Mice

Dissociation Between Neuronal and Astrocytic Calcium Activity in Response to Locomotion in Mice

Mechanistic multiscale modelling of energy metabolism in human astrocytes reveals the impact of morphology changes in Alzheimer’s Disease

STARDUST: a pipeline for the unbiased analysis of astrocyte regional calcium dynamics

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